Study of Mirvetuximab Soravtansine in Combination With Bevacizumab, Carboplatin, Pegylated Liposomal Doxorubicin, Pembrolizumab, or Bevacizumab + Carboplatin in Participants With Folate Receptor Alpha (FRα) Positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal, or Fallopian Tube Cancer

Study Overview
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Brief Summary
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This study comprises a Dose Escalation phase followed by a Dose Expansion phase. Dose Escalation part of the study will assess the safety and tolerability and determine the maximum tolerated dose (MTD) as the recommended Phase 2 (RP2D) dose for each regimen. Participants will be assigned to one of the 4 regimens in Dose Escalation phase: Regimen A: mirvetuximab soravtansine administered with bevacizumab; Regimen B: mirvetuximab soravtansine administered with carboplatin; Regimen C: mirvetuximab soravtansine administered with pegylated liposomal doxorubicin; or Regimen D: mirvetuximab soravtansine administered with pembrolizumab. Dose Expansion of the study will further assess safety, tolerability and preliminary anti-tumor activity of mirvetuximab soravtansine. A Dose Expansion phase is planned for Regimen A and Regimen D and will open pending Sponsor decision; participants enrolled in the Dose Expansion phase will receive study treatment at the MTD or RP2D determined during Dose Escalation. For Regimen A, participants in the Dose Expansion phase may be enrolled according to prior exposure to bevacizumab into 3 Dose Expansion Cohorts as follows: 1) Dose Expansion Cohort 1: bevacizumab naïve; 2) Dose Expansion Cohort 2: bevacizumab pretreated; and 3) Dose Expansion Cohort 3: one to three prior treatments, one of which could have been bevacizumab. A triplet Regimen (Regimen E: mirvetuximab soravtansine + bevacizumab + carboplatin) will be opened to evaluate the safety and tolerability and to assess any early signs of activity in participants dosed with the combination regimen.

Detailed Description
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Participants will continue to receive mirvetuximab soravtansine and/or the combination agent until progressive disease (PD), unacceptable toxicity, or withdrawal of consent, whichever comes first, or until the Sponsor terminates the study.

Official Title
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A Phase 1b/2 Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Mirvetuximab Soravtansine (IMGN853) in Combination With Bevacizumab, Carboplatin, Pegylated Liposomal Doxorubicin, Pembrolizumab, or Bevacizumab + Carboplatin, in Adults With Folate Receptor Alpha Positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

Conditions
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Epithelial Ovarian Cancer, Primary Peritoneal Cancer, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: Mirvetuximab soravtansine
* Drug: Bevacizumab
* Drug: Carboplatin
* Drug: Pegylated Liposomal Doxorubicin
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer FRα positive tumor expression as defined in the protocol Willing to provide an archival tumor tissue block or slides or undergo tumor biopsy. New tumor biopsy (Cycle 2 Day 8) is required for Regimen D. Measurable disease Exclusion Criteria: Primary platinum-refractory disease Diagnosis of clear cell, low grade ovarian cancer or mixed tumors Serious concurrent illness or clinically relevant active infection, including but not limited to known diagnosis of human immunodeficiency virus (HIV) and hepatitis B or C, as defined in the protocol Active autoimmune disease requiring systemic therapy in past 2 years (for Regimen D only) Women who are pregnant or breastfeeding Male participants

