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
Overview
- Phase
- Phase 1
- Intervention
- Mirvetuximab soravtansine
- Conditions
- Epithelial Ovarian Cancer
- Sponsor
- ImmunoGen, Inc.
- Enrollment
- 264
- Locations
- 12
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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.
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Regimen A (Mirvetuximab soravtansine + Bevacizumab)
Mirvetuximab soravtansine + Bevacizumab administered on Day 1 of each 21-day cycle in Dose Escalation and Dose Expansion phase.
Intervention: Mirvetuximab soravtansine
Regimen A (Mirvetuximab soravtansine + Bevacizumab)
Mirvetuximab soravtansine + Bevacizumab administered on Day 1 of each 21-day cycle in Dose Escalation and Dose Expansion phase.
Intervention: Bevacizumab
Regimen B (Mirvetuximab soravtansine + Carboplatin)
Mirvetuximab soravtansine + Carboplatin administered on Day 1 of each 21-day cycle in Dose Escalation phase.
Intervention: Mirvetuximab soravtansine
Regimen B (Mirvetuximab soravtansine + Carboplatin)
Mirvetuximab soravtansine + Carboplatin administered on Day 1 of each 21-day cycle in Dose Escalation phase.
Intervention: Carboplatin
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.
Intervention: Mirvetuximab soravtansine
Regimen E (Mirvetuximab soravtansine + Bevacizumab + Carboplatin)
Mirvetuximab soravtansine + Bevacizumab + Carboplatin administered on Day 1 of each 21-day cycle in Dose Expansion phase.
Intervention: Carboplatin
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.
Intervention: Pegylated Liposomal Doxorubicin
Regimen D (Mirvetuximab soravtansine + Pembrolizumab)
Mirvetuximab soravtansine + Pembrolizumab administered on Day 1 of each 21-day cycle in Dose Escalation and Dose Expansion phase.
Intervention: Mirvetuximab soravtansine
Regimen D (Mirvetuximab soravtansine + Pembrolizumab)
Mirvetuximab soravtansine + Pembrolizumab administered on Day 1 of each 21-day cycle in Dose Escalation and Dose Expansion phase.
Intervention: Pembrolizumab
Regimen E (Mirvetuximab soravtansine + Bevacizumab + Carboplatin)
Mirvetuximab soravtansine + Bevacizumab + Carboplatin administered on Day 1 of each 21-day cycle in Dose Expansion phase.
Intervention: Mirvetuximab soravtansine
Regimen E (Mirvetuximab soravtansine + Bevacizumab + Carboplatin)
Mirvetuximab soravtansine + Bevacizumab + Carboplatin administered on Day 1 of each 21-day cycle in Dose Expansion phase.
Intervention: Bevacizumab
Outcomes
Primary Outcomes
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
Time Frame: From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks)
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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time Frame: From first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 238.3 weeks)
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.
Secondary Outcomes
- PK Parameter: Time to Reach Cmax (Tmax) of Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4(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(At end of infusion (EOI) of Cycle 1; and at pre-infusion and EOI of Cycles 2 to 6)
- Dose Escalation (Regimens A Through D): ORR; Percentage of Participants With Confirmed Response, as Assessed by RECIST Version 1.1(From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks))
- Duration of Response (DOR) Per RECIST v1.1 by Investigator Assessment(From the date of first objective response to the time of PD (maximum exposure: 238.3 weeks))
- Pharmacokinetics (PK) Parameter: Maximum Plasma Concentration (Cmax) of Mirvetuximab Soravtansine and Total Antibody(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: CL of DM4 and SmDM4(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: Area Under the Time-Concentration Curve From Time 0 To Infinite Time (AUCinf) of Mirvetuximab Soravtansine and Total Antibody(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))
- Immunogenicity: Number of Participants With Anti-Drug Antibody (ADA) Response to Mirvetuximab Soravtansine(From first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 283.3 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(From first dose of study drug until the date of PD or death by any cause (maximum exposure: 238.3 weeks))
- PK Parameter: AUCinf of Intact DM4 and SmDM4(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(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))
- Plasma Concentration of Carboplatin(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)
- Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA)-125 Clinical Response Rate by Investigator Assessment(From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks))
- PK Parameter: Cmax of N2'-[4-[(3-carboxypropyl)Dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2'-Deacetylmaytansine (DM4) and S-methyl DM4 (SmDM4)(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: Terminal Half-Life (t½) of Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4(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(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))
- Plasma Concentration of Pegylated Liposomal Doxorubicin(At end of infusion of Cycle 1; and at pre-infusion and end of infusion of Cycles 2 to 6)