First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Mirvetuximab Soravtansine in Adults With Ovarian Cancer and Other Folate Receptor 1 (FOLR1)-Positive Solid Tumors

ImmunoGen, Inc.206 enrolled

Overview

The purpose of this study is to test mirvetuximab soravtansine (IMGN853) in participants with ovarian cancer and other FOLR-1 positive tumors.

The study consists of a dose-escalation phase that will evaluate 2 dosing schedules (Schedule A and Schedule B) of mirvetuximab soravtansine and up to 5 dose-expansion groups at the maximum tolerated dose (MTD). The first 4 escalation cohorts will be single participant cohorts. Subsequent escalation cohorts will use a standard 3+3 design, with each cohort consisting of 3 or 4 to 6 participants. Data were collected and analysed for the escalation and expansion groups by dose schedule and not by individual dose.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

206

Conditions

Tumors

Interventions

Mirvetuximab soravtansineDRUG

Mirvetuximab soravtansine IV infusion will be administered as per dose and schedule specified in the respective arms.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria * Participants with advanced solid tumor that is refractory to standard treatment, for which no standard treatment is available, or the participant refuses standard therapy. * Participants must be willing to provide an archival tumor tissue block or slides for biomarker analysis. * Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. * Time from prior therapy: 1. Systemic anti-neoplastic therapy: five half-lives or four weeks, whichever is shorter (6 weeks for prior nitrosoureas or mitomycin C). 2. Radiotherapy: wide-field radiotherapy (for example, greater than \[\>\] 30 percent \[%\] of marrow-bearing bones) completed at least four weeks, or focal radiation completed at least two weeks, prior to starting study drug. * Participants must have recovered or stabilized from all therapy-related toxicities. * Major surgery (not including placement of vascular access device or tumor biopsies) must be completed four weeks prior to Day 1. Participants must have recovered or stabilized from the side effects prior to study treatment. * Participants must have adequate hematologic, liver and kidney function. * Participants with central nervous system (CNS) disease involvement are eligible if they have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 and they meet all of the following criteria: Residual neurological symptoms less than or equal to (\<=) Grade 1; No dexamethasone requirement; and Follow-up magnetic resonance imaging (MRI) shows no progression of treated lesions and no new lesions appearing. * Participants must be willing and able to sign the informed consent form, and to adhere to the study visit schedule and other protocol requirements. * Women of childbearing potential and men must agree to use effective contraceptive methods while on study and for at least twelve weeks after the last dose of study drug. * Women of childbearing potential must have a negative pregnancy test prior to the first dose of study treatment. Exclusion Criteria * Grade \>1 neuropathy. * Any active or chronic corneal disorder, including, but not limited to the following: Sjogren's syndrome, Fuch's corneal dystrophy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and also active ocular conditions requiring ongoing treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presence of papilledema, acquired monocular vision. * Serious concurrent illness, including, but not limited to the following: 1. Clinically relevant active infection including known active hepatitis B or C, Human Immunodeficiency Virus (HIV) infection, varicella-zoster virus (shingles) or cytomegalovirus infection or any other known concurrent infectious disease, requiring IV antibiotics within 2 weeks of study enrollment. 2. Significant cardiac disease such as recent myocardial infarction (\<=6 months prior to Day 1), unstable angina pectoris, uncontrolled congestive heart failure (New York Heart Association \>class II), uncontrolled hypertension (greater than or equal to \[\>=\] Common Terminology Criteria for Adverse Events Version 4.03 \[CTCAE v4.03\] Grade 3), uncontrolled cardiac arrhythmias, severe aortic stenosis, or \>=Grade 3 cardiac toxicity following prior chemotherapy. 3. History of multiple sclerosis or other demyelinating disease, Eaton-Lambert syndrome (para-neoplastic syndrome), history of hemorrhagic or ischemic stroke within the last six months, or alcoholic liver disease. 4. Previous clinical diagnosis of treatment-related pneumonitis. * Any other concomitant anti-cancer treatment such as immunotherapy, biotherapy, radiotherapy, chemotherapy, investigative therapy, or high-dose steroids; however, low dose steroids and Luteinizing Hormone Releasing Hormone (LHRH) at doses that have been stable for \>=14 days are permitted for participants with prostate cancer. * Known hypersensitivity to previous monoclonal antibody therapy or maytansinoids. * Prior history of solid tumor malignancy within the last 3 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer (participants must have shown no evidence of active disease for 2 years prior to enrollment). * Concomitant administration of folate-containing vitamins. * Participants who have received prior allogeneic or autologous bone marrow transplants. * Women of childbearing potential who are pregnant or breast feeding.

