First in Human Study of IMGN151 in Recurrent Endometrial Cancer and Recurrent, High-grade Serous Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers

Study Overview
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Brief Summary
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IMGN151-1001 is a Phase 1, first in human, open-label dose-escalation and expansion study in adult patients with recurrent endometrial cancer, recurrent, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancers.

Detailed Description
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This Phase 1 study is designed to characterize the safety, tolerability, PK, immunogenicity, and preliminary antitumor activity of IMGN151 in patients with recurrent endometrial cancer, or recurrent, high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancers. All patients will be, in the opinion of the investigator, appropriate for nonplatinum single-agent therapy for their next line of therapy.

Official Title
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A Phase 1, First-in-Human, Open-Label, Dose-Escalation and Expansion Study of IMGN151 (Anti-FRα Antibody-drug Conjugate) in Adult Patients With Recurrent Endometrial Cancer and Recurrent, High-Grade Serous Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers

Conditions
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Endometrial Cancer, High Grade Serous Adenocarcinoma of Ovary, Primary Peritoneal Carcinoma, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: IMGN151


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years of age Patients must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Dose-Escalation Phase: Patients must have a confirmed diagnosis of recurrent endometrial cancer or high-grade serous epithelial ovarian cancer (EOC), primary peritoneal, or fallopian tube cancer. Expansion Phase: Patients must have a confirmed diagnosis of recurrent endometrial cancer or platinum-resistant, high-grade serous epithelial ovarian cancer (PROC), primary peritoneal, or fallopian tube cancer. 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. Prior anticancer therapy For Expansion Phase: Patients must have recurrent endometrial cancer or patients with PROC must have received 1-4 prior systemic lines of therapy. Neoadjuvant ± adjuvant therapies are considered 1 line of therapy. Maintenance therapy (eg, bevacizumab or poly [ADP-ribose] polymerase [PARP] inhibitors) will be considered part of the preceding line of therapy (ie, not counted independently). Therapy changed due to toxicity in the absence of progression will be considered 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. Evaluable lesions Dose-Escalation Phase: Patients may have radiologically evaluable or nonevaluable disease. Expansion Phase: Patients must have at least 1 lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the investigator). Patients must be willing to provide an archival tumor tissue block or slides or to undergo a procedure to obtain a new biopsy using a low-risk, medically routine procedure for retrospective IHC confirmation of FRα status. Patients must have completed prior therapy within the specified times below: Systemic antineoplastic therapy within 5 half-lives or 4 weeks (whichever is shorter) before the first dose of IMGN151 Focal radiation completed at least 2 weeks before the first dose of IMGN151 Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia). Patients must have completed any major surgery at least 4 weeks before the first dose of IMGN151 and have recovered or stabilized from the side effects of prior surgery before the first dose of IMGN151. Patients must have adequate hematologic, liver, and kidney functions defined as follows: Absolute neutrophil count (ANC) ≥ 1.5 ×10 9/L (1500/μL) without granulocyte colony-stimulating factor (G-CSF) in the prior 10 days or long-acting white blood cell growth factors in the prior 20 days Platelet count ≥ 100 × 10 9/L (100,000/μL) without platelet transfusion in the prior 10 days Hemoglobin ≥ 9.0 g/dL without packed red blood cell transfusion in the prior 21 days Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 or an estimated creatinine clearance of ≥ 60 mL/min Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN) Serum bilirubin ≤ 1.5 × ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 × ULN) Serum albumin ≥ 2 g/dL Patients must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements. Females of childbearing potential (FOCBP) must agree to use highly effective contraceptive method(s) while on IMGN151 and for at least 3 months after the last dose. FOCBP must have a negative serum pregnancy test at Screening and a negative serum or urine pregnancy test within 72 hours before the first dose of IMGN151. Exclusion Criteria: Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade/borderline ovarian tumor Patients with prior wide-field radiotherapy 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 in patients with CD4+ T-cell (CD4+) counts < 350 cells/µL Active cytomegalovirus infection Active COVID-19/SARS-CoV-2 infection. Although SARS-CoV-2 testing is not mandatory for study entry, testing should follow local clinical practice guidelines and standards Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before the first dose of IMGN151 Note: Testing at Screening is not required for the above infections unless clinically indicated. Patients with a 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 of the following: Myocardial infarction ≤ 6 months before the first dose Unstable angina pectoris Uncontrolled congestive heart failure (New York Heart Association > class II) Uncontrolled ≥ Grade 3 hypertension (per CTCAE v5.0) Uncontrolled cardiac arrhythmias QTc interval > 470 ms Patients with a history of hemorrhagic or ischemic stroke within 6 months before enrollment Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C) Patients with evidence of pneumonitis on baseline imaging or patients with a previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonitis Patients requiring use of folate-containing supplements (eg, folate deficiency) Patients with prior hypersensitivity to monoclonal antibodies (mAb) Females who are pregnant or breastfeeding For Expansion Phase: Patients who received a prior FRα-targeting agent Patients with untreated or symptomatic central nervous system metastases Patients with a history of other malignancy within 3 years before 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. Prior known hypersensitivity reactions to study drugs and/or any of their excipients

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
Intervention Model: Sequential Assignment
Interventional Model Description: Open-label dose escalation study with dosing every three weeks. All patients in the escalation phase will be assigned sequentially to one of up to eight doses in a 3+3 design. Once the recommended Phase 2 dose is identified, an expansion phase of the study will enroll patients into cohorts of either endometrial cancer or platinum-resistant ovarian cancer. During EscalationIMGN151 is administered via intravenous (IV) infusion on Day 1 of Cycle 1 and every subsequent 21-day cycle thereafter, at the assigned dose for each cohort during dose escalation and at the RP2D for expansion. Infusion duration will vary depending on dose and participant tolerability.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMGN151 Open Label<br>IMGN151 is administered via intravenous (IV) infusion on Day 1 of Cycle 1 and every subsequent 21-day cycle thereafter, at the assigned dose for each cohort during dose escalation, and at the RP2D for expansion. Infusion duration will vary depending on dose and participant tolerability. | Drug: IMGN151<br>* IMGN151 is an antibody-drug conjugate (ADC).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize Safety (Escalation) | Incidence of adverse events (AE), serious adverse events (SAEs), and DLTs | Up to 1 year | 
| Define Recommended Phase 2 Dose (Escalation) | Definition of RP2D | Up to 1 year | 
| Determine Objective Response Rate (Expansion) | ORR (which includes best response of CR or PR as assessed by the investigator) | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| During dose escalation and expansion to characterize study drug concentration | Study drug concentration | There are 9 blood draw collection time points at Cycles 1 and 3, 3 blood draw time points at Cycles 2,4,5 and 6, and collection at every 3 cycles after cycle 6 until end of study (approximately up to 2 years). Each cycle is 21 days. | 
| During dose escalation and expansion to measure the concentration of anti-drug antibody | Anti-drug antibody | There are 2 collection time points at Cycles 1 and 3, 1 collection time point at Cycles 2, 4, 5 and 6, and and collection at every 3 cycles after cycle 6 until end of study (approximately up to 2 years). Each cycle is 21 days. | 
| During dose expansion describe the duration of response and progression-free survival | Time to disease progression | From screening to end of study (approximately up to 2 years) for each patient | 
| During dose escalation to describe the objective response rate and duration of response | Time to disease progression | From screening to end of study (approximately up to 2 years) for each patient | 
| During dose expansion measure incidence and severity of Treatment Emergent Adverse Events by CTCAE v5.0 | Number of treatment emergent adverse events as assessed by CTCAE v5.0 | From screening to end of study (approximately up to 2 years) for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody Drug Conjugate, Platinum-Resistant, Recurrent, Phase 1/2