In the first-in-human study, indatuximab ravtansine (10, 20, 40, 80, 120, 160, 200 mg/m²) was administered to 32 patients on day 1 of each 21-day cycle. The MTD was 160 mg/m². In the phase I/IIa study, indatuximab ravtansine (40, 50, 65, 80, 100, 120, 140, 160 mg/m²) was administered to 35 patients on days 1, 8, and 15 of each 28-day cycle, and the MTD/recommended phase II dose was 140 mg/m².

Eligible relapsed/refractory myeloma patients (≥18 years, ECOG ≤2) must have failed prior therapies (1+ for Len/Dex arm, 2+ for Pom/Dex arm) and comply with REMS programs. Exclusions include recent chemotherapy/radiotherapy (3-6 weeks), active HBV/HCV/HIV, cardiac abnormalities, pregnancy, prior BT062 exposure, or hypersensitivity to biologics. Plasma cell leukemia and recent thromboembolic events (DVT/PE within 3 months) are prohibited.

The study consists of two phases: Phase I (6 months) determines the optimal dose of BT062 combined with lenalidomide/dexamethasone using a standard 3+3 dose escalation design focused on DLTs in cycle 1; Phase IIa (18 months) evaluates treatment response using M-protein and serum free light chain assessments at each 28-day cycle, with supplementary bone marrow/skeletal exams as needed.

Eligible participants must have relapsed/refractory multiple myeloma, prior exposure to immunomodulators/proteasome inhibitors, ECOG ≤2, and adequate organ function. Exclusions include recent chemotherapy/radiotherapy (within 3-6 weeks), active infections (HBV/HCV/HIV), uncontrolled cardiac disease, pregnancy, or concurrent antineoplastic therapies. The study prohibits recent major surgery, investigational agents within 4 weeks, and prior MAb therapy with detectable immune responses (HAHA/HACA/HAMA).

Eligible participants had relapsed/refractory myeloma with prior immunomodulator/proteasome inhibitor exposure, ECOG ≤2, and adequate organ function. Exclusions included recent chemotherapy/radiotherapy (3-6 weeks), active HBV/HCV/HIV, uncontrolled cardiac disease, prior BT062/HAMA/HAHA, or pregnancy. Concomitant antineoplastic therapies and high-dose corticosteroids were prohibited.

BT062 was to be administered as single-dose IV infusions via a 0.22 um in-line filter preferably in a forearm vein, according to medically accepted procedures on Days 1, 8, and 15 of each 28-day cycle. Alternatively BT062 may have been administered through a central venous line or a peripherally inserted central catheter (PICC). Other administration routes were only to be allowed after approval from Biotest. Each subject was to be monitored carefully for the effects of exposure to BT062. No subject was to have received more than 3 doses of BT062 per 28-day treatment cycle.

The study evaluated dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for BT062 in relapsed/refractory multiple myeloma using a 3+3 dose escalation design. DLTs were assessed during the first 28-day cycle, and MTD was defined as the highest dose where <2 of 6 subjects experienced DLTs. Dose escalation stopped if ≥2 DLTs occurred at any level.

Safety and efficacy assessments included qualitative/quantitative toxicities (TEAEs, SAEs), pharmacokinetic properties (Cmax of BT062 conjugate), and anti-tumor activity. Responses were graded per IMWG criteria (sCR, CR, VGPR, PR, MR, SD), with ORR (MR+PR+VGPR+CR+sCR) and CBR (ORR+SD) as key endpoints. Disease progression metrics (TTP, PFS, OS) tracked M-protein increases (≥25%), new lesions, or hypercalcemia.

For the ITT population, Kaplan-Meier estimates showed no significant difference (HR, 0.98; 95% Cl, 0.73-1.31; P=0.897) in progression-free survival (PFS) between groups Median PFS was 4.10 and 4.40 months for MIRV and IC chemotherapy, respectively. In the prespecified high FR subgroup, PFS was longer in patients in the MIRV group compared with IC chemotherapy (median, 4.80 months versus 3.30 months; HR, 0.69, 95% CI, 0.48 to 1.00; P = 0.049). Based on the Hochberg procedure used in the statistical analysis plan for the study, this P value did not meet statistical significanceBoth in the ITT group and high FR subgroup, OS were not significantly different.

Mirvetuximab soravtansine vs IC chemotherapy in the ITT group: ORR=22.00% vs 12.00%, P=0.015; cancer antigen-125 (CA-125) responses=51.00% vs 27.00%, P<0001; median PFS2 duration (time from randomization to second disease progression or death)=10.00 vs 8.40 months, HR=0.64, 95% Cl, 0.49-0.84, P<0.001); PRO in the EORTC QLQ-OV28 Abdominal/GI Symptom Subscale=32.00% vs 14.00%, P=0.016; Mirvetuximab soravtansine vs IC chemotherapy in the high FR subset, ORR=24.00% vs 10.00%, P=0.014; cancer antigen-125 (CA-125) responses=53.00% vs 25.00%, P=0.001; median PFS2 duration=10.10 vs 8.40 months, HR=0.56, 95% Cl, 0.39-0.79, P<0.001); PRO in the EORTC QLQ-OV28 Abdominal/GI Symptom Subscale=27.00% vs 13.00%, P=0.143.

A phase 1b/2 study to evaluate the safety, tolerability and pharmacokinetics of mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin, pembrolizumab, or bevacizumab + carboplatin, in adults with folate receptor alpha positive advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

Dilutions of conjugates or unconjugated maytansinoid in the appropriate culture medium were added to wells of 96-well flat-bottomed plates containing 1 x10³ cells per well The plates were incubated at 37°C, 6% CO₂ for either 5 days (continuos exposure) or for 4 hours followed by 5-day incubation in conjugate-free medium (short exposure). Cell viability was determined by the WST-8 assay in accordance with the manufacturer's protocol, and IC50 were generated using a sigmoidal dose-response (variable slope) nonlinear regression curve fit.

