A Single-arm Clinical Trial of IMGN853 in Chinese Adult Patients With Platinum-resistant, Epithelial Ovarian Cancer

This Phase III single-arm study is to evaluate the efficacy and safety of IMGN853 in Chinese adult patients with platinum-resistant high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers (hereafter referred to as PROC) with high FRα expression.

This is a single-arm, phase III clinical trial of IMGN853 in Chinese adult patients with platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal or fallopian tube cancer with high expression of folate receptor-α.

The objective of this study is to determine the efficacy of IMGN853 in platinum-resistant ovarian cancer (PROC) patients with high folate receptor alpha (FRα) expression.

A total of 35 patients will be enrolled. All patients must have measurable disease (per Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1) at baseline and be eligible for receiving IMGN853.

All patients will be treated with the IMGN853 monotherapy with a dose at adjusted ideal body weight (AIBW) of 6 mg/kg on Day 1 of every 3-week cycle (Q3W).

Eligibility Criteria:
Inclusion Criteria:

1. Female patients ≥ 18 years of age
2. Patients must have a histopathologically confirmed diagnosis of high-grade serous EOC.
3. Patients must have platinum-resistant disease:

   1. Patients must have had a response (CR or PR) after previous 1 line of platinum-based therapy for at least 4 cycles of treatment, and then progressed between \> 3 months and ≤ 6 months after the date for last dose of platinum.
   2. Patients who relapsed after \> 6 months since the last platinum-based treatment with at least 4 cycles of one line platinum-based therapy: 1) continued to receive at least 4 cycles of 2 or 3 lines of platinum-based treatment and must have had PD within 6 months from the last dose of platinum; or 2) had PD during treatment with 2 or 3 lines of platinum-containing chemotherapy.

   Note: PD should be calculated from the date of the last dose of platinum-containing therapy to the date of PD indicated by radiographic imaging.

   Note: Patients who are platinum-refractory during 1 line treatment are excluded (see exclusion criterion 3).
4. Patients must have radiological PD on or after the most recent anti-cancer therapy.
5. Patients must be willing to provide the archival tumor tissue slides or undergo low-risk routine medical procedures to collect new biopsy samples for immunohistochemistry (IHC) confirmation of FRα positivity.
6. Per VENTANA FOLR1 (FOLR-2.1) Assay criteria, patient's tumor must be positive for FRα expression by a central laboratory.
7. Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically assessed by the investigator).
8. Patients must have received at least 1 but no more than 3 lines of prior systemic anti-cancer therapy, including at least 1 line of therapy containing bevacizumab, and for whom monotherapy is appropriate for the next line of treatment:

   1. Neoadjuvant ± adjuvant is considered as 1 line of therapy;
   2. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered as part of the prior line of therapy (ie, not counted independently);
   3. Therapy changed due to toxicity in the absence of PD will be considered as part of the same line (ie, not counted independently);
   4. Hormonal therapy (except as maintenance therapy) will be considered as a separate line of therapy.
9. Patients must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
10. Patients must have completed prior therapy within the following specified times:

    1. Systemic anti-tumor therapy (the last prior systemic anti-tumor therapy should be at least 5 half-lives or 4 weeks from the initiation of the investigational drug, whichever is shorter);
    2. Focal radiotherapy: previous focal radiotherapy should be at least 2 weeks from the initiation of investigational drug.
11. All toxicities (except alopecia) associated with prior therapy must be stable or resolved (Grade 1 or normal).
12. Any major surgery that a patient has undergone must have been completed at least 4 weeks prior to the first dose of IMGN853 and the postoperative complications of prior surgical treatment have resolved or are stable.
13. Patients must have adequate hematologic, hepatic, and renal functions as defined by the following parameters (without G-CSF \[a 20-day drug washout period for long-acting growth factors\], human albumin injection and other corrective treatment drugs are not allowed within 14 days before obtaining laboratory test values):

