Rinatabart Sesutecan (Rina-S, PRO1184, GEN1184) for Advanced Solid Tumors (GCT1184-01/ PRO1184-001)

This is a Phase 1/2 study of Rina-S; also known as GEN1184, formerly known as PRO1184, a folate receptor alpha (FRα) targeted antibody-drug conjugate, to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of Rina-S in participants with selected locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma.

The study consists of multiple parts:

Part A: monotherapy cohorts

Part B: tumor-specific monotherapy dose-expansion cohorts

Part C: platinum-resistant ovarian cancer (PROC) monotherapy cohort

Part D: combination therapy cohorts

Part E: a monotherapy PROC cohort

Parts F and G: a monotherapy endometrial cancer (EC) cohort

Part H: a monotherapy PROC cohort

Part I: platinum-sensitive ovarian cancer (PSOC) cohort

Part J: a monotherapy PROC cohort

Part K: a monotherapy high-grade ovarian cancer cohort

Part L: a drug-drug interaction substudy

Participants will continue to receive study treatment until the first instance of disease progression, unacceptable toxicity, investigator decision, consent withdrawal, study termination by the Sponsor, pregnancy, or death.

• Rina-S (Drug), also known as PRO1184, Rinatabart sesutecan, GEN1184: Intravenous infusion of Rina-S
• Carboplatin (Drug): Carboplatin intravenous infusion
• Bevacizumab (Drug): Bevacizumab intravenous infusion
• Pembrolizumab (Drug): Pembrolizumab intravenous infusion
• Erythromycin (Drug): Erythromycin oral administration
• Itraconazole (Drug): Itraconazole oral administration

Primary outcomes

• Parts A, B, and D - Incidence of Treatment-Emergent Adverse Events (TEAEs) [Safety and Tolerability] [Through end of treatment, up to approximately 1 year.]
• Parts A, and D - Number of Participants with Dose Limiting Toxicity (DLT) [At the end of Cycle 1 (each cycle is 21 days)]
• Parts C, E, F, G, H, I, and J- Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR, Parts C and F) or Investigator (Part E, G, I, and J) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [Through end of treatment, up to approximately 1 year.]: Participants who achieve partial response (PR) or complete response (CR) per RECIST v1.1 criteria.
• Part K (US Participants Only) - Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Findings by Holter [Cycles 1 to 3 (each cycle is 21 days)]
• Part L - Peak Plasma Concentration (Cmax) of Rina-S [Cycles 1 and 2 (each cycle is 21 days)]: Measurement of maximum plasma concentration after the administration of Rina-S.\[
• Part L - Area Under the Plasma Concentration Versus Time Curve (AUC) of Rina-S [Cycles 1 and 2 (each cycle is 21 days)]: Measurement of AUC after the administration of Rina-S.

Secondary outcomes

• Parts A, B, and D - Best Overall Response (BOR) [Up to approximately 1 year.]: Participants who achieve CR or PR. Best response as assessed by the investigator per RECIST v1.1 criteria for all tumor types other than pleural mesothelioma which will use modified RECIST (mRECIST) v1.1.
• Parts A, B, D, and E - ORR [Up to approximately 1 year.]: Participants who achieve PR or CR per RECIST v1.1 criteria.
• Parts A, B, and D - Disease Control Rate (DCR) [Up to approximately 1 year.]: Participants who achieve stable disease, PR or CR per RECIST v1.1 criteria.
• Parts A, B, C, D, E, F, G, H, I, and J - Progression-Free Survival (PFS) [Through end of treatment, up to approximately 1 year.]: Time from start of treatment to first documented disease progression or death
• Parts C, E, F, G, H, I and J - Overall survival (OS) [Up to approximately 2 years.]: Time from the start of study treatment to the date of death from any cause
• Parts A, B, C, D, E, F, G, H, I and J - Duration of Objective Response (DOR) [From date of enrollment until the date of first documented disease progression or date of study withdrawal, whichever came first, assessed up to 12 months.]: Time from the first documentation of an objective tumor response (CR or PR) to the first documented tumor progression or death
• Parts A, B, D, and E - Cmax for Rina-S [Through end of treatment, up to approximately 1 year.]: Measurement of maximum plasma concentration after the administration of Rina-S.
• Parts A, B, D, and E - AUC for Rina-S [Through end of treatment, up to approximately 1 year.]: Measurement of AUC after the administration of Rina-S.
• Parts A, B, D, and E -Time to Reach Cmax (Tmax) for Rina-S [Through end of treatment, up to approximately 1 year]
• Parts A, B, D, and E - Trough Concentrations (Ctrough) for Rina-S [Through end of treatment, up to approximately 1 year]
• Parts A, B, D, and E- Apparent Terminal Half-life (t1/2) for Rina-S [Through end of treatment, up to approximately 1 year]
• Parts C, D, E, H and J - CA-125 Response Determined Using the Gynecologic Cancer Intergroup (GCIG) Criteria [Through end of treatment, up to approximately 1 year]
• Parts C, E, F, G, H, I, J, K and L - Number of Participants with Type, Incidence, Severity, Seriousness as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and Relatedness of Adverse Events (AEs) [Through end of treatment, up to approximately 1 year]
• Part E - Number of Participants With Antidrug Antibodies (ADA) [Through end of treatment, up to approximately 1 year]
• Part L - Number of Participants with DLT [At the end of Cycle 1 (each cycle is 21 days)]