Dilutions of conjugates or unconjugated maytansinoid in the appropriate culture medium were added to wells of 96-well flat-bottomed plates containing 1 x10³ cells per well The plates were incubated at 37°C, 6% CO₂ for either 5 days (continuos exposure) or for 4 hours followed by 5-day incubation in conjugate-free medium (short exposure). Cell viability was determined by the WST-8 assay in accordance with the manufacturer's protocol, and IC50 were generated using a sigmoidal dose-response (variable slope) nonlinear regression curve fit.

Dilutions of conjugates or unconjugated maytansinoid in the appropriate culture medium were added to wells of 96-well flat-bottomed plates containing 1 x10³ cells per well The plates were incubated at 37°C, 6% CO₂ for either 5 days (continuos exposure) or for 4 hours followed by 5-day incubation in conjugate-free medium (short exposure). Cell viability was determined by the WST-8 assay in accordance with the manufacturer's protocol, and IC50 were generated using a sigmoidal dose-response (variable slope) nonlinear regression curve fit.

The primary endpoint was the incidence of DLTs occurring during the first two cycles (4 weeks) of study drug administration. DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 12.00 mg/m² and in two of three patients treated with 15.00 mg/m². The maximum tolerated dose was identified as 10.00 mg/m².

Three patients (9.68%) had objective responses [all confirmed partial responses (PRs) with durations of 2.60, 6.10, and 4.00 months]; 11 patients (35.48%) had stable disease, and 13 patients (41.94%) had progressive disease. Objective responses were achieved in two of six patients (33.33%) at a DL of 10.0 mg/m², and in one of nine patients (11.11%) at 12.0 mg/m² with maximum reduction in RECIST target lesions of 32.30%-51.20%.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA ≥100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade ≥2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA ≥100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade ≥2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA ≥100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade ≥2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Eligibility required metastatic disease progression post-platinum chemotherapy and PD-1/PD-L1 inhibitors, CEACAM5 expression ≥2+, measurable lesions (RECIST v1.1), and ECOG 0-1. Exclusion criteria included untreated brain metastases, major comorbidities, active infections, uncontrolled hypertension, prior treatments targeting CEACAM5 or maytansinoids, and severe organ dysfunction. Specific Triplet Cohort exclusions included autoimmune diseases, transplant history, interstitial lung disease, or recent live vaccines.

Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor

The study involves evaluating dose-limiting toxicities (DLTs) in both Doublet (Part 1 and 2) and Triplet Cohorts, including grade 4 neutropenia, thrombocytopenia, non-hematologic AEs, keratopathy, and refractory hypertension. Key efficacy measures include objective response rate (ORR) in the Doublet Cohort (Part 2) and Triplet Cohort, calculated per RECIST v1.1 criteria for solid tumors.

Safety assessments covered treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and clinically significant abnormalities in lab parameters, ECG, and urinalysis. Efficacy endpoints in the Doublet Cohort included duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR). Pharmacokinetic parameters such as Cmax, AUC0-14d, and Ctrough were analyzed for tusamitamab ravtansine and ramucirumab. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs).

Participants had advanced CEACAM5+ cancers (CRC/NSCLC/gastric favored; CEA >5ng/mL accepted). Mandatory criteria: measurable disease (expansion phase), archived tumor tissue, and biopsy consent (CRC/gastric cohorts). Exclusions included active CNS metastases, unresolved ocular/cardiac disorders (LVEF<50%), prior CEACAM5/DM1/DM4 therapy, strong CYP3A inhibitor use, or contraindications to ophthalmic medications (glaucoma/hypertension/allergies). Reproductive-age patients required contraception for ≥3 months post-treatment.

In cohort Q2W-LD, 38 patients were screened for eligibility and 28 patients were enrolled and treated with tusamitamab ravtansine across four LD-DLs ranging from 120 to 170 mg/m2 between March 13, 2017, and February 17, 2020, at study sites in Canada, France, Republic of Korea, and Spain (Table 1). In cohort Q3W, 21 patients were screened for eligibility and 15 patients were enrolled and initiated treatment with tusamitamab ravtansine across four DLs ranging from 120 to 190 mg/m2 between July 15, 2019, and October 20, 2020, at study sites in Canada, France, and Spain (Table 1).

Eligible participants had advanced/metastatic NSQ NSCLC (no EGFR/BRAF/ALK/ROS mutations), CEACAM5 expression ≥2+, measurable disease (RECIST 1.1), and ECOG 0-1. Exclusions included uncontrolled brain metastases, active infections, autoimmune diseases, prior anti-PD-1/PD-L1 therapy, recent live vaccines, significant allergies, or unresolved toxicities (≥Grade 2). Prior chemotherapy for metastatic disease or CEACAM5-targeted treatments was prohibited.

Across all cohorts, dose-limiting toxicities (DLTs) included severe hematologic (grade 4 neutropenia, febrile neutropenia, thrombocytopenia) and non-hematologic events (grade 4 AEs, keratopathy) observed during Cycle 1. Efficacy endpoints assessed in Doublet and Quadruplet Cohorts included objective response rate (ORR), defined per RECIST v1.1 as confirmed complete (CR) or partial response (PR), with CR requiring disappearance of target lesions and PR a ≥30% reduction in lesion sum diameters.

Safety assessments covered treatment-emergent adverse events (TEAEs) and serious AEs (TESAEs). Key efficacy measures included progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR) across cohorts, evaluated via RECIST v1.1 criteria. Pharmacokinetic parameters (Ctrough, Ceoi) were measured for tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA ≥100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade ≥2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Eligibility required metastatic disease progression post-platinum chemotherapy and PD-1/PD-L1 inhibitors, CEACAM5 expression ≥2+, measurable lesions (RECIST v1.1), and ECOG 0-1. Exclusion criteria included untreated brain metastases, major comorbidities, active infections, uncontrolled hypertension, prior treatments targeting CEACAM5 or maytansinoids, and severe organ dysfunction. Specific Triplet Cohort exclusions included autoimmune diseases, transplant history, interstitial lung disease, or recent live vaccines.

Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor

The study involves evaluating dose-limiting toxicities (DLTs) in both Doublet (Part 1 and 2) and Triplet Cohorts, including grade 4 neutropenia, thrombocytopenia, non-hematologic AEs, keratopathy, and refractory hypertension. Key efficacy measures include objective response rate (ORR) in the Doublet Cohort (Part 2) and Triplet Cohort, calculated per RECIST v1.1 criteria for solid tumors.

