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

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

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. All mirvetuximab soravtansine doses were calculated according to adjusted ideal body weight.

Study Overview

• Status: Completed
• Conditions: Fallopian Tube Cancer; Epithelial Ovarian Cancer; Primary Peritoneal Cancer
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Carboplatin; Drug: Bevacizumab; Drug: Pegylated Liposomal Doxorubicin; Drug: Mirvetuximab soravtansine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 264
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg - Leuvens Kankerinstituut
• Canada
  • Montreal, Canada
    • Centre hospitalier de l'Université de Montréal (CHUM)
  • Montreal, Canada
    • McGill University Health Center
• Spain
  • Barcelona, Spain
    • Hospital Vall d'Hebron
  • Madrid, Spain, 28033
    • MD Anderson
• United States
  • California
    • Los Angeles, California, United States
      • University of California at Los Angeles
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Nevada
    • Reno, Nevada, United States
      • City of Hope
  • Ohio
    • Hilliard, Ohio, United States, 43026
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Peggy and Charles Stephenson Oklahoma Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer
• Folate receptor α (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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Adverse events (AEs) were any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function that developed or worsened during the clinical study, not necessarily having a causal relationship to study drug. Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death. Serious AEs included death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes previously listed. TEAEs were any AE that emerged on or after the first dose, and within 30 days of the last dose. Serious and other non-serious AEs regardless of causality are reported in the AE module.	From first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 238.3 weeks)
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	ORR was defined as percentage of participants with confirmed response (complete response [CR] + partial response [PR]). CR: Disappearance of all target or non-target lesions. All pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR: At least 30 percent (%) decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD. The 95% confidence interval (CI) was based on binomial distribution.	From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation (Regimens A Through D): ORR; Percentage of Participants With Confirmed Response, as Assessed by RECIST Version 1.1	ORR was defined as percentage of participants with confirmed response (CR + PR). CR: Disappearance of all target or non-target lesions. All pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least 30% decrease in the SLD of target lesions, taking as reference the baseline SLD.	From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks)
Progression-Free Survival (PFS); Time From the Date Of First Dose Until The Date Of Progressive Disease (PD) Or Death By Any Cause, As Defined By RECIST Version 1.1	PFS was defined as the time from the date of the first dose of study drug until the date of PD or death from any cause, whichever occurred first, estimated using the Kaplan-Meier method. PFS was defined based on radiological assessments and determined by the investigator. PD was defined as at least a 20% increase in the SLD of target lesions, taking as reference the smallest (nadir) SLD since and including baseline. In addition to the relative increase of 20%, the SLD must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of non-target lesions and appearance of new lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.	From first dose of study drug until the date of PD or death by any cause (maximum exposure: 238.3 weeks)
Duration of Response (DOR) Per RECIST v1.1 by Investigator Assessment	DOR was defined as the time from the date of the first response (CR or PR), to the date of PD or death from any cause, whichever occurred first. DOR was only defined for patients who had a best overall response of CR or PR, estimated using the Kaplan-Meier method. The response-evaluable population included all patients with radiographic assessment at baseline, who received at least 1 dose of combination treatment and had at least 1 post-dose radiographic tumor assessment or who died within 105 days of first dose.	From the date of first objective response to the time of PD (maximum exposure: 238.3 weeks)
Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA)-125 Clinical Response Rate by Investigator Assessment	A CA-125 response was defined as a ≥ 50% reduction in CA-125 levels from baseline. GCIG CA125 response rate was defined as the number of participants with a CA-125 confirmed response divided by the number of participants in the CA-125 response-evaluable population multiplied by 100. The CA-125 evaluable population included all participants whose pretreatment sample was ≥2.0 times the upper limit of normal, within 2 weeks prior to the first dose of combination treatment, and who had at least 1 post-baseline CA-125 evaluation.	From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks)
