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A Study of Mirvetuximab Soravtansine vs. Investigator's Choice of Chemotherapy in Women With Folate Receptor (FR) Alpha Positive Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal or Fallopian Tube Cancer (FORWARD I)

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ClinicalTrials.gov Identifier: NCT02631876
Recruitment Status : Completed
First Posted : December 16, 2015
Results First Posted : June 9, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborator:
Gynecologic Oncology Group
Information provided by (Responsible Party):
ImmunoGen, Inc.

Tracking Information
First Submitted Date  ICMJE December 10, 2015
First Posted Date  ICMJE December 16, 2015
Results First Submitted Date  ICMJE May 6, 2020
Results First Posted Date  ICMJE June 9, 2020
Last Update Posted Date October 14, 2020
Actual Study Start Date  ICMJE March 2, 2016
Actual Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2020)
  • Progression-Free Survival (PFS), as Assessed by BIRC Per RECIST Version 1.1 in All Participants Randomized to the Study [ Time Frame: From the date of randomization until the time of death or PD (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    PFS was defined as the time from randomization until PD or death whichever occurred first, estimated using the Kaplan-Meier method. PD: At least a 20% increase in the sum of the longest diameters (SoD) of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD 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.
  • PFS, as Assessed by BIRC Per RECIST Version 1.1 in Participants With High Folate Receptor Alpha Level (≥ 75% of Tumor Staining) [ Time Frame: From the date of randomization until the time of death or PD (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    PFS was defined as the time from randomization until PD or death whichever occurred first, estimated using the Kaplan-Meier method. PD: At least a 20% increase in the SoD of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 11, 2015)
Number of treatment emergent adverse events (TEAEs) and clinically significant changes in laboratory/clinical tests as a measure of safety [ Time Frame: Up to 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2020)
  • Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by BIRC Per RECIST1.1 [ Time Frame: From randomization until first BOR of CR or PR (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    ORR was defined as percentage of participants with a best overall response (BOR) of complete response (CR) or 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 SoD of target lesions, taking as reference the baseline SoD.
  • Overall Survival (OS) [ Time Frame: From the date of randomization until the time of death (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    OS was defined as the time from the date of randomization until the date of death from any cause. Participants who did not experience the event of death were censored at their last date known to be alive. OS was estimated using the Kaplan-Meier method.
  • Number of Participants Achieving at Least a 15% (≥ 15-Point) Absolute Improvement From Baseline on the EORTC QLQ-OV28 Abdominal/Gastrointestinal (AB/GI) Symptom Subscale at Week 8/9 Assessment [ Time Frame: Baseline, Week 8/9 ]
    European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer 28 (EORTC QLQ-OV28) is a 28-item ovarian cancer supplemental module. It comprises of 6 symptom scales (AB/GI symptoms, peripheral neuropathy, other chemotherapy side-effects, hormonal symptoms, body image, attitude to disease, treatment), and sexual functioning. Participants were asked to indicate extent to which they experienced AB/GI symptoms. Participants responded on a scale of 1-4(1=not at all, 2=a little, 3=quite a bit, 4=very much) to following: Did you have abdominal pain? Did you have a bloated feeling in your abdomen? Did you have problems with your clothes feeling too tight? Did you experience any change in bowel habit as a result of your disease or treatment? Were you troubled by passing wind/gas/flatulence? Have you felt full too quickly after beginning to eat? Have you had indigestion/heartburn? Data were transformed to a scale from 0-100. Lower scores=better health.
  • 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: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    Adverse event (AE): any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to study drug. Severity: graded per National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v4.03 on following scale: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death. Relation of AE to treatment was determined by investigator. Serious AEs: death, life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent/significant disability or incapacity, congenital anomaly or birth defect, or an important medical event that required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs: any AE that emerged on or after the first dose, and within 30 days of the last dose. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported AEs module.
  • Gynecologic Cancer Intergroup (GCIG) CA-125 Response Rate: Percentage of Participants With GCIG CA-125 Confirmed Clinical Responses [ Time Frame: From first dose of study drug until CA-125 response (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    CA-125 Response rate wasdefined 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.