Safety assessments covered treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and clinically significant abnormalities in lab parameters, ECG, and urinalysis. Efficacy endpoints in the Doublet Cohort included duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR). Pharmacokinetic parameters such as Cmax, AUC0-14d, and Ctrough were analyzed for tusamitamab ravtansine and ramucirumab. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs).

Eligible participants had advanced/metastatic NSQ NSCLC (no EGFR/BRAF/ALK/ROS mutations), CEACAM5 expression ≥2+, measurable disease (RECIST 1.1), and ECOG 0-1. Exclusions included uncontrolled brain metastases, active infections, autoimmune diseases, prior anti-PD-1/PD-L1 therapy, recent live vaccines, significant allergies, or unresolved toxicities (≥Grade 2). Prior chemotherapy for metastatic disease or CEACAM5-targeted treatments was prohibited.

Across all cohorts, dose-limiting toxicities (DLTs) included severe hematologic (grade 4 neutropenia, febrile neutropenia, thrombocytopenia) and non-hematologic events (grade 4 AEs, keratopathy) observed during Cycle 1. Efficacy endpoints assessed in Doublet and Quadruplet Cohorts included objective response rate (ORR), defined per RECIST v1.1 as confirmed complete (CR) or partial response (PR), with CR requiring disappearance of target lesions and PR a ≥30% reduction in lesion sum diameters.

Safety assessments covered treatment-emergent adverse events (TEAEs) and serious AEs (TESAEs). Key efficacy measures included progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR) across cohorts, evaluated via RECIST v1.1 criteria. Pharmacokinetic parameters (Ctrough, Ceoi) were measured for tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine.

Eligible participants required ≥18 years, measurable lesions (RECIST v1.1), ECOG 0-1, CEACAM5+ tumors, and metastatic disease. Cohort-specific criteria: mBC (Cohort A) needed 2-4 prior chemotherapy lines; mPAC (Cohorts B/C) required progression after gemcitabine/5-FU regimens (B) or 1st-line fluoropyrimidine (C). Key exclusions: active infections (HIV/hepatitis), untreated brain metastases, unresolved Grade ≥2 toxicities, corneal disorders, prior CEACAM5/DM4 therapy, major surgery <2 weeks, or inadequate organ function. Cohort C additionally excluded prior taxane/gemcitabine exposure.

The primary focus was evaluating Objective Response Rate (ORR) across cohorts (A:26.1w, B:51.6w, C:43.3w), defined as confirmed CR (complete lesion disappearance) or PR (≥30% target lesion reduction) per RECIST v1.1. Dose-limiting toxicities (DLTs) in Cohort C included Grade 4 neutropenia ≥7 days, Grade 3-4 neutropenia with infection, ≥Grade 3 thrombocytopenia with bleeding, Grade 4 non-hematologic AEs, or Grade ≥3 keratopathy during Cycle 1 (28 days).

Secondary outcomes included TEAEs/TESAEs (up to 150 weeks), lab abnormalities (hematology/chemistry per NCI CTCAE v5.0), PFS (time to progression/death), DCR (CR+PR+SD), DOR (response duration), ATAs against tusamitamab ravtansine, and PK parameters (Cmax, AUC0-14d, CL for tusamitamab/gemcitabine/dFdU in Cohort C during Cycle 1). Assessments spanned treatment exposure periods specific to each cohort.

Eligible patients had CEACAM5+ advanced solid tumors (archival tissue required) with no standard alternatives. Exclusions: ECOG ≥2, active CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved corneal disorders, strong CYP3A inhibitor use (unless discontinued ≥2 weeks pre-dose), or inadequate contraception. Reproductive-age participants required contraception for 6 months post-treatment.

Eligible participants had CEACAM5-high metastatic/unresectable gastric/GEJ adenocarcinoma (measurable lesions, ECOG 0-1). Key exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved corneal disorders, recent thrombotic/hemorrhagic events (within 2-6 months), uncontrolled hypertension, or CYP3A inhibitor use. Reproductive-age participants required contraception (7 months post-treatment for females, 4 for males).

Participants received ramucirumab 8 milligram/kilogram (mg/kg) via intravenous (IV) infusion followed by tusamitamab ravtansine loading dose at 170 mg/meter square (m^2) via IV infusion on Cycle 1 Day 1 (each cycle was 2 weeks); and then ramucirumab 8 mg/kg via IV infusion followed by tusamitamab ravtansine 100 mg/m^2 via IV infusion at Cycle 2 and every 2 weeks (Q2W) in all subsequent cycles until disease progression, unacceptable adverse event (AE), death, initiation of a new anticancer therapy, or the participant's or investigator's decision to stop the treatment.

The study assessed dose-limiting toxicities (DLTs) during the first 28 days, defined as grade 4 neutropenia ≥7 days, febrile neutropenia, significant thrombocytopenia with bleeding, grade 4 non-hematologic AEs, or grade ≥3 keratopathy. Objective response rate (ORR) was evaluated per RECIST v1.1 as the percentage of participants achieving complete or partial response based on tumor assessments every 6 weeks.

Safety outcomes included treatment-emergent AEs (TEAEs/TESAEs) up to 30 days post-treatment (~92 weeks). Efficacy endpoints comprised duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR) assessed via RECIST v1.1. Pharmacokinetic analysis measured Ctrough for tusamitamab ravtansine and ramucirumab, alongside antitherapeutic antibody (ATA) detection against tusamitamab ravtansine.

Eligible patients (≥18y, ECOG 0-1) have CEACAM5+ (≥2+ in 50% cells) metastatic NSCLC (post-chemo/IO), ER+ breast cancer (hormone-refractory), or gastric cancer (exhausted SOC). Key exclusions: untreated brain metastases, recent thromboembolism (<6mo), CYP3A modulator use, unresolved grade ≥2 toxicity (except alopecia), prior CEACAM5/DM4 therapy, corneal disorders, or contact lens use. Required organ function: ANC ≥1.5x109/L, platelets ≥100x109/L, eGFR ≥50mL/min, and serum albumin ≥25g/L. Reproductive-age participants must use contraception (females: 7 months post-treatment; males: 4 months).

