Mirvetuximab Soravtansine Monotherapy in Platinum-Sensitive Epithelial, Peritoneal, and Fallopian Tube Cancers (PICCOLO)

PICCOLO (IMGN853-0419) is a Phase 2 multicenter, open label study designed to evaluate the safety and efficacy of Mirvetuximab Soravtansine in participants with platinum-sensitive ovarian, primary peritoneal or fallopian tube cancers with high folate receptor-alpha (FRα) expression.

Mirvetuximab Soravtansine (MIRV) is an investigational antibody drug conjugate designed to selectively kill cancer cells. The antibody (protein) part of MIRV targets tumors by delivering a cell-killing drug to the tumor cells carrying a tumor-associated protein called folate receptor alpha (FRα). It is being developed for the treatment of subjects with recurrent platinum-sensitive, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Patients will have had at least 2 prior lines of therapy. These will include at least 2 lines of platinum-containing therapy or 1 line with a documented platinum allergy. FRα positivity will be defined by the Ventana FOLR1 (FOLR1- 2.1) CDx assay (Ventana FOLR1 Assay)

Eligibility Criteria:
Key Inclusion Criteria:

1. Patients ≥ 18 years of age
2. Patients must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
3. Patients must have a confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer
4. Patients must have platinum-sensitive disease defined as radiographic progression greater than 6 months from last dose of most recent platinum therapy 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
5. Patients must have progressed radiographically on or after their most recent line of anticancer therapy
6. Patients must have at least 1 lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator)
7. 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 immunohistochemistry (IHC) confirmation of FRα positivity
8. Patient's tumor must be positive for FRα expression as defined by the Ventana FOLR1 Assay
9. Prior anticancer therapy

   1. Patients must have received at least 2 prior systemic lines of platinum therapy and be considered by the Investigator as appropriate for single-agent non-platinum therapy (documentation required - eg, high risk of hypersensitivity reaction; risk of further cumulative toxicity with additional platinum, including but not limited to myelosuppression, neuropathy, renal insufficiency or other) i. Note: Patients who have had a documented platinum allergy may have had only 1 prior line of platinum
   2. Patients may have received up to but no more than 1 prior independent non-platinum cytotoxic therapy
   3. Patients must have had testing for breast cancer susceptibility gene (BRCA) mutation (tumor or germline) and, if positive, must have received a prior poly (ADP-ribose) polymerase ( (PARP) inhibitor as either treatment or maintenance therapy
   4. Neoadjuvant ± adjuvant therapies are considered 1 line of therapy
   5. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (ie, not counted independently)
   6. Therapy changed due to toxicity in the absence of progression will be considered part of the same line (ie, not counted independently)
10. Patients must have completed prior therapy within the specified times below:

    1. Systemic antineoplastic therapy within 5 half-lives or 4 weeks (whichever is shorter) prior to first dose of MIRV
    2. Focal radiation completed at least 2 weeks prior to first dose of MIRV
11. Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia)
12. Patients must have completed any major surgery at least 4 weeks prior to first dose of MIRV and have recovered or stabilized from the side effects of prior surgery prior to first dose of MIRV
13. Patients must have adequate hematologic, liver and kidney functions defined as:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (1500/μL) without granulocyte colony-stimulating factor (G-CSF) in the prior 10 days or long-acting white blood cell (WBC) growth factors in the prior 20 days
    2. Platelet count ≥ 100 x 10\^9/L (100,000/μL) without platelet transfusion in the prior 10 days
    3. Hemoglobin ≥ 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 21 days
    4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
    5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN
    6. Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin \< 3.0 x ULN)
    7. Serum albumin ≥ 2 g/dL
14. Patients must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements
15. Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) while on MIRV and for at least 3 months after the last dose
16. WCBP must have a negative pregnancy test within the 4 days prior to the first dose of MIRV

Key Exclusion Criteria-

1. Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade/borderline ovarian tumor
2. Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow
3. Patients with \> Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE)
4. 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
5. Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:

   1. Active hepatitis B or C infection (whether or not on active antiviral therapy)
   2. HIV infection
   3. Active cytomegalovirus infection
   4. Any other concurrent infectious disease requiring IV antibiotics within 2 weeks prior to the first dose of MIRV

   Note: Testing at screening is not required for the above infections unless clinically indicated.
6. Patients with a history of multiple sclerosis (MS) or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome)
7. Patients with clinically significant cardiac disease including, but not limited to, any of the following:

   1. Myocardial infarction ≤ 6 months prior to first dose
   2. Unstable angina pectoris
   3. Uncontrolled congestive heart failure (New York Heart Association \> class II)
   4. Uncontrolled ≥ Grade 3 hypertension (per CTCAE)
   5. Uncontrolled cardiac arrhythmias
8. Patients with a history of hemorrhagic or ischemic stroke within 6 months prior to enrollment
9. Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C)
10. Patients with a previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonitis
11. Patients requiring use of folate-containing supplements (eg, folate deficiency)
12. Patients with prior hypersensitivity to monoclonal antibodies (mAb)
13. Women who are pregnant or breastfeeding
14. Patients who received prior treatment with MIRV or other FRα-targeting agents
15. Patients with untreated or symptomatic central nervous system (CNS) metastases
16. Patients with a history of other malignancy within 3 years prior to enrollment

    Note: patients with 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) are eligible.
17. Prior known hypersensitivity reactions to study drugs and/or any of their excipients