Phase 1a/1b Study of IGM-8444 Alone and in Combination in Subjects With Relapsed, Refractory, or Newly Diagnosed Cancers

Study Overview
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Brief Summary
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This study is a first-in-human, Phase 1a/1b, 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 or hematologic cancers, as well as newly diagnosed cancers, and an open-label, randomized study of IGM-8444+FOLFIRI (± bevacizumab).

Detailed Description
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Patients will be enrolled in Phase 1a, which consists of two stages: a dose-escalation stage and an expansion stage. IGM-8444 will be used as a single agent and in combination with numerous other agents where standard therapeutic regimens do not exist, have proven to be ineffective or intolerable, or are considered inappropriate. Colorectal patients may be enrolled in Phase 1b, an open-label, randomized study of IGM-8444+FOLFIRI (± bevacizumab) IGM-8444 will be investigated in numerous tumor types including all-comers solid tumors, colorectal carcinoma (CRC), sarcoma, non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL). IGM-8444 will be administered intravenously (IV). An alternative dosing schedule may be evaluated.

Official Title
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An Open-label, Multicenter, Phase 1a/1b Study of IGM-8444 as a Single Agent and in Combination in Subjects With Relapsed, Refractory, or Newly Diagnosed Cancers

Conditions
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Solid Tumor, Colorectal Cancer, Non Hodgkin Lymphoma, Sarcoma, Chondrosarcoma, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: IGM-8444
* Drug: FOLFIRI
* Drug: Bevacizumab (and approved biosimilars)
* Drug: Birinapant
* Drug: Venetoclax
* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years at time of signing ICF ECOG Performance Status of 0 or 1 Histologic documentation of incurable, locally advanced or metastatic tumor of the type being evaluated in individual cohorts. Adequate hepatic and renal function and adequate bone marrow reserve function. For combination cohorts, patients must be eligible to receive the chemotherapy or targeted agent. Ph1a only: No more than three prior therapeutic regimens. Ph1b only: Must be FOLFIRI naive subjects and must have received only 1 prior therapeutic regimen administered for the treatment of cancer in the advanced/metastatic setting. Key Exclusion Criteria: Inability to comply with study and follow-up procedures. Prior DR5 agonist therapy. Concomitant use of agents well-known to cause liver toxicity. Concomitant use of anti-cancer agents Palliative radiation to bone metastases within 2 weeks prior to Day 1. Major surgical procedure within 4 weeks prior to Day 1. Untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible. Prior use of any chemotherapeutic agent or small molecule inhibitors (SMI) within 2 weeks or 5 half-lives, prior to the first dose of study treatment Treatment with a monoclonal antibody, or any other anticancer agent (including biologic, experimental, or hormonal therapy) investigational or otherwise, that is not chemotherapy or a SMI, within 4 weeks or five half-lives prior to first dose of study treatment. Ph1b: Subjects who have previously received FOLFIRI treatment for advanced or metastatic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph1a: IGM-8444 Single Agent Alternate Dosing Escalation<br>IGM-8444 will be administered intravenously as a single agent on an alternate dosing schedule. | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>|
| Experimental: Ph1a: IGM-8444 + FOLFIRI ± bevacizumab Escalation and Expansion<br>IGM-8444 will be administered intravenously in combination with FOLFIRI. | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>Drug: FOLFIRI<br>* Chemotherapy Regimen<br>* Other names: Irinotecan;Drug: Bevacizumab (and approved biosimilars)<br>* Targeted Therapy<br>* Other names: Avastin;|
| Experimental: Ph1a: IGM-8444 + Birinapant Escalation and Expansion<br>IGM-8444 will be administered intravenously in combination with Birinapant which will also be administered intravenously. | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>Drug: Birinapant<br>* SMAC-mimetic Investigational Drug<br>|
| Experimental: Ph1a: IGM-8444 + Venetoclax Escalation and Expansion<br>IGM-8444 will be administered intravenously in combination with Venetoclax. | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>Drug: Venetoclax<br>* Targeted Therapy<br>* Other names: Venclexta;|