The study measures intratumoral DM4 and tusamitamab ravtansine concentrations via PK assay on Cycle 2 Day 3 (~5 weeks). Additional pharmacodynamic assessments include CEACAM5 expression changes (IHC), RNA sequencing (DESeq2), tumor microenvironment analysis (quanTIseq/TIL signatures), somatic genomic profiling (WGS), and circulating CEA levels tracked every 8 weeks for up to 2 years. PK parameters (AUCinf, Cmax, Tmax) are evaluated through serial plasma sampling across cycles.

Safety monitoring records CTCAE v5.0 grade 3-4 AEs during treatment (≤2 years), while efficacy is assessed per RECIST v1.1 for PD/SD/PR/CR every 8 weeks. Systemic PK analysis quantifies tusamitamab ravtansine (clearance, volume), DM4 metabolites (Lys-SPDB-DM4, Me-DM4), and calculates Thalf (ln (2)/Lambda z) using trapezoidal AUC methods from baseline through Cycle 4.

Eligible participants were ≥18 years with metastatic non-squamous NSCLC progressing after platinum/immunotherapy, CEACAM5 expression ≥2+ in ≥50% tumor cells, measurable lesions, and ECOG 0-1. Exclusions included active brain metastases, other malignancies within 3 years, unresolved toxicities ≥Grade 2, HIV/hepatitis, corneal disorders, prior docetaxel/CEACAM5-targeted therapy, corticosteroid contraindications, or hypersensitivity to study drugs.

The study assessed Progression-free Survival (PFS) as the time from randomization to first documented disease progression (PD) or death per RECIST 1.1 criteria, with PD defined as 20% increase in target lesions (minimum 5mm absolute increase) or new lesions. Overall Survival (OS) was measured from randomization to death from any cause up to 189 weeks.

Objective Response Rate (ORR) measured the percentage of participants achieving complete (CR) or partial response (PR) per RECIST 1.1, where CR required lesion disappearance and PR required ≥30% decrease in target lesions. Time to Deterioration (TTD) in symptoms and functions was evaluated using EORTC QLQ-LC13/C30 scales, with deterioration defined as ≥10-point worsening. Safety endpoints included treatment-emergent adverse events (TEAEs/TESAEs), lab abnormalities, and Duration of Response (DOR) from first CR/PR to PD/death.

Eastern Cooperative Oncology Group (ECOG) 0, 1, metastatic or locally advanced unresectable solid tumors with progressive disease (PD) after standard treatment or known intolerance to available treatment, based on the predicted prevalence of CD166 expression, were breast cancer, castration-resistant prostate cancer, nonsmall cell lung cancer (NSCLC), epithelial ovarian cancer, head and neck squamous cell cancer (HNSCC), cholangiocarcinoma, and endometrial carcinoma.

Inclusion: (Arm A) HR+/HER2- breast cancer (0-2 prior metastatic chemo); (Arms B/C) CD166+ TNBC (1-3 prior lines; Arm C requires PD-L1+ by FDA test). All: RECIST-measurable disease, ECOG 0-1, adequate labs, contraception. Stable brain mets (≤1 cm/asymptomatic) allowed. Exclusion: Active malignancy (2 years), untreated symptomatic CNS mets, unresolved toxicity (Grade>1), corneal disorders, transplants. Arm C: Autoimmune disease/CPI intolerance, immunosuppressive steroids (>10 mg prednisone), maytansinoid exposure, pregnancy. Exceptions require Medical Monitor approval.

Inclusion: Metastatic/locally advanced unresectable tumors with progression post-standard therapy or intolerance; archival/fresh biopsy; ≥18 years. Exclusion: Active corneal disorders, serious infections, autoimmune/cardiac diseases, neurological conditions (e.g., stroke within 6 months, demyelinating disorders), non-healing wounds, monoclonal antibody allergies, warfarin use, or major surgery within 3 months.

An open-label phase 1b dose escalation study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and maximum tolerated dose of anetumab ravtansine in combination with pegylated liposomal doxorubicin 30 mg/m² given every 3 weeks in subjects with mesothelin-expressing platinum-resistant recurrent ovarian, fallopian tube or primary peritoneal cancer.

In all treated patients, ORR=27.70% (95% CI 17.30% to 40.20%), including one complete (1.50%) and 17 partial responses (26.20%). Mdor=7.60 months (95% CI 3.30 to 10.20), mPFS=5.0 months (95% CI 3.20 to 6.00). In high mesothelin expression patients (N=19), who received 3 prior lines of systemic therapy, ORR=42.10% (95% CI 20.30% to 66.50%), mDOR=8.30 months (95% CI 4.10 to 12.00), mFPS=8.50 months (95% CI 4.00 to 11.40).

An open label phase 1b dose escalation study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and maximum tolerated dose of anetumab ravtansine in combination with pemetrexed 500 mg/m² and cisplatin 75 mg/m² in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous non-small-cell lung cancer.

Mesothelin-positive patients with selected adenocarcinomas (NSCLC, triple negative breast, gastric including gastroesophageal junction) and thymic carcinoma will receive anetumab ravtansine as monotherapy at 6.50 mg/kg IV on a 21-day cycle. Patients with cholangiocarcinoma will receive anetumab ravtansine in combination with cisplatin (25 mg/m² IV day 1 and 8 on a 21-day cycle for up to 6 cycles) and patients with pancreatic adenocarcinoma will receive anetumab ravtansine in combination with gemcitabine (1000 mg/m² IV day 1 and 8 on a 21-day cycle).

An open-label phase 1b dose escalation study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and maximum tolerated dose of anetumab ravtansine in combination with pegylated liposomal doxorubicin 30 mg/m² given every 3 weeks in subjects with mesothelin-expressing platinum-resistant recurrent ovarian, fallopian tube or primary peritoneal cancer.

