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

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ClinicalTrials.gov Identifier: NCT04553692
Recruitment Status : Recruiting
First Posted : September 17, 2020
Last Update Posted : December 14, 2021
Sponsor:
Information provided by (Responsible Party):
IGM Biosciences, Inc.

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

Condition or disease Intervention/treatment Phase
Solid Tumor Colorectal Cancer Gastric Cancer Non Hodgkin Lymphoma Non-Small Cell Lung Cancer Sarcoma Chondrosarcoma Small Lymphocytic Lymphoma Chronic Lymphocytic Leukemia Drug: IGM-8444 Drug: FOLFIRI Drug: Bevacizumab (and approved biosimilars) Drug: Birinapant Drug: Venetoclax Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : September 23, 2020
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : October 2023


Arm Intervention/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 Name: 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 Name: 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 Name: Venclexta




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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: Study duration of approximately 36 months ]
    Preliminary efficacy of objective response rate (ORR)

  6. Duration of Response (DoR) [ Time Frame: Study duration of approximately 36 months ]
    Preliminary efficacy of duration of response (DoR)

  7. Progression-Free Survival (PFS) [ Time Frame: Study duration of approximately 36 months ]
    Preliminary efficacy of progression-free survival (PFS)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04553692


Contacts
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Contact: Clinical Trials 650 265 6428 clinicaltrials@igmbio.com

Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Clinical Trials       clinicaltrials@igmbio.com   
United States, Colorado
SCRI at Healthone Recruiting
Denver, Colorado, United States, 80218
Contact: Clinical Trials       clinicaltrials@igmbio.com   
United States, Connecticut
Yale Cancer Center Recruiting
New Haven, Connecticut, United States, 06510
Contact: Clinical Trials       clinicaltrials@igmbio.com   
United States, Florida
Florida Cancer Specialists Recruiting
Sarasota, Florida, United States, 34232
Contact: Clinical Trials       clinicaltrials@igmbio.com   
United States, Oklahoma
Stephenson Cancer Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Clinical Trials       clinicaltrials@igmbio.com   
United States, Tennessee
SCRI - Tennessee Recruiting
Nashville, Tennessee, United States, 37203
Contact: Clinical Trials       clinicaltrials@igmbio.com   
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: Clinical Trials       clinicaltrials@igmbio.com   
The University of Texas, MD Anderson Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Trials       clinicaltrials@igmbio.com   
Sponsors and Collaborators
IGM Biosciences, Inc.
Investigators
Layout table for investigator information
Study Director: Eric Humke, MD, PhD IGM Biosciences
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Responsible Party: IGM Biosciences, Inc.
ClinicalTrials.gov Identifier: NCT04553692    
Other Study ID Numbers: IGM-8444-001
First Posted: September 17, 2020    Key Record Dates
Last Update Posted: December 14, 2021
Last Verified: December 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by IGM Biosciences, Inc.:
Relapsed and/or Refractory
Metastatic Cancer
Advanced Tumors
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Chondrosarcoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Sarcoma
Neoplasms, Connective and Soft Tissue
Leukemia, Lymphoid
Leukemia
Leukemia, B-Cell
Neoplasms, Connective Tissue
Leucovorin
Bevacizumab
Fluorouracil
Irinotecan
Venetoclax
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic