Phase I Study of IGM-8444 as a Single Agent and in Combination in Subjects With Relapsed and/or Refractory Solid Cancers

Sponsor
IGM Biosciences, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04553692
Collaborator
(none)
320
Enrollment
9
Locations
10
Arms
36.2
Anticipated Duration (Months)
35.6
Patients Per Site
1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a first-in-human, Phase 1, multicenter, open-label study to determine the safety, tolerability and pharmacokinetics of IGM-8444 as a single agent and in combination in subjects with relapsed and/or refractory solid cancers

Detailed Description

Patients will be enrolled in two stages: a dose-escalation stage and an expansion stage.

The escalation stage will investigate single agent IGM-8444 in patients with solid tumors, IGM-8444 in combination with FOLFIRI for colorectal carcinoma patients, IGM-8444 in combination with birinapant in patients with solid tumors, and IGM-8444 in combination with venetoclax in patients with CLL/SLL. The IGM-8444 single agent expansion cohort will enroll solid tumor patients and may include relapsed/refractory non-Hodgkin lymphoma patients. The IGM-8444 + FOLFIRI with or without bevacizumab combination expansion cohorts will enroll colorectal carcinoma patients. The IGM-8444 + birinapant combination expansion cohort will enroll solid tumor patients, IGM-8444 in combination with venetoclax will enroll patients with CLL/SLL.

IGM-8444 will be administered intravenously (IV).

An alternative dosing schedule may be evaluated.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
320 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-label, Multicenter, Phase I Study of IGM-8444 as a Single Agent and in Combination in Subjects With Relapsed and/or Refractory Solid Cancers
Actual Study Start Date :
Sep 23, 2020
Anticipated Primary Completion Date :
Aug 1, 2023
Anticipated Study Completion Date :
Oct 1, 2023

Arms and Interventions

ArmIntervention/Treatment
Experimental: IGM-8444 Single Agent Escalation

IGM-8444 will be administered intravenously as a single agent.

Drug: IGM-8444
DR5 Agonist Investigational Drug

Experimental: IGM-8444 Single Agent Alternate Dosing Escalation

IGM-8444 will be administered intravenously as a single agent on an alternate dosing schedule.

Drug: IGM-8444
DR5 Agonist Investigational Drug

Experimental: IGM-8444 + FOLFIRI Escalation

IGM-8444 will be administered intravenously in combination with FOLFIRI.

Drug: IGM-8444
DR5 Agonist Investigational Drug

Drug: FOLFIRI
Chemotherapy Regimen
Other Names:
  • Fluorouracil or 5-FU
  • Leucovorin
  • Irinotecan
  • Experimental: IGM-8444 Single Agent Expansion

    IGM-8444 will be administered intravenously as a single agent in disease specific cohorts.

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Experimental: IGM-8444 + FOLFIRI Expansion

    IGM-8444 will be administered intravenously in combination with FOLFIRI.

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Drug: FOLFIRI
    Chemotherapy Regimen
    Other Names:
  • Fluorouracil or 5-FU
  • Leucovorin
  • Irinotecan
  • Experimental: IGM-8444 + FOLFIRI + Bevacizumab (and approved biosimilars) Expansion

    IGM-8444 will be administered intravenously in combination with FOLFIRI and bevacizumab (and approved biosimilars).

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Drug: FOLFIRI
    Chemotherapy Regimen
    Other Names:
  • Fluorouracil or 5-FU
  • Leucovorin
  • Irinotecan
  • Drug: Bevacizumab (and approved biosimilars)
    Targeted Therapy
    Other Names:
  • Avastin
  • Experimental: IGM-8444 + Birinapant Escalation

    IGM-8444 will be administered intravenously in combination with Birinapant which will also be administered intravenously.

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Drug: Birinapant
    SMAC-mimetic Investigational Drug

    Experimental: IGM-8444 + Birinapant Expansion

    IGM-8444 will be administered intravenously in combination with Birinapant which will also be administered intravenously.

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Drug: Birinapant
    SMAC-mimetic Investigational Drug

    Experimental: IGM-8444 + Venetoclax Escalation

    IGM-8444 will be administered intravenously in combination with Venetoclax.

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Drug: Venetoclax
    Targeted Therapy
    Other Names:
  • Venclexta
  • Experimental: IGM-8444 + Venetoclax Expansion

    IGM-8444 will be administered intravenously in combination with Venetoclax.

