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

• Status: Recruiting
• Trial end date: 2023-10-01
• Target enrollment: 0
• Participant gender: All

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

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: IGM Biosciences, Inc.
• Treatments: Bevacizumab; Fluorouracil; Irinotecan; Leucovorin; Venetoclax

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