Eligible patients: platinum-resistant/refractory high-grade ovarian/fallopian tube/primary peritoneal cancer (GCIC criteria; measurable disease required for Phase 2); ECOG ≤2; adequate hematologic/organ function; MSLN-positive (≥30% tumor cells with 2+ staining) for Phase 2 only. Key exclusions: recent chemotherapy/radiotherapy (≤4 weeks); strong CYP3A4 modulators; uncontrolled comorbidities (HTN, cardiovascular/CNS events, infections); pregnancy; prior bevacizumab/weekly paclitaxel in platinum-resistant setting. Brain metastases allowed if stable ≥4 weeks post-radiation without steroids.

Inclusion: Unresectable/metastatic pancreatic cancer (1-2 prior chemo lines; 2+/3+ mesothelin expression in ≥30% tumor cells), ECOG 0-1, adequate organ function. Exclusion: Prior mesothelin-targeted therapy, significant cardiac/ocular/CNS conditions, active infections (HIV/HBV/HCV), recent major surgery, unresolved toxicity >Grade 1, or pregnancy. Brain metastases allowed if stable >6 months post-therapy with negative imaging.

Inclusion: Metastatic/unresectable pancreatic adenocarcinoma (mesothelin-positive; ≥5% tumor cells for escalation, ≥30% 2+/3+ for expansion), ≥1 prior systemic therapy, ECOG 0-1, measurable disease, accessible lesions for biopsies, adequate organ function. Exclusion: Active CNS metastases/uncontrolled infections; recent major surgery/live vaccines; unresolved CTCAE ≥G2 toxicities (except alopecia/G2 neuropathy); autoimmune/inflammatory diseases (exceptions: stable hypothyroidism/vitiligo); strong CYP3A4 modulators; pregnancy/HIV-HBV-HCV (unless controlled); prior organ transplants. Corneal disorders may exclude per ophthalmologist assessment.

Inclusion: Japanese patients (≥20 years) with ECOG 0-1, life expectancy ≥12 weeks, advanced solid tumors (refractory/no standard therapy), measurable disease (RECIST 1.1), and adequate organ function. Exclusion: Recent anticancer therapy (<2 weeks), significant cardiac disease (CHF NYHA III/IV, recent MI/unstable angina, QTc >470 ms, LVEF <50%, uncontrolled hypertension), active HIV/HBV/HCV, LQTS history, or clinically significant eye disorders.

The study will assess treatment-emergent adverse events (TEAEs) graded by NCI CTCAE v4.03 over 9 weeks. Pharmacokinetic parameters (Cmax, AUC, tmax) for BAY94-9343, its total antibody compound, DM4, and metabolite DM4-Me will be measured across cycles (1-6) at multiple timepoints, including dose-normalized values (Cmax/D, AUC/D) and body-weight-adjusted metrics (Cmax,norm, AUCnorm) to evaluate drug exposure.

Inclusion: Adults with unresectable, mesothelin-positive (≥10% tumor cells, 2+/3+ intensity) lung adenocarcinoma (stage IIIB/IV), prior platinum/immunotherapy, ECOG ≤2, measurable disease (RECIST), and adequate organ function. Exclusion: Concurrent cancers, uncontrolled CVD (NYHA III/IV CHF, recent MI/stroke, QTc >480 ms), active HBV/HCV/HIV, unresolved CTCAE >1 toxicity (except alopecia/anemia), recent major surgery/radiotherapy to target lesions, strong CYP3A4 modulators, or prior anetumab ravtansine exposure. Corneal disorders may disqualify per investigator assessment.

The Recommended Phase 2 Dose (RP2D) will be determined as the highest dose with ≤1 dose-limiting toxicity (DLT), defined as treatment-emergent adverse events (TEAEs) like prolonged grade 4 neutropenia during Cycle 1. Efficacy endpoints include the proportion of subjects achieving partial/complete response (≥30% reduction/disappearance of target lesions per RECIST), assessed at 6 weeks.

Key secondary outcomes include progression-free survival (time to progression/death; RECIST-defined as ≥20% lesion growth + ≥5mm absolute increase), duration of response (time from CR/PR to progression), and overall survival (time to death from any cause). Safety will be monitored via CTCAE v4.0-graded serious/non-serious adverse events during the safety run-in phase (2 months).

Inclusion: Advanced/metastatic NSCLC patients (Phase I: no standard therapy; Phase II: ≥1 prior platinum regimen) with mesothelin expression (≥30% tumor cells, Ventana IHC 2+/3+), ECOG 0-1, measurable disease (Phase II), and adequate organ function. Exclusion: Prior anti-PD-1/PD-L1 therapy (except anti-CTLA-4 with specific criteria), CNS metastases (unless asymptomatic/stable), uncontrolled CVD (NYHA III/IV CHF, recent angina/MI), active infections, autoimmune diseases (exceptions for stable conditions), recent major surgery/radiotherapy, or corneal disorders. Pregnant women and those with untreated HBV/HCV or severe immunosuppression are excluded.

The Phase I portion aims to determine the Maximum Tolerated Dose (MTD) of anetumab ravtansine combined with atezolizumab, defined as the highest dose level where ≤1 out of 6 patients experience dose-limiting toxicities (DLTs) within 21 days. In Phase II, efficacy will be assessed via the confirmed response rate (CR/PR on two consecutive scans ≥4 weeks apart), analyzed using exact binomial 95% CIs.

Phase I will evaluate clinical activity (CR, PR, SD, PD via descriptive statistics) and adverse event incidence (CTCAE v4.0 graded) over 21 days post-treatment. Phase II endpoints include overall survival (time to death, Kaplan-Meier estimation up to 2 years), progression-free survival (time to progression/death; 1- and 2-year rates reported), and safety monitoring.

Inclusion: Malignant pleural mesothelioma patients (post-platinum therapy, mesothelin-positive [≥30% tumor cells], measurable disease per RECIST/mRECIST) with ECOG <2, adequate organ function, and contraception compliance. Exclusion: Active brain metastases, recent anti-PD-1/PD-L1 therapy, unresolved CTCAE >1 toxicity (except neuropathy/alopecia), CYP3A4 modulators, pregnancy, HIV/HBV/HCV (unless controlled), corneal epitheliopathy, or interstitial lung disease. Prior transfusions/G-CSF within 4 weeks or live vaccines within 30 days are prohibited.

