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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
264
University of California at Los Angeles
Los Angeles, California, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
City of Hope
Reno, Nevada, United States
The Ohio State University
Hilliard, Ohio, United States
Peggy and Charles Stephenson Oklahoma Cancer Center
Oklahoma City, Oklahoma, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg - Leuvens Kankerinstituut
Leuven, Belgium
Centre Hospitalier de l'universite de Montreal (CHUM)
Montreal, Canada
McGill University Health Center
Montreal, Canada
...and 2 more locations
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.
Time frame: 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.
Time frame: From first dose of study drug until first CR or PR (maximum exposure: 238.3 weeks)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
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)
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.
Time frame: 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.
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
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.
Time frame: 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).
Time frame: From first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 283.3 weeks)
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