  • PFS, as Assessed by Investigator Per RECIST Version 1.1 [ Time Frame: From the date of randomization until the time of death or PD (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    PFS was defined as the time from randomization until PD or death whichever occurred first, estimated using the Kaplan-Meier method. PD: At least a 20% increase in the SoD of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD 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), as Assessed by BIRC Per RECIST v1.1 [ Time Frame: From the date of first response (CR or PR) until the date of PD (maximum exposure: 86.9 weeks for mirvetuximab soravtansine arm and 62.9 weeks for IC chemotherapy arm) ]
    DOR was defined as the time from the date of the first response (CR or PR), whichever was recorded first, until the date of PD. PD: At least a 20% increase in the SoD of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. DOR was only defined for participants who had a BOR of CR or PR using the method of Kaplan-Meier.
  • Area Under the Plasma Concentration-Versus Time Curve From Time of Dose Until Tlast (AUClast) of Mirvetuximab Soravtansine,Total M9346A Antibody, DM4, and S-methyl DM4 [ Time Frame: Pre-dose and within 5 minutes after mirvetuximab soravtansine infusion on Day 1 of Cycles 1 and 3; and Day 8 and 15 of Cycles 1 and 3 ]
    PK parameters were calculated using standard non-compartmental methods.
  • Number of Participants With Anti-Drug Antibodies (ADA) [ Time Frame: Pre-dose and within 5 minutes after mirvetuximab soravtansine infusion on Day 1 of Cycles 1, 2, and 4; pre-dose on Day 1 of Cycle 6 ]
    An electrochemiluminescent method was used for the detection of anti-mirvetuximab soravtansine antibodies in plasma from samples collected in dipotassium ethylenediaminetetraacetic acid (K2EDTA) tubes. The qualitative assay was designed to detect anti-mirvetuximab soravtansine antibodies in human plasma.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2015)
  • Objective response rate (ORR); the proportion of patients 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 years ]
  • PK parameters: maximum plasma concentration (Cmax) of IMGN853 [ Time Frame: Up to 2 years ]
  • PK parameters: area under the time-concentration curve (AUC) of IMGN853 [ Time Frame: Up to 2 years ]
  • PK parameters: terminal half-life (t½) of IMGN853 [ Time Frame: Up to 2 years ]
  • PK parameters: clearance (Cl) of IMGN853 [ Time Frame: Up to 2 years ]
  • PK parameters: volume of distribution at steady state (Vss) of IMGN853 [ Time Frame: Up to 2 years ]
  • PK parameters: maximum time (Tmax) of IMGN853 [ Time Frame: Up to 2 years ]
  • Immunogenicity: Presence of Anti-Drug Antibody (ADA) [ Time Frame: Up to 2 years ]
  • Quality of life as assessed using Fact-O Questionnaire [ Time Frame: Up to 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Mirvetuximab Soravtansine vs. Investigator's Choice of Chemotherapy in Women With Folate Receptor (FR) Alpha Positive Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal or Fallopian Tube Cancer
Official Title  ICMJE FORWARD I: A Randomized, Open Label Phase 3 Study to Evaluate the Safety and Efficacy of Mirvetuximab Soravtansine (IMGN853) Versus Investigator's Choice of Chemotherapy in Women With Folate Receptor Alpha Positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer
Brief Summary This is a Phase 3, open label, randomized study designed to compare the safety and efficacy of mirvetuximab soravtansine to that of selected single-agent chemotherapy (Investigator's choice) in women with platinum-resistant FR-alpha positive advanced EOC, primary peritoneal cancer and/or fallopian tube cancer.
Detailed Description Participants will be randomized to either mirvetuximab soravtansine or investigator's choice chemotherapy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Epithelial Ovarian Cancer
  • Primary Peritoneal Carcinoma
  • Fallopian Tube Cancer
  • Ovarian Cancer
Intervention  ICMJE
  • Drug: Mirvetuximab soravtansine
    Mirvetuximab Soravtansine will be administered per dose and schedule specified in the arm.