Pharmacokinetics (PK) Parameter: Maximum Plasma Concentration (Cmax) of Mirvetuximab Soravtansine and Total Antibody	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles. Results are reported in micrograms/milliliter (µg/mL).	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: Cmax of N2'-[4-[(3-carboxypropyl)Dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2'-Deacetylmaytansine (DM4) and S-methyl DM4 (SmDM4)	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles. Results are reported in nanograms (ng)/mL.	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 From Time 0 To Infinite Time (AUCinf) of Mirvetuximab Soravtansine and Total Antibody	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles. Results are reported in mg*hours (h)/mL.	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: AUCinf of Intact DM4 and SmDM4	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles. Note that '9999' is used because AUCinf cannot be calculated for n<3.	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 Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles. PK parameters were calculated using standard non-compartmental methods. The terminal t½ is an estimate (extrapolation) of the time it takes for the concentration or amount in the body of that drug to be reduced by exactly one-half (50%). If extrapolated AUC was greater than 20% (due to insufficient number of participants with data samples) the upper range of t½ was not reported.	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 (up to 336 hours) (additionally at Day 22 for Regimen C)
PK Parameter: Clearance (CL) of Mirvetuximab Soravtansine and Total Antibody	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.	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: CL of DM4 and SmDM4	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.	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 Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4	Blood samples from participants were analyzed to characterize PK when administered in 3- or 4-week cycles.	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 Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4	Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles. PK parameters were derived using non-compartmental PK analysis.	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 (up to 336 hours) (additionally at Day 22 for Regimen C)
Plasma Concentration of Bevacizumab	Blood samples from participants at the end of infusion were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.	At end of infusion (EOI) of Cycle 1; and at pre-infusion and EOI of Cycles 2 to 6
Plasma Concentration of Carboplatin	Blood samples from participants at the end of infusion were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.	At end of infusion, 6 and 24 hours post-infusion of Cycle 1; and at pre-infusion and end of infusion of Cycles 2, 4, 5 and 6; at pre-infusion, end of infusion and 6 and 24 hours post-infusion of Cycle 3
Plasma Concentration of Pegylated Liposomal Doxorubicin	Blood samples from participants at the end of infusion were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.	At end of infusion of Cycle 1; and at pre-infusion and end of infusion of Cycles 2 to 6
Immunogenicity: Number of Participants With Anti-Drug Antibody (ADA) Response to Mirvetuximab Soravtansine	Blood samples were collected to measure the presence of ADAs for mirvetuximab soravtansine. Seronegative is defined as a participant that tests negative at all visits. Treatment-emergent ADA is defined as a participant that is seronegative prior to dosing on Day 1 of Cycle 1 and tests positive in both screening and confirmatory assays at one or more subsequent visits. Treatment-unaffected ADA is defined as a participant test positive in both screening and confirmatory assays prior to dosing on Day 1 of Cycle 1 with a post-dose titer increase of less than or equal to 4-fold (based on a 2-fold sample dilution). Treatment-boosted ADA is defined as a participant test positive in both screening and confirmatory assays prior to dosing on Day 1 of Cycle 1 with a post-dose titer increase of more than a 4-fold increase (based on a 2-fold sample dilution).	From first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 283.3 weeks)

Collaborators and Investigators

• Sponsor: ImmunoGen, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2016
• Primary Completion (Actual): March 12, 2021
• Study Completion (Actual): March 12, 2021

Study Registration Dates

• First Submitted: November 6, 2015
• First Submitted That Met QC Criteria: November 13, 2015
• First Posted (Estimated): November 17, 2015

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Phase 1; Antibody; ADC; Antibody drug conjugate; Primary peritoneal cancer; Fallopian tube cancer; Epithelial ovarian cancer; IMGN853; ImmunoGen; Folate receptor alpha; Mirvetuximab
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Peritoneal Diseases; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Digestive System Neoplasms; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Abdominal Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Immunoconjugates; Carboplatin; Bevacizumab; Pembrolizumab; Doxorubicin; Liposomal doxorubicin; Maytansine; Mirvetuximab soravtansine
• Other Study ID Numbers: IMGN853-0402; KEYNOTE PN409 (Other Identifier: Merck)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No