    Drug: IGM-8444
    DR5 Agonist Investigational Drug

    Drug: Venetoclax
    Targeted Therapy
    Other Names:
  • Venclexta
  • Outcome Measures

    Primary Outcome Measures

    1. Adverse Events of IGM-8444 as a single agent as single agent and in combination with FOLFIRI +/- bevacizumab, IGM-8444 in combination with birinapant, and IGM-8444 in combination with venetoclax [From Cycle 1 Day 1 through 28 days after the final dose of study drug]

      Incidence of treatment-related AEs graded according to the NCI Common Technology Criteria for Adverse Events (CTCAE) v5.0

    2. Recommended Phase 2 Dose (RP2D) of IGM-8444 as a single agent as single agent and in combination with FOLFIRI +/- bevacizumab, IGM-8444 in combination with birinapant, and IGM-8444 in combination with venetoclax [4 weeks]

      The number and proportion of patients experiencing at least one DLT will be used as the primary measure to evaluate the RP2D of IGM-8444

    Secondary Outcome Measures

    1. Area Under the Curve (AUC) of IGM-8444 [At pre-defined intervals from Cycle 1 Day 1 through end of treatment at approximately 6 months]

      Area Under the Curve (AUC) of IGM-8444 as a single agent and in combination with FOLFIRI +/- bevacizumab, IGM-8444 in combination with birinapant, and IGM-8444 in combination with venetoclax

    2. Clearance (CL) of IGM-8444 [At pre-defined intervals from Cycle 1 Day 1 through end of treatment at approximately 6 months]

      Clearance (CL) of IGM-8444 as a single agent and in combination with FOLFIRI +/- bevacizumab, IGM-8444 in combination with birinapant, and IGM-8444 in combination with venetoclax

    3. Volume of distribution (V) of IGM-8444 [At pre-defined intervals from Cycle 1 Day 1 through end of treatment at approximately 6 months]

      Volume of distribution (V) of IGM-8444 as a single agent and in combination with FOLFIRI +/- bevacizumab, IGM-8444 in combination with birinapant, and IGM-8444 in combination with venetoclax

    4. Immunogenicity [through end of treatment at approximately 6 months]

      Immunogenicity as assessed by detection of anti-drug antibodies (ADAs) to IGM-8444

    5. Objective Response Rate (ORR) [Study duration of approximately 36 months]

      Preliminary efficacy of objective response rate (ORR)

    6. Duration of Response (DoR) [Study duration of approximately 36 months]

      Preliminary efficacy of duration of response (DoR)

    7. Progression-Free Survival (PFS) [Study duration of approximately 36 months]

      Preliminary efficacy of progression-free survival (PFS)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:
    • Age ≥ 18 years at time of signing Informed Consent Form

    • Life expectancy of at least 12 weeks

    • ECOG Performance Status of 0 or 1

    • Patients who are either refractory to or intolerant of existing standard therapy or for whom no effective further standard of care therapy exists.

    • No more than three prior therapeutic regimens ("therapeutic" is defined as any cytotoxic, biologic, or targeted therapy [approved or investigational] with intent to treat the cancer) administered for the treatment of cancer in the advanced/metastatic setting.

    • For dose escalation cohorts only: Patients with either measurable or evaluable disease.

    • Patients with histologic documentation of incurable, locally advanced or metastatic prostate cancer with non-measurable disease are eligible if they have an increase in prostate-specific antigen (PSA) level of > 50% from current level, the absolute increase is ≥ 5 ng/mL, and the increase is confirmed a second time.

    • Patients with histologic documentation of incurable, locally advanced or metastatic ovarian cancer with non-measurable disease are eligible if they have an increase of > 2 × the baseline level in CA-125 (or > 2 × the ULN in case of prior normal CA-125 level) and the increase is confirmed a second time.

    • Adequate organ function as evidenced by (hematologic parameters must be assessed at least 14 days from the last growth factor support or prior transfusion, if any):

    • ANC ≥ 1000/μL.

    • Total hemoglobin ≥ 9 g/dL.

    • Platelet count ≥ 100,000/μL.

    • Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or estimated creatinine clearance ≥ 50 mL/min (Cockcroft Gault or other institutional methods).

    • Serum aspartate transaminase (AST) and serum ALT ≤ 2 × ULN.

    • AST and ALT ≤ 3 × ULN is allowed if liver function abnormalities are due to underlying malignancy.

    • Total serum bilirubin ≤ 1.5 × ULN regardless of liver involvement secondary to tumor.

    • Inclusion of patients with increased serum indirect bilirubin (≤ 3 × ULN) due to Gilbert's syndrome is permitted.

    • Alkaline phosphatase ≤ 2.5 × the ULN

    • Albumin ≥3.0 g/dL.

    • No clinically significant pleural or peritoneal effusion requiring drainage.

    For birinapant combination cohorts only:
    • ANC ≥ 1500/μL.
    For venetoclax combination cohorts only:
    • Documented diagnosis of CLL that meets the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria

    • Measurable nodal disease by computed tomography (CT) for SLL

    • Relapsed/refractory disease with an indication for treatment

    • Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as follows, unless cytopenia is due to marrow involvement of CLL Platelet counts ≥ 75,000/μL For those patients with a screening lymphocyte count < 5,000 cells/μL, historical data confirming a lymphocyte count 5,000 cells/μL at time of diagnosis is required

    Key Exclusion Criteria:
    • Prior DR5 agonist therapy.

    • Prior Bcl-family inhibitor therapy

    • Known clinically significant history of liver disease including Child-Pugh Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol abuse, non-alcoholic steatohepatitis (NASH), or cirrhosis.

    • Diagnosis of any secondary malignancy within 3 years prior to enrollment

    • Untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control).

    • Current Grade > 1 toxicity (except alopecia and anorexia) from prior therapy. Patients with current Grade 2 chronic toxicities that are well-controlled by medications may be enrolled after discussion with medical monitor.

    • For birinapant-containing combination cohort only:

    • Patients who have previously received birinapant treatment

    • History of allergic reactions attributed to compounds of similar chemical or biologic composition to birinapant

    • Known HIV positivity

    • Requires concomitant chronic use of anti-tumor necrosis factor (anti-TNF) therapies (e.g. infliximab, golimumab, certolizumab, adalimumab, etanercept) within 5 half-lives of drug prior to Cycle 1 Day 1

    • Requires systemic or chronic topical steroids or immunosuppressive therapy within 4 weeks prior to study treatment or anticipated need of systemic corticosteroids or immunosuppressive therapy during study participation

    • Evidence of active, non-infectious pneumonitis or history of clinically significant interstitial lung disease

    • Chondrosarcoma Cohort: Mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes

    • For venetoclax-containing combination cohort only:

    • Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leukemia, or DLBCL or CNS involvement by CLL

    • Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

    • History of confirmed progressive multifocal leukoencephalopathy (PML)

    • Known HIV positivity

    • Hypersensitivity to venetoclax or to any of the excipients

    • Malabsorption syndrome or other condition that precludes enteral route of administration

    • Inability to swallow a large number of tablets

    • Treatment with any other anti-cancer agent, investigational or otherwise) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to first dose of study treatment

    • Patients who have received the following agents:

    • Strong and moderate CYP3A inhibitors (Appendix 12) within 7 days prior to the first dose of study drug administration

    • Strong and moderate CYP3A inducers (Appendix 12) within days prior to the first dose of study drug administration

    • Consumed grapefruit, grapefruit juice, Seville oranges (including marmalade containing Seville oranges), Seville orange juice, or star fruit within 3 days prior to the first dose of study drug and throughout venetoclax administration

    • Vaccination with a live vaccine within 28 days prior to study treatment

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1City of Hope Comprehensive Cancer CenterDuarteCaliforniaUnited States91010
    2SCRI at HealthoneDenverColoradoUnited States80218
    3Yale Cancer CenterNew HavenConnecticutUnited States06510
    4Florida Cancer SpecialistsSarasotaFloridaUnited States34232
    5Norton Cancer InstituteLouisvilleKentuckyUnited States40241
    6Stephenson Cancer CenterOklahoma CityOklahomaUnited States73104
    7SCRI - TennesseeNashvilleTennesseeUnited States37203
    8Mary Crowley Cancer ResearchDallasTexasUnited States75230
    9The University of Texas, MD AndersonHoustonTexasUnited States77030

    Sponsors and Collaborators

    • IGM Biosciences, Inc.

    Investigators

    • Study Director: Eric Humke, MD, PhD, IGM Biosciences

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    IGM Biosciences, Inc.
    ClinicalTrials.gov Identifier:
    NCT04553692
    Other Study ID Numbers:
    • IGM-8444-001
    First Posted:
    Sep 17, 2020
    Last Update Posted:
    Mar 15, 2022
    Last Verified:
    Mar 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by IGM Biosciences, Inc.
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Mar 15, 2022