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

Locations

Arms

36.2

Anticipated Duration (Months)

Patients Per Site

0.9

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

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.

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

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 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

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
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

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
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
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
Immunogenicity [through end of treatment at approximately 6 months]
Immunogenicity as assessed by detection of anti-drug antibodies (ADAs) to IGM-8444
Objective Response Rate (ORR) [Study duration of approximately 36 months]
Preliminary efficacy of objective response rate (ORR)
Duration of Response (DoR) [Study duration of approximately 36 months]
Preliminary efficacy of duration of response (DoR)
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:

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

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
2	SCRI at Healthone	Denver	Colorado	United States	80218
3	Yale Cancer Center	New Haven	Connecticut	United States	06510
4	Florida Cancer Specialists	Sarasota	Florida	United States	34232
5	Norton Cancer Institute	Louisville	Kentucky	United States	40241
6	Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
7	Providence Portland Medical Center	Portland	Oregon	United States	97213
8	SCRI - Tennessee	Nashville	Tennessee	United States	37203
9	Mary Crowley Cancer Research	Dallas	Texas	United States	75230
10	The University of Texas, MD Anderson	Houston	Texas	United States	77030