Inclusion: Part A/B-metastatic/unresectable solid tumors (ovarian/NSCLC/breast cancers, mesothelioma) refractory to prior therapy; Part C-BRCA-tested, platinum-resistant ovarian cancer (1-3 prior lines, FRalpha+ must have received mirvetuximab soravtansine); Part D-platinum-sensitive/refractory ovarian cancer (cohort-specific prior therapies); Part F-endometrial cancer (1-3 prior lines, post-PD-[L]1 inhibitor). Exclusions: ILD/pneumonitis, strong CYP3A inhibitors (dose escalation), prior topoisomerase-1 inhibitor ADCs.

In Parts A, B, and D, safety assessments include incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) evaluated through the end of treatment (up to ~1 year). DLTs are specifically analyzed at the end of Cycle 1 (21-day cycles). Parts C and F report objective response rate (ORR) via blinded independent central review (BICR) per RECIST v1.1.

Efficacy measures include best overall response (BOR), ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Pharmacokinetic parameters (Cmax, AUC, Tmax, Ctrough, t1/2) of Rina-S are assessed. Parts C and D evaluate CA-125 response using GCIG criteria, and Parts C and F assess adverse events (CTCAE v5.0).

Exclusions: prior topoisomerase-1 inhibitor ADCs; primary platinum-refractory disease (progression ≤91 days post-1st-line platinum); active malignancy within 3 years (exceptions: low-risk cancers); active CNS metastases (unless stable ≥4 weeks post-treatment); symptomatic GI obstruction/ascites requiring frequent paracentesis. Other protocol-specific criteria may apply.

The primary efficacy endpoints include progression-free survival (PFS), defined as time from randomization to first progression or death per RECIST v1.1, and overall survival (OS), measured from randomization to death from any cause. Secondary endpoints include objective response rate (ORR), duration of response (DOR), CA-125 response per GCIG criteria (≥50% reduction), PFS2 (time to second progression/death), and quality of life assessments via EORTC-QLQ-C30 (GHS/QoL score changes and time to deterioration [TTD]). Safety will be monitored through TEAEs, lab abnormalities, and ECG/QTc changes (Holter monitoring during Cycle 1).

Inclusion criteria: histologically confirmed high-grade serous/endometrioid ovarian, peritoneal, or fallopian tube cancer (regardless of FRalpha status) with 1-4 prior lines. Must have received platinum chemo, bevacizumab (if standard), and PARP inhibitors (if BRCA-mutated and eligible); prior mirvetuximab soravtansine required if FRalpha+ (unless contraindicated). Platinum-resistant disease defined as progression 91-183 days post-platinum (1st line) or ≤183 days (2nd-4th lines).