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

Tumors Clinical Trial

— IMGN853-0401  

Official title:

A Phase 1, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of IMGN853 in Adults With Ovarian Cancer and Other FOLR1-Positive Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01609556
• Other study ID #: IMGN853-0401
• Status: Completed
• Phase: Phase 1
• Start date: June 28, 2012
• Est. completion date: March 19, 2018

Study information

• Verified date: January 2021
• Source: ImmunoGen, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 206
• Est. completion date: March 19, 2018
• Est. primary completion date: March 19, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Tumors

Intervention

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

Locations

Country	Name	City	State
Canada	McGill University Health Centre	Montreal	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Ohio State University	Columbus	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	University of Kansas Medical Center Research Institute	Fairway	Kansas
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Oklahoma Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	CTRC at the University of Texas Health Science Center	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
ImmunoGen, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Cycle 1 (21 days)
Primary	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.	Cycle 1 (21 days)
Secondary	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.	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)
Secondary	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.	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)
Secondary	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.	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)
Secondary	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.	Baseline up to end of treatment (EOT) (up to maximum 124 weeks)
Secondary	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.	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)
Secondary	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.	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)
Secondary	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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Mirvetuximab Soravtansine and Total M9346A Antibody at RP2D	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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	AUC0-inf of Free DM4 and S-Methyl DM4 at RP2D	PK parameters were calculated using standard non-compartmental methods. PK analysis of free 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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Area Under the Plasma Concentration-Versus Time Curve From Time of Dose Until Tlast (AUClast) of Mirvetuximab Soravtansine and Total M9346A Antibody at RP2D	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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	AUClast of Free DM4 and S-Methyl DM4 at RP2D	PK parameters were calculated using standard non-compartmental methods. PK analysis of free 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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Terminal Half-Life (t1/2) of Mirvetuximab Soravtansine,Total M9346A Antibody, DM4, and S-Methyl DM4 at RP2D	PK parameters were calculated using standard non-compartmental methods. PK analysis of mirvetuximab soravtansine, total M9346A antibody, 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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Clearance (CL) of Mirvetuximab Soravtansine and Total M9346A Antibody at RP2D	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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	CL of DM4 and S-Methyl DM4 at RP2D	PK parameters were calculated using standard non-compartmental methods. PK analysis of 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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Time to Reach Maximum Observed Concentration (Tmax) of Mirvetuximab Soravtansine, Free DM4, S-Methyl DM4, and Total M9346A Antibody at RP2D	PK parameters were calculated using standard non-compartmental methods. PK analysis of mirvetuximab soravtansine, free DM4, S-methyl DM4, 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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Volume of Distribution at Steady State (Vss) of Mirvetuximab Soravtansine Free DM4, S-Methyl DM4, and Total M9346A Antibody at RP2D	PK parameters were calculated using standard non-compartmental methods. PK analysis of mirvetuximab soravtansine, free DM4, S-methyl DM4, 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.	Cycle 1, 3: Day 1 (pre-infusion; within 10 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)
Secondary	Objective Response Rate (ORR): Percentage of Participants With Objective Response as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	ORR was defined as percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). CR: Disappearance of all target or non-target lesions. All pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR: At least 30 percent (%) decrease in the sum of the longest diameters (SoD) of target lesions, taking as reference the baseline SoD.	From first dose of study drug until first BOR of CR or PR (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)
Secondary	Duration of Response (DOR) as Assessed by RECIST v1.1	DOR was defined as the time from the date of the first response (CR or PR), whichever was recorded first, until the date of progressive disease (PD). PD: At least a 20% increase in the SoD of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. DOR was only defined for participants who had a BOR of CR or PR using the method of Kaplan-Meier.	From the date of first response (CR or PR) until the date of PD (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)
Secondary	Progression-Free Survival (PFS) as Assessed by RECIST v1.1	PFS was defined as the time from initiation of study drug until PD or death whichever occurred first, estimated using the Kaplan-Meier method. PD: At least a 20% increase in the SoD of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of non-target lesions and appearance of new lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.	From first dose of study drug until PD or death whichever occurred first (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)
Secondary	Time to Progression (TTP) as Assessed by RECIST v1.1	TTP was defined as the time from initiation of study drug until PD, estimated using the method of Kaplan-Meier. PD: At least a 20% increase in the SoD of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of non-target lesions and appearance of new lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.	From first dose of study drug until PD (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)
Secondary	Number of Participants With Anti-Drug Antibodies (ADA)	During the conduct of the study, a single immunogenicity assay was developed to concurrently detect human antibodies against all components of mirvetuximab soravtansine, including the humanized anti-FOLR1 antibody, the cleavable disulfide linker, and the cytotoxic maytansinoid, DM4. Therefore, immunogenicity results were reported as ADA titers, and did not distinguish between human anti-drug or anti-human titers.	Baseline up to follow-up visit (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)
Secondary	Number of Participants With Gynecologic Cancer Intergroup (GCIG) CA-125 Criteria Clinical Responses	CA-125 response was defined as at least 50% reduction in CA-125 levels from baseline. The date of response corresponded to the date when the CA 125 level was first reduced by 50%.	From first dose of study drug until CA-125 response (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)