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (Mirvetuximab soravtansine + Bevacizumab)<br>Mirvetuximab soravtansine + Bevacizumab administered on Day 1 of each 21-day cycle in Dose Escalation and Dose Expansion phase. | Drug: Mirvetuximab soravtansine<br> <br> * Other names: IMGN853;Drug: Bevacizumab<br> <br> |
| Experimental: Regimen B (Mirvetuximab soravtansine + Carboplatin)<br>Mirvetuximab soravtansine + Carboplatin administered on Day 1 of each 21-day cycle in Dose Escalation phase. | Drug: Mirvetuximab soravtansine<br> <br> * Other names: IMGN853;Drug: Carboplatin<br> <br> |
| Experimental: Regimen C (Mirvetuximab soravtansine + Pegylated liposomal doxorubicin)<br>Mirvetuximab soravtansine + Pegylated liposomal doxorubicin administered on Day 1 of each 28-day cycle in Dose Escalation Phase. | Drug: Mirvetuximab soravtansine<br> <br> * Other names: IMGN853;Drug: Pegylated Liposomal Doxorubicin<br> <br> |
| Experimental: Regimen D (Mirvetuximab soravtansine + Pembrolizumab)<br>Mirvetuximab soravtansine + Pembrolizumab administered on Day 1 of each 21-day cycle in Dose Escalation and Dose Expansion phase. | Drug: Mirvetuximab soravtansine<br> <br> * Other names: IMGN853;Drug: Pembrolizumab<br> <br> |
| Experimental: Regimen E (Mirvetuximab soravtansine + Bevacizumab + Carboplatin)<br>Mirvetuximab soravtansine + Bevacizumab + Carboplatin administered on Day 1 of each 21-day cycle in Dose Expansion phase. | Drug: Mirvetuximab soravtansine<br> <br> * Other names: IMGN853;Drug: Bevacizumab<br> <br> Drug: Carboplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation (Regimens A Through D): Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Baseline up to approximately 5.3 years | 
| Dose Expansion (Regimens A and D) and Triplet (Regimen E): Objective Response Rate (ORR); Percentage of Participants With Confirmed Response, as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Confirmed response includes complete Response (CR) + partial response (PR). | From first dose of study drug until first CR or PR (up to approximately 5.3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Expansion (Regimens A and D) and Triplet (Regimen E): Number of Participants With TEAEs |  | Baseline up to approximately 5.3 years | 
| Dose Escalation (Regimens A Through D): ORR; Percentage of Participants With Confirmed Response (CR + PR), as Assessed by RECIST Version 1.1 |  | From first dose of study drug until first CR or PR (up to approximately 5.3 years) | 
| Progression-Free Survival (PFS); Time From the Date of First Dose Until the Date of PD or Death by Any Cause, as Defined by RECIST Version 1.1 |  | From first dose of study drug until the date of PD or death by any cause (up to approximately 5.3 years) | 
| Duration of Response (DOR); the Time From First Objective Response (CR/PR) to the Time of PD Among Those who Have Achieved a PR or CR |  | From the date of first objective response to the time of PD (up to approximately 5.3 years) | 
| Number of Participants With Gynecologic Cancer Intergroup (GCIG) CA125 Clinical Response |  | Baseline up to approximately 5.3 years | 
| PK Parameter: Maximum Plasma Concentration (Cmax) of Intact Mirvetuximab Soravtansine Antibody Drug Conjugate (ADC), Total Antibody, N2'-[4-[(3-carboxypropyl)dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2'-deacetylmaytansine (DM4), and S-methyl DM4 |  | Cycles 1 and 3: Day 1 (pre-infusion, within 10 minutes of end of infusion [EOI], and 6 hours post-infusion); Days 2 and 3 (24- and 48-hours post-infusion); Days 8 and 15 (additionally at Day 22 for Regimen C) | 
| PK Parameter: Area Under the Time-Concentration Curve (AUC) of Intact Mirvetuximab Soravtansine ADC, Total Antibody, DM4, and S-methyl DM4 |  | Cycles 1 and 3: Day 1 (pre-infusion, within 10 minutes of EOI, and 6 hours post-infusion); Days 2 and 3 (24- and 48-hours post-infusion); Days 8 and 15 (additionally at Day 22 for Regimen C) | 
| PK Parameter: Terminal Half-Life (t½) of Intact Mirvetuximab Soravtansine ADC, Total Antibody, DM4, and S-methyl DM4 |  | Cycles 1 and 3: Day 1 (pre-infusion, within 10 minutes of EOI, and 6 hours post-infusion); Days 2 and 3 (24- and 48-hours post-infusion); Days 8 and 15 (additionally at Day 22 for Regimen C) | 
| PK Parameter: Clearance (CL) of Intact Mirvetuximab Soravtansine ADC, Total Antibody, DM4, and S-methyl DM4 |  | Cycles 1 and 3: Day 1 (pre-infusion, within 10 minutes of EOI, and 6 hours post-infusion); Days 2 and 3 (24- and 48-hours post-infusion); Days 8 and 15 (additionally at Day 22 for Regimen C) | 
| PK Parameter: Volume of Distribution at Steady State (Vss) of Intact Mirvetuximab Soravtansine ADC, Total Antibody, DM4, and S-methyl DM4 |  | Cycles 1 and 3: Day 1 (pre-infusion, within 10 minutes of EOI, and 6 hours post-infusion); Days 2 and 3 (24- and 48-hours post-infusion); Days 8 and 15 (additionally at Day 22 for Regimen C) | 
| PK Parameter: Time to Reach Cmax (Tmax) of Intact Mirvetuximab Soravtansine ADC, Total Antibody, DM4, and S-methyl DM4 |  | Cycles 1 and 3: Day 1 (pre-infusion, within 10 minutes of EOI, and 6 hours post-infusion); Days 2 and 3 (24- and 48-hours post-infusion); Days 8 and 15 (additionally at Day 22 for Regimen C) | 
| Concentration of Bevacizumab, Carboplatin, and Pegylated Liposomal Doxorubicin |  | Bevacizumab and Pegylated Liposomal Doxorubicin: Cycles 1 to 6: Day 1 (pre-infusion, within 10 minutes of EOI); Carboplatin: Cycles 1, 2, 3, 4, 5, 6: Day 1 (pre-infusion, within 10 minutes of EOI; Cycles 1, 3: Days 1 and 2 (6- and 24-hours post-infusion) | 
| Immunogenicity: Number of Participants With Anti-Drug Antibody (ADA) to Mirvetuximab Soravtansine |  | Baseline up to approximately 5.3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epithelial ovarian cancer, Fallopian tube cancer, Primary peritoneal cancer, IMGN853, ADC, Antibody drug conjugate, ImmunoGen, Antibody, Phase 1, Folate receptor alpha