The Phase II portion will evaluate confirmed tumor response rate (CR + PR per RECIST 1.1) over 2 years, comparing treatment arms via one-sided z-test (alpha=0.10). The Phase I component will determine the Recommended Phase 2 Dose (RP2D) of anetumab ravtansine combined with pembrolizumab, assessing toxicity in all treated patients (DLT evaluability excludes non-toxicity-related discontinuations).

Key Phase II endpoints include duration of response (Kaplan-Meier estimation from treatment start, log-rank test for arm comparison), overall survival (death from any cause, Kaplan-Meier/log-rank), and progression-free survival (time to progression/death per RECIST 1.1). Pharmacodynamic analyses will correlate megakaryocyte potentiating factor levels with response (Wilcoxon/Jonckheere-Terpstra tests) and explore mononuclear phagocyte system biomarkers (linear regression). Adverse events will be tracked via PRO-CTCAE over 2 years.

Key efficacy endpoints included OS (time to death; log-rank test), Objective Response Rate (ORR, CR+PR per mRECIST), Disease Control Rate (DCR, CR+PR+SD), Duration of Response (DOR), and Durable Response Rate (DRR, response ≥180 days). Symptom improvement (MDASI-MPM) and pain metrics (TTWP, improvement rates) were tracked. Treatment-emergent adverse events (TEAEs) and fatal outcomes were analyzed through Jul-2019.

Inclusion Criteria: Adults (≥18) with unresectable epithelial mesothelioma or nonsquamous NSCLC (chemotherapy-naive or pretreated, though NSCLC subjects must have received FDA-approved therapies first) and measurable disease (RECIST 1.1/mRECIST), ECOG 0-1, life expectancy ≥12 weeks, and adequate organ function. Exclusion Criteria: Prior/distinct cancers (unless cured >3 years prior), bleeding disorders (CTCAE ≥G2), active CNS metastases, uncontrolled cardiovascular disease (NYHA III/IV), hypertension (≥160/100 mmHg), biliary obstruction, organ transplantation, drug hypersensitivity, active HBV/HCV/HIV, serious infections (CTCAE ≥G2), recent anticancer therapies/radiotherapy (within 4 weeks), or anticoagulation started within 2 weeks pre-treatment.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.03 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3x10⁶ MIA PaCa-2/vector,3x10⁶ MIA PaCa-2/meso, 1x10⁶ HT-29/vector, 1x10⁶ HT-29/meso ,3x10⁶ OVCAR-3, or 3x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.03 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3x10⁶ MIA PaCa-2/vector, 3x10⁶ MIA PaCa-2/meso,1x10⁶ HT-29/vector, 1x10⁶ HT-29/meso, 3x10⁶ OVCAR-3, or 3x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg, 0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3x10⁶ MIA PaCa-2/vector, 3x10⁶ MIA PaCa-2/meso,1x10⁶ HT-29/vector, 1x10⁶ HT-29/meso, 3x10⁶ OVCAR-3, or 3x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg, 0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.03 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g,7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive ovarian cancer cell line- and patient-derived xenograft models. For the OVCAR-3 and OVCAR-8 xenograft models,tumor cells in Matrigel were inoculated subcutaneously to the right lower flank region of female nude/nude mice. In the monotherapy experiments,anetumab ravtansine was administered intravenously (i.v.) at 2.5 mg/kg three times every third day (Q3Dx3). For the in vivo combination studies with pegylated liposomal doxorubicin (PLD) or copanlisib in OVCAR-8 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,7,28,32 and 35,or on days 1,4,28 and 35,respectively. For the in vivo combination studies in OVCAR-3 xenografts,anetumab ravtansine was administered i.v. at 2.5 mg/kg on days 1,4,43 and 46. For the Ov6668 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg on day 1 and at 15 mg/kg on days 16,30,43,57 and 71. For the ST081 xenografts,anetumab ravtansine was administered i.v. at 3.75 mg/kg every second week (Q2W). PLD was administered i.v. at 4 mg/kg on days 1,7,28 and 35 (OVCAR-8 xenografts),on days 1 and 30 (Ov6668 xenografts) or on days 0 and 7 (ST081 xenografts). Carboplatin was administered i.v. at 80 mg/kg QWx2. Copanlisib was administered at 10 mg/kg,2 days on/5 days off,i.v.,starting on day 2. Bevacizumab was administered intraperitoneally (i.p.) at 0.3 mg/kg,every fifth day (Q5D).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg,0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg,0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. BAY 94-9343 administered at 0.05 mg/kg,0.2 mg/kg (corresponding to 14.3 mg/kg ADC; Q3Dx3).

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

For subcutaneous tumor models,female NMRI nu/nu mice (18-25 g, 7-10 weeks) from Taconic M&B were implanted on day 0 with either 3 x10⁶ MIA PaCa-2/vector,3 x10⁶ MIA PaCa-2/meso,1 x10⁶ HT-29/vector,1 x10⁶ HT-29/meso,3 x10⁶ OVCAR-3,or 3 x10⁶ NCI-H226 cells suspended in 0.1 mL 50% Matrigel. Patient-derived pancreatic (PAXF736) model was performed at Oncotest GmbH and ovarian (OVCAR6719) and mesothelioma (Meso7212) models at EPO Berlin-Buch GmbH. 0.01 mg/kg , 0.05 mg/kg , 0.2 mg/kg Anetumab ravtansine was i.v. to the tumor-bearing mice.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Four groups of mice,each consisting of 58 animals was set up and vital Hela cells were inoculated in a dose of 110e5 cells in 100 l by subcutaneous injection in the left inner flank on day 0. Animals in the treatment groups received 2 mg/kg,5 mg/kg,and 10 mg/kg anetumab ravtansine in 200 l injection buffer twice weekly by i.p. injection. Animals in the control group received injection buffer only.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Four groups of mice,each consisting of 58 animals was set up and vital Hela cells were inoculated in a dose of 110e5 cells in 100 l by subcutaneous injection in the left inner flank on day 0. Animals in the treatment groups received 2 mg/kg,5 mg/kg,and 10 mg/kg anetumab ravtansine in 200 l injection buffer twice weekly by i.p. injection. Animals in the control group received injection buffer only.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Mice were subcutaneously inoculated with 5x10⁶ MSLN positive T1889 cells mixed with Matrigel. Treatment then began, and the experiments ran for a total of 4 weeks. The first treatment cohort of 32 mice consisted of vehicle control, isotype ADC control, and 15 mg/kg ARav, dosed at Q7D via intraperitoneal injection. A second treatment cohort of 30 mice occurred with groups consisting of vehicle control (Q14D), 7.5 mg/kg ARav (Q14D) monotherapy, 7.5 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy. A third treatment cohort of 32 mice occurred with groups consisting of vehicle control (Q14D), 3.75 mg/kg ARav (Q14D) monotherapy, 3.75 mg/kg ARav (Q14D) and 4 mg/kg cisplatin (Q7D) combination therapy, and 4 mg/kg cisplatin (Q7D) monotherapy.

