Mirvetuximab Soravtansine (IMGN853), in Folate Receptor Alpha (FRα) High Recurrent Ovarian Cancer

A Randomized Phase II Trial of Mirvetuximab Soravtansine (IMGN853), in Folate Receptor Alpha (FRα) High Recurrent Ovarian Cancer Eligible for Platinum-based Chemotherapy. Supported by: DIAGNOSTIC PROTOCOL for the VENTANA FOLR1 (FOLR1-2.1) CDx Assay Ventana No. RD004881; Protocol Document No. D152967

This is a multi-center, randomized, two-arm, open-label, comparative phase II trial of Mirvetuximab soravtansine (IMGN853), in folate receptor alpha (FRα) high recurrent ovarian cancer eligible for platinum-based chemotherapy.

136 patients will be randomized into the follow-ing two treatment arms as specified below:

Arm A: Control arm Platinum-based chemotherapy Arm B: Carboplatin + Mirvetuximab soravtansine (IMGN853)

Inclusion Criteria:

1. All patients must have a pathologically documented, definite diagnosis of epithelial cancer of the ovary, the fallopian tube or the peritoneum

2. Relapsed disease with a platinum-free interval >3 months

3. All histologic subtypes of ovarian carcinoma including carcinosarcoma (malignant mixed Mullerian tumors, MMMT)

4. Patients with wildtype BRCA1/2 mutation status or with a deleterious BRCA1/2 mutation in germline or somatic testing if they underwent PARP inhibitor therapy in previous treatment line.

5. Patients must be willing to provide archival tumor tissue from current relapse or previous surgeries/biopsies for central confirmation of FRα high status by PS2+ scoring:

   all tumors must exhibit ≥75% of tumor cells with FRα membrane staining and ≥ 2+ intensity by immunohistochemistry (IHC) using the Ventana FOLR1 (FOLR1 2.1) CDx assay.

6. Patients must have measurable disease or evaluable disease in combination with GCIG CA-125 criteria.

7. Patients had one or more prior lines of chemotherapy. The last line of chemotherapy must have included platinum (min. 4 cycles) and has resulted in a partial or complete response.

8. Major surgery (not including placement of vascular access device, tumor punch/scrape biopsies or secondary wound closure) must be completed four weeks prior to Day 1.

9. Patients must have adequate hematological, liver, cardiac and kidney function:

   1. Hemoglobin ≥ 10.0 g/dL.
   2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   3. Platelet count ≥ 100 x 109/L.
   4. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
   5. Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase/Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN.
   6. Serum creatinine ≤ 1.5 x institutional ULN and glomerular filtration rate of at least 40 ml/minute according to Cockroft-Gault formula.

10. Patient is female and ≥18 years of age at the time of the first screening visit.

11. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

12. Patients must be willing and able to sign the informed consent form, and to adhere to the study visit schedule and other protocol requirements.

13. Women of childbearing potential (a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently ster-ile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) must have a negative serum pregnancy test within 3 days from day 1 of cycle 1 and agree to use a highly effective method of contraception while on study treatment and for at least 8 months after end of treatment. Such methods include:

    1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

       • oral
       • intravaginal
       • transdermal

    2. Progestogen-only hormonal contraception associated with inhibition of ovulation:

       • oral
       • injectable
       • implantable

    3. Intrauterine device (IUD)

    4. Intrauterine hormone-releasing system (IUS)

    5. Bilateral tubal occlusion

    6. Vasectomized partner

    7. Sexual abstinence

Exclusion Criteria:

1. Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors)
2. Ovarian tumors of low malignant potential (e.g. borderline tumors).
3. Unknown BRCA status.
4. Patients who are planned to receive bevacizumab for the current relapse.
5. Other malignancy within the last 3 years (except cervix or breast in situ carcinoma, type I stage I endometrial cancer)
6. Patients who underwent surgery for the current relapse with macroscopic complete resection
7. Prior systemic anticancer therapy within 28 days before randomization
8. Prior treatment with folate receptor-targeting investigational agents is not allowed.
9. Patients with > Grade 1 peripheral neuropathy.
10. Serious concurrent illness or clinically-relevant active infection
11. Previous clinical diagnosis of non-infectious interstitial lung disease, including non-infectious pneumonitis.
12. Active or chronic corneal disorders such as Sjogren's syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal transplantation, active herpetic keratitis, 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. Active or chronic corneal disorder
13. Required use of folate-containing supplements (e.g. folate deficiency)
14. Women of childbearing potential (WOCBP) not protected by highly effective contraceptive methods.
15. Pregnant and/or breast-feeding women.
16. Known hypersensitivity to one of the chemotherapy re-gimes and/or PARP inhibitors and/or any of their excipients.
17. Patients with prior hypersensitivity to monoclonal antibodies.
18. Patients with potential risks according to contraindication, warnings or interactions of the used chemotherapeutic agents as stated in the SmPCs are not eligible for participation in this trial.
19. Patients with untreated or symptomatic central nervous system (CNS) metastases