A Study of Mirvetuximab Soravtansine vs. Investigator's Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

Study Overview
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Brief Summary
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This Phase 3 study is designed to compare the efficacy and safety of mirvetuximab soravtansine vs. investigator's choice chemotherapy in patients with platinum-resistant high-grade epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, whose tumors express a high-level of FRα. Patients will be, in the opinion of the Investigator, appropriate for single-agent therapy for their next line of therapy. Folate receptor alpha (FRα) positivity will be defined by the Ventana FOLR1 (FOLR1-2.1) CDx assay.

Detailed Description
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Patients will be randomized to either mirvetuximab soravtansine (MIRV) or Investigator's Choice chemotherapy (paclitaxel, PEGylated liposomal doxorubicin, or topotecan).

Official Title
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MIRASOL: A Randomized, Open-label, Phase 3 Study of Mirvetuximab Soravtansine vs. Investigator's Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

Conditions
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Epithelial Ovarian Cancer, Peritoneal Cancer, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: Mirvetuximab Soravtansine
* Drug: Paclitaxel
* Drug: Topotecan
* Drug: Pegylated liposomal doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients ≥ 18 years of age Patients must have a confirmed diagnosis of high-grade serious epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer Patients must have platinum-resistant disease: Patients who have only had 1 line of platinum based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between >3 months and ≤ 6 months after the date of the last dose of platinum Patients who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression. Note: Patients who are platinum-refractory during front-line treatment are excluded Patients must have progressed radiographically on or after their most recent line of therapy Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low risk, medically routine procedure for IHC confirmation of FRα positivity Patient's tumor must be positive for FRα expression as defined by the Ventana FOLR1 (FOLR-2.1) CDx assay Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator) Patients must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment: Adjuvant ± neoadjuvant considered one line of therapy Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (ie, not counted independently) Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (ie, not counted independently) Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 Time from prior therapy: Systemic antineoplastic therapy (5 half-lives or 4 weeks, whichever is shorter) Focal radiation completed at least 2 weeks prior to first dose of study drug Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities Major surgery must be completed at least 4 weeks prior to first dose and have recovered or stabilized from the side effects of prior surgery Patients must have adequate hematologic, liver and kidney functions defined as: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1,500/μL) without G-CSF in the prior 10 days or long-acting WBC growth factors in the prior 20 days Platelet count ≥ 100 x 10^9/L (100,000/μL) without platelet transfusion in the prior 10 days Hemoglobin ≥ 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 21 days Serum creatinine ≤ 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN Serum albumin ≥ 2 g/dL Patients or their legally authorized representative must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) (as defined in Section 5.9.6 in the protocol) while on study drug and for at least 3 months after the last dose of MIRV or at least 6 months after the last dose of paclitaxel, pegylated liposomal doxorubicin, or topotecan WCBP must have a negative pregnancy test within 4 days prior to the first dose of study drug Exclusion Criteria: Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade or borderline ovarian tumor Patients with primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first line platinum-containing chemotherapy Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow Patients with > Grade 1 peripheral neuropathy per CTCAE v5.0 Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following: Active hepatitis B or C infection (whether or not on active antiviral therapy) HIV infection Active cytomegalovirus infection Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before starting study drug Note: Testing at screening is not required for the above infections unless clinically indicated Patients with history of multiple sclerosis or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome) Patients with clinically significant cardiac disease including, but not limited to, any one of the following: Myocardial infarction ≤ 6 months prior to first dose Unstable angina pectoris Uncontrolled congestive heart failure (New York Heart Association > class II) Uncontrolled ≥ Grade 3 hypertension (per CTCAE) Uncontrolled cardiac arrhythmias Patients assigned to PLD stratum only: Left ventricular ejection fraction (LVEF) below the institutional limit of normal as measured by echocardiography (ECHO) or multigated acquisition (MUGA) scan Patients with a history of hemorrhagic or ischemic stroke within six months prior to randomization Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C) Patients with a previous clinical diagnosis of non-infectious interstitial lung disease (ILD), including noninfectious pneumonitis Patients with required use of folate-containing supplements (eg, folate deficiency) Patients with prior hypersensitivity to monoclonal antibodies Women who are pregnant or lactating Patients with prior treatment with MIRV or other FRα-targeting agents Patients with untreated or symptomatic central nervous system (CNS) metastases Patients with a history of other malignancy within 3 years prior to randomization. Note: does not include tumors with a negligible risk for metastasis or death (eg, adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast Prior known hypersensitivity reactions to study drugs and/or any of their excipients People who are detained through a court or administrative decision, receiving psychiatric care against their will, adults who are the subject of a legal protection order (under tutorship/curatorship), people who are unable to express their consent, and people who are subject to a legal guardianship order Simultaneous participation in another research study, in countries or localities where this is the health authority guidance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mirvetuximab soravtansine (MIRV; IMGN853)<br>MIRV 6 mg/kg adjusted ideal body weight (AIBW) every 3 weeks (Q3W) | Drug: Mirvetuximab Soravtansine<br>* Mirvetuximab soravtansine is an antibody drug conjugate designed to target folate receptor α (FRα). It consists of the humanized anti-FRα mAb M9346A attached via a cleavable disulfide linker to the cytotoxic maytansinoid, DM4.<br>* Other names: IMGN853;|
| Active Comparator: Investigator's choice of chemotherapy<br>Paclitaxel (Pac; 80 mg/m2) administered once per week (QW) within a 4-week cycle Pegylated liposomal doxorubicin (PLD; 40 mg/m2) administered every 4 weeks (Q4W) Topotecan (Topo; 4 mg/m2) administered either on Days 1, 8, and 15 every 4 weeks or for 5 consecutive days (1.25 mg/m2 Days 1-5) every 3 weeks (Q3W) | Drug: Paclitaxel<br>* Paclitaxel is a taxane that can stabilize microtubules to inhibit cell division. It was approved for treatment of recurrent epithelial ovarian cancer.<br>Drug: Topotecan<br>* Topotecan induces irreversible DNA damage. It inhibits topoisomerase 1, leading to both single and double strand DNA break that eventually promote apoptosis. Topotecan was approved for treatment of epithelial ovarian cancer after failure of initial or subsequent chemotherapy.<br>Drug: Pegylated liposomal doxorubicin<br>* Pegylated liposomal doxorubicin is a standard chemotherapy regimen used for treating platinum-resistant ovarian cancer. The active component doxorubicin is an anthracycline that intercalates DNA, leading to inhibition of replication and subsequently, the inhibition of proper cell division.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The time from date of randomization until Investigator-assessed progressive disease or death, whichever occurs first. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Adverse events (AEs) will be evaluated according to the NCI CTCAE v5.0. AEs will be coded using the latest Medical Dictionary for Regulatory Activities (MedDRA) version and summarized per system organ class (SOC) and preferred term (PT). | Up to 2 years | 
| Objective Response Rate (ORR) | Objective response includes best response of complete response (CR) or partial response (PR). | Up to 2 years | 
| Overall survival | The time from date of randomization until the date of death | Up to 2 years | 
| Primary patient-reported outcomes | The number of patients achieving at least 15 point absolute improvement at Week 8 or Week 9 in the abdominal/GI scale of the European Organization for Research and Treatment of Cancer (EORTC) ovarian cancer specific quality of life questionnaire (QLQ-OV28). A higher score represents a better quality of life. | Up to 2 years | 
| Duration of response (DOR) | The time from initial response until Investigator-assessed progressive disease for all patients who achieve a confirmed objective response | Up to 2 years | 
| CA-125 response | Serum CA-125 response determined using the GCIG criteria | Up to 2 years | 
| Progression-free survival 2 (PFS 2) | The time from date of randomization until second disease progression or death whichever occurs first. Results will be summarized by arm | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Platinum-resistant, Folate-receptor alpha expression, Phase 3, Antibody-drug conjugate, mirvetuximab soravtansine, IMGN853, Epithelial Ovarian Cancer, Peritoneal Cancer, Fallopian Tube Cancer