The in vivo antitumor activity of Anetumab ravtansine was evaluated in a Mesothelin positive xenograft tumor models. Four groups of mice,each consisting of 58 animals was set up and vital Hela cells were inoculated in a dose of 110e5 cells in 100 l by subcutaneous injection in the left inner flank on day 0. Animals in the treatment groups received 2 mg/kg,5 mg/kg,and 10 mg/kg anetumab ravtansine in 200 l injection buffer twice weekly by i.p. injection. Animals in the control group received injection buffer only.

Eligible patients must have histologically confirmed, CanAg-positive (≥75% tumor cells with 2+/3+ staining) non-colorectal/pancreatic solid tumors that are inoperable/metastatic and refractory to standard therapy, excluding those with leptomeningeal or progressive brain disease. Key requirements include ECOG 0-2, adequate organ function (ANC ≥1,500/mm ³, platelets ≥100,000/mm ³, creatinine ≤1.5 mg/dL), no active infections, and ≥4-week washout from prior therapies. Strict exclusion criteria address comorbidities, concurrent malignancies, and treatment-related restrictions to ensure patient safety.

ligibility requires histologically confirmed metastatic/locally advanced gastric/GEJ adenocarcinoma (AJCC IIIA-IV) with CanAg-positive expression, ECOG PS<1, one prior chemotherapy line failure, measurable disease per RECIST, and adequate organ function (ANC>1,500/mm ³, platelets>100,000/mm ³, creatinine≤1.5xULN). Key exclusions include active infections, grade≥2 neuropathy, CNS metastases, recent malignancies (<2yrs disease-free except non-melanoma skin/cervical CIS/prostate cancer), concurrent anticancer therapies, and significant comorbidities (uncontrolled diabetes, recent MI, heart failure). Reproductive-age patients require negative pregnancy testing and contraception compliance.

Eligibility: Metastatic TNBC patients (≥18y, ECOG<2) with CA6-positive disease and 1-3 prior chemotherapy lines (must include anthracycline/taxane). Exclusions: active CNS metastases, prior maytansinoid/eribulin therapy, Grade ≥2 neuropathy, corneal disorders, CYP3A4 inhibitor use, or contraindications to ocular prophylaxis. Contraception required during/6 months post-treatment.

Eligibility: CA6-positive solid tumor patients (≥15% tumor cell staining) without standard therapy options. Exclusions: ECOG≥2, organ dysfunction, unresolved toxicities (Grade>1), recent antitumor therapy (<3 weeks washout), pulmonary/cardiac comorbidities, corneal disorders, CYP3A inhibitor use, or midazolam contraindications (for specific cohort). Contraception required.

Eligible patients must have confirmed CD19+ DLBCL (de novo/transformed, >30% expression via recent biopsy) with ≥1 prior rituximab-containing regimen and relapsed/refractory status (post-1L ineligible for transplant or post-2L including ASCT). Exclusions cover primary refractory cases and mediastinal DLBCL. Archived FFPE tissue (≤6 months old) or fresh FNA is mandatory for eligibility assessment.

Eligible participants must have relapsed/refractory CD19+ B-cell NHL (excluding Burkitt's, lymphoblastic, or CLL) with prior standard treatment failure (including post-transplant cases). Exclusions include CNS involvement, non-measurable disease, ECOG >2, life expectancy <3 months, recent chemo/RT (4 weeks), prior radioimmunotherapy (12 weeks), protein anaphylaxis, HIV/HBV/HCV, organ dysfunction, pregnancy, inadequate contraception, or investigator-assessed safety risks.

Eligible patients must have confirmed CD19+ DLBCL (de novo/transformed, >30% expression via recent biopsy) with ≥1 prior rituximab-containing regimen and relapsed/refractory status (post-1L ineligible for transplant or post-2L including ASCT). Exclusions cover primary refractory cases and mediastinal DLBCL. Archived FFPE tissue (≤6 months old) or fresh FNA is mandatory for eligibility assessment.

Eligible patients must have confirmed CD19+ DLBCL (de novo/transformed, >30% expression via recent biopsy) with ≥1 prior rituximab-containing regimen and relapsed/refractory status (post-1L ineligible for transplant or post-2L including ASCT). Exclusions cover primary refractory cases and mediastinal DLBCL. Archived FFPE tissue (≤6 months old) or fresh FNA is mandatory for eligibility assessment.

A total of 37 patients were enrolled from October 10, 2011 to December 19, 2013. One patient was included but did not receive the study treatment, leaving 36 treated patients in the safety population. Of the 36 patients, 19 were treated in part 1 of the study: 7 at 55 mg/m2; 4 at 70 mg/m2; and 8 at 90 mg/m2. The selected dose was determined as 70 mg/m2 and was used in part 2 of the study. As detailed, the 90-mg/m2 dose was associated with no improvement in ORR and an increased occurrence of AEs. An additional 17 patients were included and treated during part 2 of the study. All patients were expected to receive treatment at 70 mg/m2; however, 2 patients received the reduced dose of 55 mg/m2 owing to infusion-related toxicities.

Eligible patients must have confirmed CD19+ DLBCL (de novo/transformed, >30% expression via recent biopsy) with ≥1 prior rituximab-containing regimen and relapsed/refractory status (post-1L ineligible for transplant or post-2L including ASCT). Exclusions cover primary refractory cases and mediastinal DLBCL. Archived FFPE tissue (≤6 months old) or fresh FNA is mandatory for eligibility assessment.