| Experimental: Ph1a: IGM-8444 + Docetaxel + Gemcitabine Escalation and Expansion<br>IGM-8444 will be administered intravenously in combination with Docetaxel and Gemcitabine. | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>Drug: Gemcitabine<br>* Chemotherapy<br>* Other names: Gemzar;Drug: Docetaxel<br>* Chemotherapy<br>* Other names: Docefrez;|
| Experimental: Ph1a: IGM-8444 + Venetoclax + Azacitidine Escalation and Expansion<br>IGM-8444 will be administered intravenously in combination with Venetoclax and Azacitidine. | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>Drug: Venetoclax<br>* Targeted Therapy<br>* Other names: Venclexta;Drug: Azacitidine<br>* Chemotherapy<br>* Other names: VIDAZA;|
| Experimental: Ph1b: IGM-8444 + FOLFIRI ± Bevacizumab<br>IGM-8444 will be administered intravenously in combination with FOLFIRI ± bevacizumab | Drug: IGM-8444<br>* DR5 Agonist Investigational Drug<br>Drug: FOLFIRI<br>* Chemotherapy Regimen<br>* Other names: Irinotecan;Drug: Bevacizumab (and approved biosimilars)<br>* Targeted Therapy<br>* Other names: Avastin;|
| Experimental: Ph1b: FOLFIRI ± Bevacizumab<br>Standard of Care FOLFIRI ± bevacizumab will be administered intravenously | Drug: FOLFIRI<br>* Chemotherapy Regimen<br>* Other names: Irinotecan;Drug: Bevacizumab (and approved biosimilars)<br>* Targeted Therapy<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ph1a: Adverse Events of IGM-8444 as single agent and with FOLFIRI ± bevacizumab, IGM-8444 with birinapant, IGM-8444 with venetoclax, IGM-8444 with venetoclax and azacitadine, and IGM-8444 with gemcitabine and docetaxel | Incidence of treatment-related AEs graded according to the NCI Common Technology Criteria for Adverse Events (CTCAE) v5.0 | From Cycle 1 Day 1 through 28 days after the final dose of study drug | 
| Ph1a: To identify the recommended expansion dose for IGM-8444 as single agent, with FOLFIRI ± bevacizumab, IGM-8444 with birinapant, IGM-8444 with venetoclax, IGM-8444 with venetoclax and azacitadine, and IGM-8444 with gemcitabine and docetaxel | Relationship between IGM-8444 dose and safety, PK, activity, and endpoints. | 4 weeks | 
| Ph1b: Objective Response Rate (ORR) | The ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by investigators | Study duration of approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ph1a: Area Under the Curve (AUC) of IGM-8444 | Area Under the Curve (AUC) of IGM-8444 as a single agent and in combination with the anticancer agents listed above. | At pre-defined intervals from Cycle 1 Day 1 through end of treatment at approximately 6 months | 
| Ph1a: Clearance (CL) of IGM-8444 | Clearance (CL) of IGM-8444 as a single agent and in combination with the anticancer agents listed above. | At pre-defined intervals from Cycle 1 Day 1 through end of treatment at approximately 6 months | 
| Ph1a: Volume of distribution (V) of IGM-8444 | Volume of distribution (V) of IGM-8444 as a single agent and in combination with the anticancer agents listed above. | At pre-defined intervals from Cycle 1 Day 1 through end of treatment at approximately 6 months | 
| Ph1a: Immunogenicity | Immunogenicity as assessed by detection of anti-drug antibodies (ADAs) to IGM-8444 | through end of treatment at approximately 6 months | 
| Ph1a: Objective Response Rate (ORR) | Preliminary efficacy of objective response rate (ORR) | Study duration of approximately 36 months | 
| Ph1a and Ph1b: Duration of Response (DoR) | Preliminary efficacy of duration of response (DoR) | Study duration of approximately 36 months | 
| Ph1a and Ph1b: Progression-Free Survival (PFS) | PFS is defined as the time from first dose (Ph1a) or randomization (Ph1b) to the first documented disease progression per RECIST 1.1 by investigator or death, whichever occurs first. | Study duration of approximately 36 months | 
| Ph1a and Ph1b: Overall Survival (OS) | OS is defined as the time from first dose (Ph1a) or randomization (Ph1b) to death due to any cause | Study duration of approximately 36 months | 
| Ph1b: Adverse events of IGM-8444 + FOLFIRI ± bevacizumab | Incidence of treatment-related AEs graded according to the NCI Common Technology Criteria for Adverse Events (CTCAE) v5.0 | From Cycle 1 Day 1 through 28 days after the final dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed and/or Refractory, Metastatic Cancer, Advanced Tumors, Hematological cancer, Newly diagnosed