  • Drug: Paclitaxel
    Paclitaxel will be administered per dose and schedule specified in the arm.
  • Drug: Pegylated liposomal doxorubicin
    Pegylated liposomal doxorubicin will be administered per dose and schedule specified in the arm.
  • Drug: Topotecan
    Topotecan will be administered per dose and schedule specified in the arm.
Study Arms  ICMJE
  • Experimental: Mirvetuximab Soravtansine
    Participants will receive mirvetuximab soravtansine at 6 milligrams/kilogram (mg/kg) adjusted ideal body weight (AIBW) administered intravenously (IV) on Day 1 of a 3 week cycle. Participants will continue to receive study drug until they experience progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (as assessed by the blinded independent review committee [BIRC]), experience unacceptable toxicity, or withdraw consent, whichever comes first, or until the sponsor terminate the study. (Maximum exposure: 86.9 weeks)
    Intervention: Drug: Mirvetuximab soravtansine
  • Experimental: Investigator's Choice (IC) Chemotherapy
    Participants will receive a dose of IC chemotherapeutic agent calculated using body surface area (BSA). Paclitaxel will be administered at 80 milligrams/square meter (mg/m^2) as a 1-hour IV infusion on Days 1, 8, 15, and 22 of a 4-week cycle; or topotecan will be administered at 4 mg/m^2 over 30 minutes on Days 1, 8, and 15 of a 4-week cycle. Alternatively, topotecan could be administered at 1.25 mg/m^2 over 30 minutes on Days 1 to 5 of a 3-week cycle; or pegylated liposomal doxorubicin will be administered at 40 mg/m^2 as a 1 mg/minute IV infusion on Day 1 of a 4-week cycle. After Cycle 1, if tolerated, pegylated liposomal doxorubicin could be administered as a 1-hour infusion. Participants will continue to receive study drug until they experience PD per RECIST version 1.1 (as assessed by BIRC), experience unacceptable toxicity, or withdraw consent, whichever comes first, or until the sponsor terminate the study. (Maximum exposure: 62.9 weeks)
    Interventions:
    • Drug: Paclitaxel
    • Drug: Pegylated liposomal doxorubicin
    • Drug: Topotecan
Publications * Moore KN, Oza AM, Colombo N, Oaknin A, Scambia G, Lorusso D, Konecny GE, Banerjee S, Murphy CG, Tanyi JL, Hirte H, Konner JA, Lim PC, Prasad-Hayes M, Monk BJ, Pautier P, Wang J, Berkenblit A, Vergote I, Birrer MJ. Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann Oncol. 2021 Jun;32(6):757-765. doi: 10.1016/j.annonc.2021.02.017. Epub 2021 Mar 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 16, 2019)
366
Original Estimated Enrollment  ICMJE
 (submitted: December 11, 2015)
247
Actual Study Completion Date  ICMJE January 2020
Actual Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participants must be diagnosed with advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer
  • Participants must have folate receptor alpha positive tumor expression as defined in the protocol
  • Participants must have platinum-resistant ovarian cancer, defined as progression within 6 months from completion of a minimum of four cycles of platinum-containing therapy.
  • Participants must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment
  • Participants must have at least one lesion that meets the definition of measurable disease by RECIST 1.1

Exclusion Criteria:

  • Diagnosis of clear cell, low grade ovarian cancer or mixed tumors
  • Participants with primary platinum-refractory disease
  • Serious concurrent illness or clinically relevant active infection as defined in the protocol
  • Prior treatment with mirvetuximab soravtansine
  • Women who are pregnant or breast feeding
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Bosnia and Herzegovina,   Canada,   Czechia,   France,   Ireland,   Italy,   Russian Federation,   Serbia,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02631876
Other Study ID Numbers  ICMJE IMGN853-0403
Has Data Monitoring Committee Yes
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  ICMJE Not Provided
Current Responsible Party ImmunoGen, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE ImmunoGen, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Gynecologic Oncology Group
Investigators  ICMJE
Study Director: CMO ImmunoGen ImmunoGen, Inc.
PRS Account ImmunoGen, Inc.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP