Phase 1/2 Study of Rina-S in Patients With Locally Advanced and/or Metastatic Solid Tumors

More details:

Overview

Rinatabart sesutecan (Rina-S; GEN1184, formerly PRO1184) is an investigational antibody–drug conjugate (ADC) directed at folate receptor alpha (FRα), being developed for FRα-expressing solid tumors, notably ovarian and endometrial cancers. As of October 2025, human data from the ongoing Phase 1/2 RAINFOL-01 trial support antitumor activity in heavily pretreated ovarian and endometrial cancer, and a global Phase 3 trial in platinum‑resistant ovarian cancer is recruiting. In August 2025, FDA granted Breakthrough Therapy Designation for advanced endometrial cancer that has progressed after platinum chemotherapy and PD-(L)1 therapy. (ir.genmab.com)

Mechanism of action

• Target: Folate receptor alpha (FRα). (db.antibodysociety.org)
• Payload/linker: An exatecan (topoisomerase I inhibitor) payload coupled via ProfoundBio’s proprietary hydrophilic, protease‑cleavable “sesutecan” linker; reported to enable a homogeneous high DAR (8) and promote efficient payload delivery with favorable ADC properties and bystander effect. (businesswire.com)

Clinical development

• Phase 1/2 (RAINFOL‑01; NCT05579366): Multicenter study with dose escalation and expansion in FRα‑expressing solid tumors (including dedicated ovarian and endometrial cohorts; additional parts include combinations and a QTc substudy). (clinicaltrials.ucsd.edu)
• Phase 3 (NCT06619236): Randomized, open‑label Rina‑S vs investigator’s choice chemotherapy in platinum‑resistant ovarian cancer; recruiting internationally. (dana-farber.org)
• Regulatory: FDA Breakthrough Therapy Designation (Aug 26, 2025) for recurrent/progressive endometrial cancer after platinum and PD‑(L)1; FDA Fast Track Designation (Jan 2024) for FRα‑expressing high‑grade serous/endometrioid platinum‑resistant ovarian cancer. (ir.genmab.com)

Efficacy

• Endometrial cancer (ASCO 2025, RAINFOL‑01 B2 cohort, monotherapy):
• 64 patients received Rina‑S 100 mg/m² (n=22) or 120 mg/m² (n=42) Q3W after prior platinum and PD‑(L)1.

• Confirmed ORR: 50.0% at 100 mg/m² (including 2 CRs); 47.1% at 120 mg/m²; median DOR not reached at 7.7 and 9.8 months’ median follow‑up, respectively. (globenewswire.com)

• Ovarian cancer (PROC; SGO 2025, RAINFOL‑01 B1 cohort, monotherapy):

• Rina‑S 120 mg/m² Q3W: confirmed ORR 55.6% (95% CI 30.8–78.5); median DOR not reached at ~48 weeks’ follow‑up. Responses were seen regardless of FRα expression. (ir.genmab.com)
• Earlier dose‑optimization data at ESMO 2024 showed higher activity at 120 mg/m² vs 100 mg/m² (ORR 50.0% vs 18.2%) in advanced ovarian cancer, informing selection of 120 mg/m² for Phase 3. (globenewswire.com)

Notes: These are noncomparative early‑phase data presented at scientific meetings; Phase 3 results are not yet available. (dana-farber.org)

Safety

• In RAINFOL‑01, commonly reported treatment‑emergent adverse events included diarrhea, nausea, vomiting, fatigue, decreased appetite, constipation, dyspnea, urinary tract infection, and headache. Grade ≥3 AEs occurred in about 32% (100 mg/m²) to 50% (120 mg/m²) of endometrial cancer patients; hematologic toxicities were described as manageable with low discontinuation rates. No ocular toxicity, peripheral neuropathy, or interstitial lung disease signals were reported in the endometrial cohort at the time of ASCO 2025 reporting. (curetoday.com)

Further reading

• Phase 1/2 trial record (RAINFOL‑01; study design and parts). (clinicaltrials.ucsd.edu)
• Phase 3 trial pages (NCT06619236). (dana-farber.org)
• ASCO 2025 program listings (endometrial cohort first disclosure; abstract 3039) and Phase 3 TPS abstract listing. (mfn.se)
• ESMO 2024 mini‑oral abstract (Phase 1/2 dose escalation/expansion overview). (oncologypro.esmo.org)
• AACR 2025 preclinical abstract (mechanism; combination preclinical data). (aacrjournals.org)
• Mechanistic details on sesutecan linker–exatecan payload (SITC 2023 release). (businesswire.com)
• Genmab media releases summarizing RAINFOL‑01 efficacy data (SGO 2025 and ASCO 2025). (ir.genmab.com)
• FDA Breakthrough Therapy Designation announcement in endometrial cancer (Aug 26, 2025). (ir.genmab.com)

Disclosure: Efficacy and safety results cited above are from early‑phase cohorts reported in conference abstracts and company communications; peer‑reviewed full manuscripts were not identified as of October 7, 2025. (oncologypro.esmo.org)

Last updated: Oct 2025

Inclusion Criteria:

Part A and B:

* Histologically or cytologically confirmed metastatic or unresectable solid malignancy including ovarian cancer (must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer), endometrial cancer, non-small cell lung cancer (Part A), EGFR-mutated NSCLC (Part B), breast cancer (hormone receptor positive, HER2-negative and triple-negative) (Part A), mesothelioma.

* Previously received therapies known to confer clinical benefit.

* Measurable disease per RECIST v1.1 for all tumor types other than pleural mesothelioma which will use mRECIST v1.1 at baseline.

Part C:

Participants must have histologically or cytologically confirmed metastatic or unresectable epithelial ovarian cancer as specified below.

* High grade serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (excluding endometrioid, clear cell carcinomas, mucinous, low grade, and those with a sarcomatous or neuroendocrine element)

* Participants must have received 1 to 3 prior lines of therapy. Participants who had 1 to 4 prior lines of therapy are allowed if mirvetuximab soravtansine (MIRV) was the last line of therapy. Participants must have progressed radiographically on or after their most recent line of therapy.

* Participants must have platinum-resistant ovarian cancer.

* Participants must have received prior bevacizumab.

* Participants with known or suspected deleterious germline or somatic BRCA mutations (as determined by Food and Drug Administration \[FDA\]-approved test in a Clinical Laboratory Improvement Amendments \[CLIA\]-certified laboratory) and who achieved a complete or partial response to platinum-based chemotherapy must have been treated with a poly ADP-ribose polymerase (PARP) inhibitor as maintenance treatment.

* Participants must have known FRα status based on an FDA approved test. Those who are FRα positive must have previously received MIRV, unless the participant has a documented medical exception.

* Participants who are FRα negative, in accordance with the FDA approved test (Ventana folate receptor \[FOLR1\] RxDx Assay), and were treated with MIRV, are excluded.

* Measurable disease per the RECIST v1.1 at baseline.

Part D:

Cohort D1 (Rina-S+carboplatin):

* Participants must have platinum-sensitive ovarian cancer.

* Participants must have received 1 to 3 prior lines of therapy.

Cohort D2 (Rina-S+bevacizumab):

* Participants must have primary platinum-refractory, platinum-resistant, or platinum-sensitive ovarian cancer.

* Participants with primary platinum-refractory ovarian cancer must have received ≤2 prior lines of therapy. Primary platinum-refractory ovarian cancer is defined as a lack of response or by progression within 91 days after completing front-line platinum containing therapy.

* Participants must have received 1 to 3 prior lines of therapy for platinum-resistant ovarian cancer (PROC), and up to 4 prior lines of therapy for platinum-sensitive ovarian cancer (PSOC). Prior treatments may have included bevacizumab, PARP inhibitor, and MIRV.

* Participants with PSOC must have disease progression on or after maintenance treatment, or at least 6 months (\>183 days) or more from the last dose of platinum-based therapy.

Cohort D3 (Rina-S+pembrolizumab):

* Endometrial cancer (any subtype excluding sarcoma).

* Participants must have received prior platinum-based chemotherapy for recurrent or advanced disease.

Part F:

* Participants must have histologically or cytologically confirmed endometrial cancer as specified below.

* Advanced, recurrent, metastatic, or primary unresectable endometrial cancer (any subtype excluding neuroendocrine tumors, carcinosarcoma, or endometrial sarcoma)

* Participants must have received 1 to 3 prior lines of therapy in advanced, recurrent, or metastatic setting, and must have progressed radiographically on or after their most recent line of therapy:

* Participants must have received prior platinum-based chemotherapy and a programmed death-ligand 1 (PD-\[L\])1 inhibitor.

* Participants who progress \>12 months after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy must receive 1 additional cytotoxic systemic treatment prior to enrollment in this study.

* Hormonal therapy alone (i.e., without chemotherapy) will not be counted as a separate line of therapy.

* Measurable disease per the RECIST Version 1.1 at baseline.

Exclusion Criteria:

* History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids within the past 2 years, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

* Use of a strong cytochrome P450 3A (CYP3A) inhibitor within 14 days (dose escalation only).

* Prior therapy with a topoisomerase 1 inhibitor-based antibody drug conjugate.

Note: Other protocol-defined inclusion/exclusion may apply.