Eligible patients must have confirmed CD19+ DLBCL (de novo/transformed, >30% expression via recent biopsy) with ≥1 prior rituximab-containing regimen and relapsed/refractory status (post-1L ineligible for transplant or post-2L including ASCT). Exclusions cover primary refractory cases and mediastinal DLBCL. Archived FFPE tissue (≤6 months old) or fresh FNA is mandatory for eligibility assessment.

Eligible participants must have relapsed/refractory CD19+ non-Hodgkin's B-cell lymphoma (excluding Burkitt's, lymphoblastic, or CLL) with ECOG 0-2. Exclusions include recent chemotherapy/radiotherapy (4 weeks), prior radioimmunotherapy (12 weeks), protein/maytansinoid intolerance, organ dysfunction, pregnancy, or inadequate contraception. Investigator-assessed high-risk comorbidities also preclude participation.

Eligibility requires advanced solid tumors without standard options, with HER2- cancers (escalation) or SAR428926-target-antigen+ tumors (expansion, including TNBC/prostate/CRC/ovarian/NSCLC). Measurable lesions (RECIST v1.1) and biopsy-accessible lesions (expansion, NSCLC exempt) are mandatory. Exclusions cover prior DM1/DM4-ADC therapy, active HBV/HCV/HIV, corneal/neuropathy/cardiac issues (LVEF<50%), CYP3A inhibitor use, contact lens dependence, inadequate organ function, and contraindications to ocular medications (e.g., glaucoma). Reproductive-age participants must comply with pregnancy prevention protocols.

Advanced (metastatic or locally advanced) serous epithelial ovarian, serous fallopian tubal or serous primary peritoneal cancer or advanced clear cell or papillary renal cell carcinoma (RCC), who had received or were intolerant to all therapies known to confer clinical benefit for their disease and Eastern Cooperative Oncology Group (ECOG) performance status 2.

Eligible patients must be ≥18 years with histologically confirmed metastatic/unresectable alphav integrin-positive tumors (melanoma, breast, lung, or ovarian cancer in expansion phase, confirmed by IHC) and measurable disease. Key requirements include ECOG ≤2, adequate organ function (ANC ≥1500/mm ³, platelets ≥100K/mm ³, hepatic/renal parameters ≤1.5-2.5×ULN), and contraception use. Exclusions cover active CNS metastases, grade ≥1 residual toxicity, recent anticancer therapy (<4 weeks), uncontrolled infections, NYHA class III/IV cardiac disease, HIV/Hepatitis coinfection, pregnancy, or conditions compromising safety per investigator judgment. Patients will undergo scheduled safety and survival follow-ups post-treatment.

NCCIT cells were inoculated into 8-week old male athymic nude mice. MDA-MB-231 cells were inoculated into 7-week old female CB17 SCID mice. Calu-6,human non-small cell lung cancer cells (ATCC) were maintained in MEM Earless BSS/NEAA/10%FBS media without antibiotics and inoculated subcutaneously (SC) into the right flank of 9-week old female athymic nude mice. For the CT-3 tumour model,primary human colon tumour tissue was serially transplanted in vivo to establish a SC xenograft model. Cryopreserved tumour fragments were thawed and serially passaged SC in female SCID beige mice at 810 weeks old for two to five generations prior to implantation for studies.

Inclusion criteria for CLL patients require a confirmed diagnosis, while NHL patients must have a histologically confirmed diagnosis and be willing to undergo biopsies. Exclusion criteria apply to both groups, covering hypersensitivity to ADCs or mAbs, prior DM1/DM4 ADC treatment, corneal disorders, CNS involvement (unless treated), cardiac impairment, HIV, and active HBV/HCV (with controlled cases under antivirals eligible). Additional criteria may apply.

The study evaluates the incidence and severity of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs) over 32 months, with DLTs defined as protocol-specified adverse events during the first treatment cycle. It also measures treatment interruptions, dose reductions, and dose intensity, where relative dose intensity is calculated for subjects with non-zero exposure.

Inclusion criteria for CLL patients require a confirmed diagnosis, while NHL patients must have a histologically confirmed diagnosis and be willing to undergo biopsies. Exclusion criteria apply to both groups, covering hypersensitivity to ADCs or mAbs, prior DM1/DM4 ADC treatment, corneal disorders, CNS involvement (unless treated), cardiac impairment, HIV, and active HBV/HCV (with controlled cases under antivirals eligible). Additional criteria may apply.

The study evaluates the incidence and severity of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs) over 32 months, with DLTs defined as protocol-specified adverse events during the first treatment cycle. It also measures treatment interruptions, dose reductions, and dose intensity, where relative dose intensity is calculated for subjects with non-zero exposure.

Inclusion: CD33+ relapsed/refractory AML patients (no curative options) with ECOG 0-2. Exclusion: Recent gemtuzumab ozogamicin/allogenic transplant (≤6 months), anticancer therapy ≤3 weeks (hydroxyurea/leukophoresis allowed), prior AVE9633 exposure, organ dysfunction, comorbidities affecting safety, pregnancy/lactation, or inadequate contraception.

AVE9633 was administered at increasing doses using three treatment schedules, as outlined in Table 1. In the initial trial (so-called "Day 1 study") 22 patients received 15 to 260 mg/m2 on day 1 of a 21-day cycle. Following the completion of the first dose levels, two other trials were initiated; 20 patients received 30 to 150 mg/m2 on day 1 and day 8 of a 28-day cycle (Day 1/8 study) and 12 patients received 30 to 90 mg/m2 on day 1, day 4 and day 7 of a 28-day cycle (Day 1/4/7 study).

Eligible participants had advanced/metastatic cancer (Part B: FGFR3-altered bladder cancer), adequate organ function, and resolved prior treatment toxicities (Grade ≤1). Exclusions included recent investigational therapy, corneal/skin disorders (Grade ≥2), active infections, significant cardiac conditions (QTcF >480ms, NYHA III/IV), CNS metastases requiring steroids, or secondary malignancies impacting study interpretation. Reproductive-age participants adhered to contraception protocols.