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

• ClinicalTrials.gov Identifier: NCT02606305
• Recruitment Status: Completed
• First Posted: November 17, 2015
• Results First Posted: February 14, 2024
• Last Update Posted: February 14, 2024
• Sponsor: ImmunoGen, Inc.
• Information provided by (Responsible Party): ImmunoGen, Inc.

Tracking Information

• First Submitted Date: November 6, 2015
• First Posted Date: November 17, 2015
• Results First Submitted Date: June 12, 2023
• Results First Posted Date: February 14, 2024
• Last Update Posted Date: February 14, 2024
• Actual Study Start Date: March 2, 2016
• Actual Primary Completion Date: March 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2024)

• 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.
• 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.

• Original Primary Outcome Measures (submitted: November 13, 2015): Number of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), incidence of adverse events, clinically significant changes in laboratory/clinical tests and dose-limiting toxicities (DLTs) as a measure of safety and tolerability. [ Time Frame: Up to 2.5 years ]

Current Secondary Outcome Measures (submitted: January 19, 2024)

• Dose Escalation (Regimens A Through D): ORR; Percentage of Participants With Confirmed Response, as Assessed by 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 (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.
• 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 [ Time Frame: From first dose of study drug until the date of PD or death by any cause (maximum exposure: 238.3 weeks) ]
  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.
• Duration of Response (DOR) Per RECIST v1.1 by Investigator Assessment [ Time Frame: From the date of first objective response to the time of PD (maximum exposure: 238.3 weeks) ]
  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.
• Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA)-125 Clinical Response Rate by Investigator Assessment [ Time Frame: From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks) ]
  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.
• Pharmacokinetics (PK) Parameter: Maximum Plasma Concentration (Cmax) of Mirvetuximab Soravtansine and Total Antibody [ Time Frame: 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) ]
  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).
• PK Parameter: Cmax of N2'-[4-[(3-carboxypropyl)Dithio]-4-methyl-1-oxo-2-sulfopentyl]-N2'-Deacetylmaytansine (DM4) and S-methyl DM4 (SmDM4) [ Time Frame: 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) ]
  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.
• PK Parameter: Area Under the Time-Concentration Curve From Time 0 To Infinite Time (AUCinf) of Mirvetuximab Soravtansine and Total Antibody [ Time Frame: 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) ]
  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.
• PK Parameter: AUCinf of Intact DM4 and SmDM4 [ Time Frame: 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) ]
  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.
• PK Parameter: Terminal Half-Life (t½) of Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4 [ Time Frame: 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) ]
  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.
• PK Parameter: Clearance (CL) of Mirvetuximab Soravtansine and Total Antibody [ Time Frame: 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) ]
  Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.
• PK Parameter: CL of DM4 and SmDM4 [ Time Frame: 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) ]
  Blood samples from participants were analyzed to characterize the PK of mirvetuximab soravtansine when administered in 3- or 4-week cycles.
• PK Parameter: Volume of Distribution at Steady State (Vss) of Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4 [ Time Frame: 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) ]
  Blood samples from participants were analyzed to characterize PK when administered in 3- or 4-week cycles.
• PK Parameter: Time to Reach Cmax (Tmax) of Mirvetuximab Soravtansine, Total Antibody, DM4, and SmDM4 [ Time Frame: 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) ]
  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.
• Plasma Concentration of Bevacizumab [ Time Frame: At end of infusion (EOI) of Cycle 1; and at pre-infusion and EOI of Cycles 2 to 6 ]
  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.
• Plasma Concentration of Carboplatin [ Time Frame: 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 ]
  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.
• Plasma Concentration of Pegylated Liposomal Doxorubicin [ Time Frame: At end of infusion of Cycle 1; and at pre-infusion and end of infusion of Cycles 2 to 6 ]
  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.
• Immunogenicity: Number of Participants With Anti-Drug Antibody (ADA) Response to Mirvetuximab Soravtansine [ Time Frame: From first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 283.3 weeks) ]
  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).

Original Secondary Outcome Measures (submitted: November 13, 2015)

• Objective response rate (ORR); the proportion of patient achieving a complete response, partial response or stable disease (CR, PR or SD) according to RECIST1.1 and CA125 evaluations [ Time Frame: Up to 2.5 years ]
• Duration of response (DOR); the time from initial response until progressive disease, will be estimated for all patients who achieve a confirmed objective response (PR or CR) [ Time Frame: Up to 2.5 years ]
• Progression-free survival (PFS); the time from date of first dose until the date of objective disease progression or death by any cause as defined by RECIST 1.1 [ Time Frame: Up to 2.5 years ]
• PK parameters: maximum plasma concentration (Cmax) of IMGN853, bevacizumab, carboplatin and PLD [ Time Frame: Up to 2.5 years ]
• PK parameters: area under the time-concentration curve (AUC) of IMGN853, bevacizumab, carboplatin and PLD [ Time Frame: Up to 2.5 years ]
• PK parameters: terminal half-life (t½) of IMGN853, bevacizumab, carboplatin and PLD [ Time Frame: Up to 2.5 years ]
• PK parameters: clearance (Cl) of IMGN853, bevacizumab, carboplatin and PLD [ Time Frame: Up to 2.5 years ]
• PK parameters: volume of distribution at steady state (Vss) of IMGN853, bevacizumab, carboplatin and PLD [ Time Frame: Up to 2.5 years ]
• PK parameters: maximum time (Tmax) of IMGN853, bevacizumab, carboplatin and PLD [ Time Frame: Up to 2.5 years ]
• Immunogenicity: Presence of Anti-Drug Antibody (ADA) [ Time Frame: Up to 2.5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Epithelial Ovarian Cancer
• Primary Peritoneal Cancer
• Fallopian Tube Cancer

Intervention

• Drug: Mirvetuximab soravtansine
  Other Name: IMGN853
• Drug: Bevacizumab
• Drug: Carboplatin
• Drug: Pegylated Liposomal Doxorubicin
• Drug: Pembrolizumab

Study Arms

• 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.
  Interventions:

  • Drug: Mirvetuximab soravtansine
  • Drug: Bevacizumab
• Experimental: Regimen B (Mirvetuximab soravtansine + Carboplatin)
  Mirvetuximab soravtansine + Carboplatin administered on Day 1 of each 21-day cycle in Dose Escalation phase.
  Interventions:

  • Drug: Mirvetuximab soravtansine
  • Drug: Carboplatin
• 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.
  Interventions:

  • Drug: Mirvetuximab soravtansine
  • Drug: Pegylated Liposomal Doxorubicin
• 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.
  Interventions:

  • Drug: Mirvetuximab soravtansine
  • Drug: Pembrolizumab
• Experimental: Regimen E (Mirvetuximab soravtansine + Bevacizumab + Carboplatin)
  Mirvetuximab soravtansine + Bevacizumab + Carboplatin administered on Day 1 of each 21-day cycle in Dose Expansion phase.
  Interventions:

  • Drug: Mirvetuximab soravtansine
  • Drug: Bevacizumab
  • Drug: Carboplatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 8, 2021): 264
• Original Estimated Enrollment (submitted: November 13, 2015): 145
• Actual Study Completion Date: March 12, 2021
• Actual Primary Completion Date: March 12, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Spain, United States

Administrative Information

• NCT Number: NCT02606305
• Other Study ID Numbers: IMGN853-0402; KEYNOTE PN409 ( Other Identifier: Merck )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: ImmunoGen, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: ImmunoGen, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: ImmunoGen, Inc.
• Verification Date: January 2024