Clinical trial NCT04622774: First-in-Human Study of IMGC936 in Participants With Advanced Solid Tumors
Official title: A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation and Expansion Study of IMGC936 (Anti-ADAM9 Antibody Drug Conjugate) in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumor
Keywords: Antibody Drug Conjugate
Phase 1/2
Solid Tumors
Lead sponsor: ImmunoGen, Inc.
Sponsor class: INDUSTRY
Collaborators: name: MacroGenics
First posted: 2020-11-10
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study is a Phase 1/2, first-in-human, open-label, dose-escalation, and expansion study designed to characterize the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of IMGC936 administered by intravenous (IV) infusion.

Detailed description: This is an open-label, dose-escalation, and expansion study to determine the Maximum Tolerated Dose (MTD) and select the recommended Phase 2 dose (RP2D). Dose escalation follows a conventional 3+3 design; successive cohorts of 3 to 6 participants each will be evaluated in sequential escalating doses of single-agent IMGC936. Upon completion of the dose-escalation phase of the study, following determination of the RP2D, up to 5 expansion cohorts may be opened in tumor types selected from those enrolled in dose escalation.

Participants with relapsed or refractory, unresectable locally advanced or metastatic solid tumors including non-squamous non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), colorectal cancer (CRC), gastroesophageal cancer, or pancreatic cancer will be enrolled.

IMGC936 is administered via 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.

Sentinel dosing will be used for the first 2 dose levels of dose escalation. The first administration of IMGC936 in participants at the first 2 dose levels of dose escalation will be staggered by at least 48 hours. The dose-limiting toxicity (DLT) evaluation period is 21 days. Participants may continue on study drug until disease progression, adverse event (AE) requiring discontinuation, DLT during evaluation window, pregnancy, death, investigator decision, lost to follow up (LTFU), major protocol deviation requiring discontinuation, withdrawal of consent, or sponsor, investigator or regulatory agency terminates the study.

Tumor assessments are performed every 6 weeks (Q6W) while on study drug then every 12 weeks (Q12W). Tumor assessments continue until discontinuation criteria are met. If feasible, participants who discontinue study drug for reasons other than progressive disease (PD) (e.g., toxicity) should continue to undergo tumor assessments Q12W as post-treatment follow up until evidence of PD, initiation of another anticancer therapy, withdrawal of consent, LTFU, death, or end of study. Post-treatment follow up also includes following ongoing treatment emergent adverse events (TEAEs) until the event has resolved to baseline grade, the event is assessed by the investigator as stable, initiations of another anticancer therapy, withdrawal of consent, LTFU, death, or it has been determined that study drug or participation is not the cause of the AE.

Eligibility criteria: Inclusion Criteria:

1. Participants with histologically proven, relapsed or refractory, unresectable locally advanced or metastatic non-squamous NSCLC, TNBC, CRC, gastroesophageal cancer, or pancreatic cancer for whom no therapy with demonstrated clinical benefit is available.

   1. NSCLC: Participants must have been treated with 1 to 4 prior lines of systemic therapy with no more than 2 chemotherapy containing lines.
   2. TNBC: Participants must have been treated with 1 to 4 prior lines of systemic therapy for metastatic disease, excluding adjuvant therapies.
   3. CRC: Participants must have been treated with 1 to 3 prior lines of systemic therapy.
   4. Gastroesophageal cancer: Participants must have been treated with 1 to 3 prior lines of systemic therapy.
   5. Pancreatic cancer: Participants must have been treated with 1 to 3 prior lines of systemic therapy, with no more than 2 chemotherapy containing lines.
2. Either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and documented by computed tomography (CT) and/or magnetic resonance imaging (MRI) obtained within 28 days of Cycle 1 Day 1 (C1D1).

   * Dose escalation: Participants may have non-measurable or measurable disease
   * Dose expansion: Participants must have measurable disease
3. Age ≥ 18 years old.
4. Archival formalin-fixed paraffin-embedded (FFPE) tissue must be available. Participants may undergo a fresh tumor biopsy using a low risk, medically routine procedure to obtain a specimen for testing if a tumor sample is not available.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. If ECOG performance status is an inappropriate performance measurement for participant enrollment (for example, chronically non-ambulatory), then Karnofsky performance status must be ≥ 70.
6. Life expectancy ≥ 12 weeks.
7. Acceptable laboratory parameters as follows:

   * Platelet count ≥ 75 × 1000/microliter (μL) without transfusion within 28 days prior to initiation of study drug.
   * Absolute neutrophil count ≥ 1.5 × 1000/μL in the absence of any growth factor support within 21days prior to initiation of study drug.
   * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN); for participants with hepatic metastases, ALT and AST ≤ 5 × ULN.
   * Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, who may enroll if the conjugated bilirubin is within normal limits.
   * Estimated glomerular filtration rate (eGFR) \>30 milliliters (mL)/ minute (min)/1.73 square meter (m\^2) or an estimated creatinine clearance of \>30 mL/min.
   * Urinalysis protein and white occult blood cells within normal limits.
   * Negative serum pregnancy test for females of childbearing potential (FOCBP).
8. FOCBP, defined as not surgically sterilized (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) and between menarche and 1-year post menopause, must have a negative serum pregnancy test performed within 72 hours prior to initiation of study drug administration. Female participants must abstain from egg donation during the study.
9. FOCBP and male participants with partners of FOCBP must agree to use highly effective methods of contraception, from the time of consent through 28 weeks after discontinuation of study drug administration. Male participants must abstain from sperm donation during the study.
10. FOCBP is not pregnant or breastfeeding, or a male participant is not expecting to father children within the projected duration of the study, starting with screening visit through 28 weeks after the last dose of study drug.