Locations (12)

University of Kansas Medical Center Research Institute

Fairway, Kansas, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

Dose-Escalation Phase: Maximum Tolerated Dose (MTD) of Mirvetuximab Soravtansine

MTD was defined as the highest dose at which 1 or fewer among 6 participants or less than or equal to (\<=) 33 percent (%) experienced a dose-limiting toxicity (DLT) (calculated based on adjusted ideal body weight \[AIBW\]). AIBW was calculated as ideal body weight (IBW) + 0.4 \* (actual weight - IBW), where IBW for men was 0.9 \* height in centimeters (cm) - 88 and IBW for women was 0.9 \* height in cm - 92. DLT was defined as a treatment-emergent adverse event (TEAE) or abnormal laboratory value related to study treatment (that is, assessed as unrelated to disease, intercurrent illness, or concomitant medications), including those TEAEs and abnormal laboratory values that resulted in a failure to meet the criteria for re-treatment.

Time frame: Cycle 1 (21 days)

Dose-Escalation Phase: Recommended Phase 2 Dose (RP2D) of Mirvetuximab Soravtansine

RP2D was determined by MTD. MTD was defined as the highest dose at which 1 or fewer among 6 participants or \<=33% experienced a DLT. DLT was defined as a TEAE or abnormal laboratory value related to study treatment (that is, assessed as unrelated to disease, intercurrent illness, or concomitant medications), including those TEAEs and abnormal laboratory values that resulted in a failure to meet the criteria for re-treatment. Available clinical data indicated that the MTD defined for the Q3W schedule was equal to the RP2D.

Time frame: Cycle 1 (21 days)

Secondary Outcomes

Number of Participants With TEAEs

An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to study drug. Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 on following scale: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death. Serious AEs include death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as any AE that emerged on or after the first dose, and within 28 days of the last dose.

Data from ClinicalTrials.gov

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Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Ohio State University

Columbus, Ohio, United States

University of Oklahoma Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

CTRC at the University of Texas Health Science Center

San Antonio, Texas, United States

...and 2 more locations

Time frame: From first dose of study drug up to 28 days after last dose of study drug (maximum exposure: 36 weeks for dose-escalation Schedule A, 101.3 weeks for dose-escalation Schedule B, 124 weeks for dose-expansion EOC, 33.3 weeks for dose-expansion EC)

Number of Participants With Shift From Baseline Grade <=2 in Clinical Laboratory Parameters to Grade 3 or Grade 4 on Study

Laboratory parameters included serum chemistry (alanine aminotransferase \[ALT\]/serum glutamic pyruvic transaminase \[SGPT\], aspartate aminotransferase \[AST\]/serum glutamic oxaloacetic transaminase \[SGOT\], albumin, alkaline phosphatase, bilirubin, calcium, creatinine, glucose, magnesium, phosphorous, potassium, sodium), hematology (hemoglobin, lymphocytes, neutrophils, platelets, white blood cells) and coagulation (international normalized ratio \[INR\], partial thromboplastin time \[PTT\]). Clinically significant laboratory values were defined as per NCI CTCAE v.03 Grade 3 or higher. A grading (severity) scale was provided with grades ranging from 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening or disabling), to 5 (death). Only participants who shifted from a baseline value of Grade \<=2 to a post-baseline Grade 3/4 on-treatment, are reported.

Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings and Vital Signs

Physical examination included assessments of general appearance, skin, head (eyes, ears, nose, and throat), neck, lungs, heart, abdomen, back, lymph nodes, extremities, and neurological system. Vital signs included assessment of blood pressure, pulse rate, respiratory rate and body temperature.

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)

Standard ECGs were performed in triplicate at 2- to 5-minute intervals during the study. A single ECG was performed at the end of treatment visit and as clinically indicated.

Time frame: Baseline up to end of treatment (EOT) (up to maximum 124 weeks)

Number of Participants With Treatment-Emergent Ocular AEs

Ocular AEs included keratopathy and blurred vision. An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to study drug. TEAEs were defined as any AE that emerged on or after the first dose, and within 28 days of the last dose.

Maximum Observed Plasma Concentration (Cmax) of Mirvetuximab Soravtansine and Total M9346A Antibody at RP2D

Pharmacokinetic (PK) parameters were calculated using standard non-compartmental methods. PK analysis of mirvetuximab soravtansine and total M9346A antibody is presented for a subgroup of participants who received 6.0 mg/kg (RP2D) mirvetuximab soravtansine at Cycle 1 and Cycle 3.

Time frame: Cycle 1, 3: Day 1 (pre-infusion; within 10 minutes [min] of EOI; 2, 4, 6, 8 hrs post-infusion); Day 2, 3 (24, 48 hrs post-infusion); Day 4 or 5, 8, 15 (24 hrs post-infusion)

Cmax of Free DM4 and S-Methyl DM4 at RP2D

PK parameters were calculated using standard non-compartmental methods. PK analysis of free N2'-\[4-\[(3-carboxypropyl)dithio\]-4-methyl-1-oxo-2-sulfopentyl\]-N2'-deacetylmaytansine (DM4) and S-methyl DM4 is presented for a subgroup of participants who received 6.0 mg/kg (RP2D) mirvetuximab soravtansine at Cycle 1 and Cycle 3.