Sex: All, ages: 18 Years to any

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 or cervical cancer (Part B).
* 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, E, and H:

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 up to 3 prior lines of therapy. Participants may have had up to to 4 prior lines of therapy are allowed if MIRV is locally approved and was used as 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 or approved biosimilar.
* 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; or locally approved equivalent) 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.
* Measurable disease per the RECIST v1.1 at baseline.

Part D:

Cohort D1:

* Participants must have platinum-sensitive ovarian cancer.
* Participants must have received 1 to 3 prior lines of therapy.

Cohort D2:

* 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:

• Endometrial cancer (any subtype excluding sarcoma).

Cohort D4:

• Primary advanced or recurrent endometrial cancer (any subtype excluding sarcoma and neuroendocrine tumors).

Cohort D5

• Primary advanced or recurrent endometrial cancer (any subtype excluding sarcoma and neuroendocrine tumors).

Part F and G:

* Participants must have histologically or cytologically confirmed EC.
* Recurrent progressive EC (any subtype excluding neuroendocrine tumors, carcinosarcoma, or endometrial sarcoma) following prior therapy.
* Participants must have received 1 to 3 prior lines of therapy, 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.

Part I:

* Participants must have histologically or cytologically confirmed high grade serous or endometrioid epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer (excluding clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies or low grade/borderline ovarian tumors).
* Participants must have platinum sensitive ovarian cancer.
* Measurable disease per the RECIST Version 1.1 at baseline.

Part J:

* Participants must have high grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer including serous, endometrioid, and clear cell carcinomas, and excluding mucinous, low grade, and those with a sarcomatous or neuroendocrine element.
* Measurable disease per the RECIST Version 1.1 at baseline.

Part K:

* Participants must have histologically or cytologically confirmed metastatic or unresectable ovarian cancer (must have high grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer including serous, endometrioid, and clear cell carcinomas, and excluding mucinous, low grade, and those with a sarcomatous or neuroendocrine element).
* Participants must have primary platinum-refractory, platinum-resistant, or platinum-sensitive ovarian cancer.
* Measurable disease per the RECIST Version 1.1 at baseline.

Part L:

* Participants must have a histologically or cytologically confirmed metastatic or unresectable solid malignancy. Participants must have previously received all therapies known to confer clinical benefit (unless ineligible to receive or refused to receive or therapy is unavailable in the region). If a standard-of-care therapy is available that has not been administered, the reason that the therapy is not appropriate must be documented.
* Participants must either have ovarian cancer (must have high grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer including serous, endometrioid, and clear cell carcinomas, and excluding mucinous, low grade, and those with a sarcomatous or neuroendocrine element), or
* NSCLC.
* Age 18 to 65 years (inclusive).
* An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
* 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.
* Prior therapy with a topoisomerase 1 inhibitor-based antibody drug conjugate.

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

• Study Official, Study director, Genmab