Exclusion Criteria:

1. Active central nervous system (CNS) disease within the last 6 months.
2. 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.
3. Participants who had prior therapies within the specified times below:

   * Systemic antineoplastic therapy at least 5 half-lives or 4 weeks (whichever is shorter) prior to initiation of study drug.
   * Mediastinal or pelvic radiation therapy within 6 weeks prior to initiation of study drug administration. Palliative, limited field radiation for symptom control to soft tissues, or bone lesions within 2 weeks prior to initiation of study drug.
4. Participants must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia).
5. Clinically significant cardiovascular disease including but not limited to:

   * Myocardial infarction or unstable angina within 6 months prior to initiation of study drug.
   * Stroke or transient ischemic attack within 6 months prior to initiation of study drug.
   * Current clinically significant cardiac arrhythmias, for example, atrial fibrillation that are not well controlled with optimal medical intervention.
   * Current uncontrolled hypertension: systolic blood pressure \> 160 millimeters of mercury (mmHg), diastolic blood pressure \> 100 mmHg.
   * Current congestive heart failure (New York Heart Association class III-IV).
   * Current pericarditis or clinically significant pericardial effusion.
   * Current myocarditis.
   * Left ventricular ejection fraction (LVEF) of \< 50% by scan
   * QTc interval \> 480 milliseconds (msec)
6. Clinically significant pulmonary compromise, including pneumonia, pneumonitis, or a requirement for supplemental oxygen (excluding for sleep apnea) or history of ≥ Grade 3 drug-induced or radiation pneumonitis.
7. 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).
   * Human immunodeficiency virus infection.
   * Cytomegalovirus infection.
   * Active COVID-19/SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing should follow local clinical practice guidelines/standards.
   * Any other concurrent infectious disease requiring IV antibiotics within 2 weeks prior to initiation of study drug.
8. History of prior bone marrow, stem cell, or solid organ transplantation.
9. Second primary invasive malignancy that has not been in remission for greater than 2 years except nonmelanoma skin cancer; cervical carcinoma in situ on biopsy; or squamous intraepithelial lesion on Pap smear; localized prostate cancer (Gleason score \< 6); or resected melanoma in situ.
10. Major trauma or major surgery within 4 weeks prior to initiation of study drug.
11. Any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the study site.
12. Known hypersensitivity to any ingredient or any excipient contained in the drug formulation
13. Vaccination with any live virus vaccine within 4 weeks prior to initiation of study drug. Inactivated annual influenza vaccination is allowed.

Primary outcomes:
measure: Dose Escalation Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to approximately 3 years
measure: Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) Based on National Cancer Institute (NCI) Common Terminology Criteria for AEs Version 5.0 (CTCAE v5.0)
timeFrame: Cycle 1 (21 days for Schedule A and 28 days for Schedule B)
measure: Dose Expansion Phase: Objective Response Rate (ORR) - Percentage of Participants With Objective Response as Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Up to approximately 3 years
Secondary outcomes:
measure: Dose Escalation and Dose Expansion Phase: Maximum Study Drug Concentration (Cmax)
timeFrame: Schedule A: Cycle 1 Day 1 (C1D1), C3D1; Schedule B: C1D1, C1D15
measure: Dose Escalation and Dose Expansion Phase: Number of Participants With Antidrug Antibodies (ADA)
timeFrame: Up to approximately 3 years
measure: Dose Escalation Phase: ORR - Percentage of Participants With Objective Response as Assessed by the Investigator Using RECIST v1.1
timeFrame: Up to approximately 3 years
measure: Dose Escalation and Dose Expansion Phase: Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1
timeFrame: Up to approximately 3 years
measure: Dose Expansion Phase: Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1
timeFrame: Up to approximately 3 years
measure: Dose Expansion Phase: Number of Participants With TEAEs, SAEs, and IMGC936 Related TEAEs That Led to Discontinuation
timeFrame: Up to approximately 3 years
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD
state: California
city: Denver
country: United States
facility: Sarah Cannon Research Institute
state: Colorado
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Modena
country: Italy
facility: Policlinico di Modena
city: Rozzano
country: Italy
facility: IRCCS Humanitas
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese
city: Madrid
country: Spain
facility: START Madrid-FJD Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: START Madrid-HM CIOCC
city: Madrid
country: Spain
facility: Hospital Universitario Quirónsalud Madrid
Study officials:
affiliation: ImmunoGen, Inc.
name: CMO ImmunoGen
role: STUDY_DIRECTOR
References:
citation: Scribner JA, Hicks SW, Sinkevicius KW, Yoder NC, Diedrich G, Brown JG, Lucas J, Fuller ME, Son T, Dastur A, Hooley J, Espelin C, Themeles M, Chen FZ, Li Y, Chiechi M, Lee J, Barat B, Widjaja L, Gorlatov S, Tamura J, Ciccarone V, Ab O, McEachem KA, Koenig S, Westin EH, Moore PA, Chittenden T, Gregory RJ, Bonvini E, Loo D. Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody-drug Conjugate Targeting ADAM9-expressing Tumors. Mol Cancer Ther. 2022 Jul 5;21(7):1047-1059. doi: 10.1158/1535-7163.MCT-21-0915.