The QTc sub-study mandates compliance with UPLIFT criteria plus additional ECG monitoring, excluding patients with uncontrolled arrhythmias, severe valvular disease, or concomitant CYP3A inducers. Specific ovarian cancer exclusions for UPLIFT include non-high-grade histologies, primary platinum-refractory disease, and prior participation in DES/EXP cohorts.

The primary objectives include determining the maximum tolerated dose (MTD) or recommended Phase 2 dose of XMT-1536 (upifitamab rilsodotin) based on safety assessments. Secondary objectives evaluate safety, pharmacokinetics (PK), anti-drug antibodies, and anti-tumor efficacy including objective response rate (ORR) by investigator and independent review, duration of response (DOR), and QTc interval effects via concentration-QTc analysis.

Key inclusion criteria for DES, EXP, and UPLIFT cohorts involve ECOG 0-1, measurable disease per RECIST v1.1, adequate organ function, and resolution of prior toxicities (≤Grade 1). UPLIFT specifically requires high-grade platinum-resistant ovarian cancer (1-4 prior lines, archival tumor for NaPi2b testing). Exclusion criteria include untreated CNS metastases, active infections (HIV/HBV/HCV), significant cardiac/liver/pulmonary dysfunction, recent major surgery/systemic therapy, or prior treatment with antitubulin ADCs.

Exclusion criteria include prior treatment with mirvetuximab soravtansine or related ADCs, recent bevacizumab use, symptomatic GI obstruction, ascites/pleural effusion requiring drainage within 28 days, significant liver disease, pneumonitis/interstitial lung disease, or untreated CNS metastases/leptomeningeal involvement. Participants with clinically significant conditions per investigator judgment are also excluded.

The primary endpoint is progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR) using RECIST v1.1, defined as time from randomization to disease progression or death. Secondary endpoints include overall survival (OS), PFS by investigator assessment, adverse events (AEs) per NCI CTCAE v5.0, ECOG performance status changes, objective response rate (ORR), and concomitant medication usage.

Eligible participants must have histologically confirmed high-grade serous ovarian cancer (including fallopian tube/peritoneal) with platinum-sensitive recurrence, having received 4-8 cycles of prior platinum-based chemotherapy. Participants must provide tumor tissue for NaPi2b expression testing and meet specific BRCA mutation criteria if NED, CR, or PR was achieved without prior PARP inhibitor use.

General inclusion criteria require ECOG 0-1, measurable disease, resolved toxicities &le;Grade 1 (exceptions noted), LVEF &ge;50%, adequate organ function (e.g., ANC &ge;1500/mm3, platelets &ge;100,000/mm3, GFR &ge;45 mL/min), and no untreated CNS metastases. Key exclusions include recent major surgery, active infections (HIV/HBV/HCV), severe systemic disease, pneumonitis history, pregnancy, strong CYP3A modifiers use, or oxygen saturation <93%. Ovarian cancer-specific criteria mandate high-grade serous histology, platinum-resistant disease (1-4 prior lines, bevacizumab if 1-2 lines), and archival tumor availability. Exclusions cover low-grade/non-serous tumors, prior anti-tubulin ADCs, primary platinum resistance, and DES/EXP participation. The QTc sub-study requires adherence to UPLIFT criteria plus clinic stay for ECG assessments, excluding arrhythmias, severe valvular disease, or non-sinus rhythm (HR >45-<100).

Key inclusion criteria require ECOG 0-1, measurable disease (RECIST v1.1), resolved prior toxicities (&le;Grade 1, exceptions specified), LVEF &ge;50%, adequate organ function (ANC &ge;1500/mm ³, platelets &ge;100K/mm ³, GFR &ge;45 mL/min, bilirubin &le;ULN, AST/ALT &le;1.5x ULN, albumin &ge;3.0 g/dL), and informed consent. Exclusion criteria include recent major surgery/anti-cancer therapy (<28 days or 5 half-lives), untreated CNS metastases, active HIV/HBV/HCV infections, severe systemic disease, oxygen therapy dependence, pneumonitis history, pregnancy, recent malignancy (exceptions allowed), active corneal disease, strong CYP3A modifiers, or O ₂ saturation <93%. For ovarian cancer (UPLIFT), high-grade serous histology, platinum resistance (1-4 prior lines, bevacizumab if 1-2 lines), and tumor tissue availability are required; exclusions cover non-serous histologies, prior anti-tubulin ADCs, primary platinum resistance, and DES/EXP participation. The QTc sub-study mandates UPLIFT eligibility plus compliance with ECG monitoring (exclusions: strong CYP3A inducers, arrhythmias, severe valvular disease, HR >45-<100 bpm, non-sinus rhythm, or QT-interference ECG abnormalities).

Safety monitoring will track adverse events per CTCAE v5.0, while pharmacokinetic analysis focuses on Cmax and AUC for both drugs. Antitumor activity assessments (ORR, DCR, PFS by RECIST 1.1, OS) occur every 8-12 weeks. Tumor NaPi2b expression and blood-based biomarkers will be analyzed for correlation with treatment response. The study excludes those with unresolved toxicity from prior therapies or contraindications to study drugs.

The study aims to determine the MTD of Upifitamab Rilsodotin with carboplatin by evaluating adverse events over 24 weeks, while assessing the feasibility of this combination therapy (defined as ≥60% of participants completing ≥4 cycles without discontinuation for reasons other than progression). Safety, tolerability (CTCAE v5.0), and pharmacokinetics (Cmax, AUC) of both drugs will be monitored. Antitumor effects will be evaluated via ORR, DOR, DCR, PFS (RECIST 1.1), and OS.

Inclusion criteria require female participants ≥18 years with platinum-sensitive recurrent high-grade serous ovarian cancer (1-3 prior lines, measurable disease, ECOG 0-1). Tumor sampling is mandated, and organ function must be adequate (LVEF ≥50%, ANC ≥1500/mm ³, platelets ≥100K/mm ³). Key exclusions include carboplatin hypersensitivity requiring discontinuation, prior ADC treatment with auristatin/maytansinoid payloads, untreated CNS metastases, recent major surgery/anticancer therapy, concurrent malignancies, and blood transfusion refusal.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg qwk x 3.

Animals were randomized into treatment groups (n = 10) when the tumor target volume reached 100-150 mm³. Test articles were administered intravenously via tail vein injection. Mice received a single dose of either saline vehicle; XMT-1535 at 3 mg/kg; XMT-1536 (DAR 12.4) at 3 mg/kg; IgG1-Dolaflexin (DAR 18.1) at 3 mg/kg,or lifastuzumab vedotin (DAR 4.1) at 3 mg/kg. Tumors were measured twice per week. XMT-1536 and lifastuzumab vedotin were administered at a single dose of 3 mg/kg.

OVCAR3 cells were grown in RPMI1640 media supplemented with 20% FBS and 1% penicillin/streptomycin,seeded at a density of 5, 000 cells per well in 100 L of growth media in a 96-well,white flat-bottom plate. Following overnight incubation,the media was replaced with 100 L of fresh media containing the test compounds at a 3-fold titration up to 33 nmol/L. The treated cells were incubated for 96 hours at 37°C in the presence of 5% CO₂. In the OVCAR3 cell line,XMT-1536 was cytotoxic in a 96-hour cellular cytotoxicity assay.