    1. Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L (1,500 μL);
    2. Platelet count ≥ 100 × 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 × upper limit of normal (ULN);
    5. Both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN;
    6. Serum bilirubin ≤ 1.5 × ULN (patients with Gilbert syndrome may be enrolled if total bilirubin is \< 3.0 × ULN);
    7. Serum albumin ≥ 2 g/dL.
14. Patients or their legally authorized representatives must be willing and able to sign the ICF and comply with the requirements of the protocol.
15. Women of child bearing potential (WCBP), defined as a sexually mature woman who have not undergone surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who have had menses any time in the preceding 12 consecutive months) must agree to use effective contraceptive methods; examples included oral, parenteral, or implantable hormonal contraceptive, intrauterine device, barrier contraceptive with spermicide, partner's latex condom or vasectomy) while on study treatment and for at least 12 weeks after the last dose of investigational drug.
16. WCBP must have a negative pregnancy test within 4 days prior to the first dose of IMGN853.
17. The expected survival of the subject is at least 12 weeks as assessed by the investigator.

Exclusion Criteria:

1. Male patients.
2. Patients with endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma, or sarcoma tissue, mixed tumor containing any of the above histologies, or low grade/borderline ovarian tumor.
3. 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.
4. Patients who have received prior wide-field radiotherapy (RT) with at least 20% of the bone marrow affected.
5. Patients with \> Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE).
6. Patients with active or chronic corneal disorders, history of corneal transplant, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring treatment with intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilloedema, and /or monocular vision.
7. Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:

   1. Known acute or chronic active hepatitis B (HBsAg positive and HBV DNA viral load ≥ 2500 copies/mL or \> 500 IU/mL, if necessary, patients may receive nucleoside prophylactic anti-hepatitis B virus therapy) or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA positive);
   2. Human immunodeficiency virus (HIV) infection;
   3. Active cytomegalovirus infection;
   4. Any other concurrent infectious disease requiring systematic treatment within 2 weeks prior to the first dose of IMGN853.
8. Patients with a history of multiple sclerosis (MS) or other demyelinating diseases and/or Lambert-Eaton syndrome (paraneoplastic syndrome).
9. Patients with clinically significant cardiac disorders, including but not limited to any of the following:

   1. Myocardial infarction ≤ 6 months prior to the first dose;
   2. Unstable angina pectoris;
   3. Uncontrolled congestive cardiac failure (New York Heart Association classification \> II);
   4. Uncontrolled ≥ Grade 3 hypertension (per CTCAE criteria);
   5. Uncontrolled cardiac arrhythmias.
10. Patients with a history of hemorrhagic or ischemic stroke within 6 months prior to signing the ICF.
11. Patients with a history of hepatic cirrhosis (Child-Pugh B or C).
12. Patients with a previous clinical diagnosis of or currently ongoing non-infectious interstitial lung disease (ILD), including noninfectious pneumonitis, lung disorders such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pulmonitis, severely impaired lung function, etc.
13. Patients requiring folic acid-containing supplements (e.g., folate deficiency).
14. Known hypersensitivity to previous monoclonal antibody therapy or maytansinoids, or to the investigational drug and/or any excipients.
15. Pregnant or lactating women.
16. Patients with prior IMGN853 or other FRα-targeted drug therapies.
17. Known active central nervous system (CNS) and/or leptomeningeal metastases. Patients with untreated but asymptomatic brain metastases, or patients who have radiographically documented progression-free status for at least 4 weeks after treatment and do not require hormonal or antiepileptic therapy for at least 2 weeks may be considered for enrollment.
18. Patients with a history of other malignancies within 3 years prior to enrollment.

    Note: patients with tumors with a negligible risk of metastasis or death (e.g., adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible for inclusion.
19. Patients with pleural effusion, pericardial effusion, or ascites that cannot be controlled by drainage or other means, except the small amount of effusion that without clinical symptoms or do not require clinical intervention.
20. Patients who are detained by a court or administrative decision, receiving psychiatric care against their will, adults who are under the protection of law (under tutorship/curatorship), people who are unable to give their consent, and people who are subject to a legal guardianship.
21. Participated in other clinical studies and received their investigational drugs within 4 weeks prior to the first dose.
22. Subject has other serious systemic diseases or other reasons that are not suitable for participation in this clinical study as evaluated by the investigator.