Eligibility requires GI malignancy with GCC expression, measurable RECIST disease, ECOG 0-1, and adequate organ function (specified per protocol). Exclusions: pregnancy/lactation, major surgery/study drug <4 weeks, uncontrolled infections, HIV/hepatitis, brain metastases, or other primary malignancies (<3 years remission). Additional criteria apply, with final determination by the study site.

The primary safety assessment includes DLTs (Grade 4 neutropenia/thrombocytopenia, Grade 3+ toxicities despite management, treatment delays >2 weeks, or other severe AEs prompting discontinuation) over ~9 months. TEAEs/SAEs (death, hospitalization, disability, medically significant events) are monitored post-consent until 30 days post-treatment. The MTD of MLN0264 (1.8 mg/kg) was determined via dose-escalation, with PK analysis (Cmax and AUC0-21d for MLN0264/MMAE) at Cycle 1.

Eligibility requires GI malignancy with GCC expression, measurable RECIST disease, ECOG 0-1, and adequate organ function (specified per protocol). Exclusions: pregnancy/lactation, major surgery/study drug <4 weeks, uncontrolled infections, HIV/hepatitis, brain metastases, or other primary malignancies (<3 years remission). Additional criteria apply, with final determination by the study site.

The primary safety assessment includes DLTs (Grade 4 neutropenia/thrombocytopenia, Grade 3+ toxicities despite management, treatment delays >2 weeks, or other severe AEs prompting discontinuation) over ~9 months. TEAEs/SAEs (death, hospitalization, disability, medically significant events) are monitored post-consent until 30 days post-treatment. The MTD of MLN0264 (1.8 mg/kg) was determined via dose-escalation, with PK analysis (Cmax and AUC0-21d for MLN0264/MMAE) at Cycle 1.

Eligibility requires GI malignancy with GCC expression, measurable RECIST disease, ECOG 0-1, and adequate organ function (specified per protocol). Exclusions: pregnancy/lactation, major surgery/study drug <4 weeks, uncontrolled infections, HIV/hepatitis, brain metastases, or other primary malignancies (<3 years remission). Additional criteria apply, with final determination by the study site.

The primary safety assessment includes DLTs (Grade 4 neutropenia/thrombocytopenia, Grade 3+ toxicities despite management, treatment delays >2 weeks, or other severe AEs prompting discontinuation) over ~9 months. TEAEs/SAEs (death, hospitalization, disability, medically significant events) are monitored post-consent until 30 days post-treatment. The MTD of MLN0264 (1.8 mg/kg) was determined via dose-escalation, with PK analysis (Cmax and AUC0-21d for MLN0264/MMAE) at Cycle 1.

The study emphasizes safety monitoring (AEs/SAEs up to 30 days post-treatment) and pharmacokinetic profiling (MLN0264/MMAE levels during Cycles 1-3 and beyond). Tumor assessments occur every 2 cycles (Day 21) until progression, with survival follow-up for 6 months post-last patient enrollment. Archival tumor samples are required for GCC IHC analysis (separate consent). Protocol adherence includes strict contraception and abstinence criteria to mitigate risks.

The primary endpoint is Overall Response Rate (ORR) per RECIST v1.1, assessing CR (disappearance of all lesions) and PR (≥30% decrease in target lesions) from Cycle 2 until disease progression or study closure (up to 16 months). Secondary endpoints include lab abnormalities (Grade 3+ per NCI CTCAE), vital signs, PFS (time to progression/death), duration of response, disease control rate (CR+PR+SD≥12 weeks), OS (time to death), pharmacokinetics (Cmax, MMAE levels), GCC H-score (0-600 scale), AEs/SAEs, tumor reduction percentage, and anti-drug antibodies.

Eligible patients are adults (≥18) with histologically confirmed metastatic/inoperable pancreatic adenocarcinoma (GCC H-score≥10), ≥1 prior chemotherapy, measurable disease per RECIST v1.1, ECOG 0-1, adequate organ function (ANC≥1.5x10^9/L, platelets≥100x10^9/L, etc.), and resolved prior treatment toxicities (≤Grade 1). Fertile participants must use contraception. Key exclusions: recent radiotherapy/chemotherapy (≤4 weeks), pregnancy/lactation, uncontrolled cardiovascular disease, QTc-prolonging drugs, Grade 2+ neuropathy, active infection, brain metastases, or anticoagulant therapy.

Disease response was evaluated every 2 cycles using modified RECIST 1.1 (CR: lesion disappearance; PR: &ge;30% target lesion reduction; PD: &ge;20% increase/new lesions; SD: neither PR nor PD). Blood samples were collected pre-dose for ATA analysis. Safety monitoring included abnormal labs, vital signs, and PK parameters throughout treatment. Post-treatment follow-up continued for PFS/OS every 12 weeks until PD/subsequent therapy or 6 months post-discontinuation. The study was terminated early, limiting some data collection periods.

