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

Fallopian Tube Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02606305
• Other study ID #: IMGN853-0402
• Secondary ID: KEYNOTE PN409
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 2, 2016
• Est. completion date: March 12, 2021

Study information

• Verified date: June 2024
• Source: ImmunoGen, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 264
• Est. completion date: March 12, 2021
• Est. primary completion date: March 12, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosed with advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer

• Folate receptor a (FRa) 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

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Epithelial Ovarian Cancer
• Fallopian Tube Cancer
• Fallopian Tube Neoplasms
• Ovarian Neoplasms
• Peritoneal Neoplasms
• Primary Peritoneal Cancer

Intervention

Drug:
• Mirvetuximab soravtansine

• Bevacizumab

• Carboplatin

• Pegylated Liposomal Doxorubicin

• Pembrolizumab

Locations

Country	Name	City	State
Belgium	Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg - Leuvens Kankerinstituut	Leuven
Canada	Centre Hospitalier de l'universite de Montreal (CHUM)	Montreal
Canada	McGill University Health Center	Montreal
Spain	Hospital Vall D'Hebron	Barcelona
Spain	MD Anderson	Madrid
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Ohio State University	Hilliard	Ohio
United States	University of California at Los Angeles	Los Angeles	California
United States	Peggy and Charles Stephenson Oklahoma Cancer Center	Oklahoma City	Oklahoma
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	City of Hope	Reno	Nevada

Sponsors (1)

Lead Sponsor	Collaborator
ImmunoGen, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)