Phase 1: MLN0264 1.2 milligram per kilogram (mg/kg) starting dose, Intravenous (IV), on Day 1 of 3 week cycles, for up to 1 year or until disease progression or unacceptable toxicity. Dosage of MLN0264 will be increased to 1.5 mg/kg then 1.8 mg/kg using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or recommended Phase 2 Dose (RP2D).Phase 2: MLN0264, IV, on Day 1 of 3 week cycles, for up to 1 year or until disease progression or unacceptable toxicity. Dosage for this phase will be determined from results of Phase 1 MTD/RP2D.

The Phase 1 safety assessment monitored DLTs (Grade 4 hematologic toxicities, Grade 3+ non-hematologic events despite management, treatment delays >2 weeks) during Cycle 1 and TEAEs/SAEs up to 30 days post-treatment (~35 weeks). Pharmacokinetic analysis of MLN0264, MMAE, and total antibody (Cmax, Tmax, AUCinf, AUCint, Ctrough) was performed at Cycles 1-2. Key evaluations included lab abnormalities, vital signs, and RP2D determination (MTD defined as dose where ≤1/6 participants experienced DLT). Phase 2 assessed ORR per RECIST (CR+PR), PFS (time to progression/death), DOR (confirmed response to PD), DCR (CR+PR+SD≥12 weeks), OS, tumor reduction, GCC H-score (0-600), and ATAs over ~1 year.

Eligible patients had GI/gastric adenocarcinoma with GCC expression (H-score≥10), measurable RECIST disease, ECOG 0-1, and adequate organ function. Phase 1 included various GI carcinomas while Phase 2 focused on gastric/GEJ cancers. Key exclusions: recent chemotherapy/investigational drugs (<4 weeks), pregnancy/lactation, uncontrolled cardiovascular disease, CNS metastases, significant infections, neuropathy ≥Grade 2, strong CYP3A4 inhibitors (<2 weeks), or hepatitis/HIV. All prior treatment toxicities (except alopecia) must have resolved to ≤Grade 1.

Tumor assessments utilized RECIST 1.1 criteria: CR (lesion disappearance + normal markers), PR (&ge;30% target lesion reduction), SD (no qualifying shrinkage/growth), PD (&ge;20% increase/new lesions). Blood samples for PK/ATA analysis were collected pre-dose (all cycles) and at specified post-dose intervals (Cycles 1-3). Safety follow-up continued for 30 days post-treatment, while survival/PFS was monitored every 12 weeks until death/progression or 6 months post-discontinuation. Clinically significant findings were investigator-determined, including abnormal labs (serum chemistry, hematology, coagulation) and vital signs (BP, heart rate, temperature).

The study assessed efficacy endpoints including ORR (CR+PR per RECIST 1.1), PFS (time to progression/death), DOR (response duration), DCR (CR+PR+SD≥12 weeks), and OS (up to 17 months) in participants with GCC-positive gastric/GEJ adenocarcinoma (H-score≥10). Pharmacokinetic analysis measured serum concentrations of MLN0264, total antibodies (conjugated/unconjugated), and MMAE during Cycles 1-14 (pre/post-dose timepoints). Tumor response was evaluated via imaging every other cycle (Day 21), with GCC expression quantified by IHC H-score (0-600). Safety monitoring included AEs/SAEs, lab abnormalities (Grade 3+ per NCI CTCAE), vital signs, and ATA development (pre-dose each cycle).

Eligible participants had metastatic/unresectable gastric/GEJ adenocarcinoma (≥1 prior chemotherapy), measurable RECIST 1.1 lesions, ECOG 0-1, and adequate organ function (ANC≥1.5x10^9/L, platelets≥100x10^9/L, bilirubin≤1.5xULN). Key exclusions: recent radiotherapy/chemotherapy (<4 weeks), anticoagulant use, symptomatic brain metastases, Grade 2+ neuropathy, strong CYP3A4 inhibitors (<2 weeks), uncontrolled cardiovascular disease, or HIV. Females of childbearing potential required dual contraception, while males practiced barrier methods until 4 months post-treatment. Archival tumor GCC testing (H-score) was mandatory for enrollment.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.

To evaluate the efficacy of TAK-264 in mouse models of pancreatic cancer,ten pancreatic PDX models were treated with 10 mg/kg of TAK-264 for at least 17 days. Each treatment group contained 56 mice with tumor pieces (~3mm³ fragments) injected into the right and left flank to give ~10 evaluable tumors. Mice were randomized into control or TAK-264 groups when tumor volumes reached ~150-300 mm³.