MC# 21-36 - 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

  • Agent(s): IGM-8444
  • Disease Type(s): Colorectal, Chronic Lymphocytic Leukemia
  • Phase(s): I
  • Drug Classification(s): Monoclonal Antibody, Small Molecule, Targeted Therapy
  • Molecular Target(s): DR5, cIAP-1
Ask Us About This Trial

Mechanism of Action

IGM-8444 is an agonist antibody to DRS on the cell surface. Binding of the antibody to DRS mimics the interaction between DRS and its natural ligand, TRAIL.  Crosslinking activates the death receptor pathway leading to induction of apoptosis.  Birinipant is a small molecule SMAC mimetic. SMAC is also an activator of apoptosis.  Therefore, there could be a stronger apoptotic signal if the two agents are combined.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of IGM-8444 can be given with an acceptable level of side effects and in combination with other drugs
  • The effects of IGM-8444 (good and bad) and in combination with other drugs
  • How much of IGM-8444 is absorbed into the blood and how fast it is removed
Inclusion Criteria
  1. Signed ICF
  2. Age ≥ 18 years at time of signing ICF
  3. Ability to comply with the study protocol, in the investigator’s judgement
  4. Life expectancy of at least 12 weeks
  5. ECOG Performance Status of 0 or 1
  6. Histologic or cytologic documentation of incurable, locally advanced, or metastatic cancer
  7. Patients who are either refractory to or intolerant of existing standard therapy or for whom no effective further standard of care therapy exists
  8. 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
  9. 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 (Bubley et al., 1999)
    • 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
  10. For chemotherapy combination dose escalation cohorts only:
    • Histologic documentation of incurable, locally advanced or metastatic colon or rectal adenocarcinoma or carcinoma
    • Patients with incurable, locally advanced or metastatic colon or rectal adenocarcinoma or carcinoma for whom FOLFIRI is considered an appropriate therapy
      • Other incurable, locally advanced or metastatic tumor types investigators deem appropriate for FOLFIRI therapy may be enrolled with medical monitor approval
  11. Archival or fresh tumor tissue available for biomarker evaluation unless approved by medical monitor
  12. 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
  13. International normalized ratio (INR) ≤ 1.5 and no clinically significant bleeding event within 6 months
  14. At least 2 weeks prior to Day 1 or 5 half-lives, whichever is shorter, must have elapsed from the use of anti-tumor therapy, including chemotherapy, biologic, experimental, or hormonal therapy with the following exceptions:
    • Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer
    • Hormone-replacement therapy or oral contraceptives
  15. For women of childbearing potential or men, agreement to use one highly effective form of non-hormonal contraception or one highly effective form and one effective form of non-hormonal contraception through the course of study treatment and for 3 months after the last dose of IGM-8444 single agent treatment, for 3 months after 5-fluorouracil-based chemotherapy treatment, for 6 months after bevacizumab (and approved biosimilars) treatment, for 3 months after last dose of birinapant, and for 30 days after venetoclax treatment
    • A woman is considered not to be of childbearing potential if she is postmenopausal, defined by amenorrhea for ≥ 12 months and age ≥ 45 years, and FSH and estradiol are within post-menopausal range, or age ≥ 60, or has undergone hysterectomy and/or bilateral oophorectomy
    • Highly effective forms of contraception are defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly
    • Effective forms of contraception are defined as acceptable birth control methods that result in a failure rate of more than 1% per year when used consistently and correctly
  16. For women of childbearing potential, a negative serum pregnancy test within 7 days prior to commencement of dosing; women who are considered not to be of childbearing potential are not required to have a pregnancy test
  17. Male patients must agree to abstain from sperm donation for 3 months after the last dose of IGM-8444, for 3 months after 5-fluorouracil-based chemotherapy treatment, for 6 months after bevacizumab (and approved biosimilars) treatment, for 3 months after last dose of birinapant, and for 30 days after venetoclax treatment
  18. For solid tumor dose expansion cohorts only: At least one target lesion that can be accurately measured per RECIST v.1.1
  19. For single agent dose expansion cohorts only:
    • All-comers Cohort: Histologic documentation of incurable, locally advanced or metastatic cancer or non-Hodgkin’s Lymphoma
      • Patients with non-Hodgkin’s Lymphoma must have received at least 2 prior systemic therapies
    • Colorectal cancer Cohort: Histologic documentation of incurable, locally advanced or metastatic colon or rectal adenocarcinoma or carcinoma
    • Non-small cell lung cancer Cohort: Histologic documentation of incurable, locally advanced or metastatic non-small cell lung cancer
    • Sarcoma Cohort: Histologic documentation of incurable, locally advanced or metastatic soft tissue sarcoma
    • Gastric Cohort: Histologic documentation of incurable, locally advanced or metastatic gastric adenocarcinoma
  20. For chemotherapy combination dose expansion cohort only:
    • Histologic documentation of incurable, locally advanced or metastatic colon or rectal adenocarcinoma or carcinoma
    • Patients with incurable, locally advanced or metastatic colon or rectal adenocarcinoma or carcinoma for whom FOLFIRI ± bevacizumab (and approved biosimilars) is considered an appropriate therapy
  21. For birinapant combination cohorts only:
    • ANC ≥ 1500/μL
    • Chondrosarcoma Expansion Cohort: Surgically unresectable or metastatic disease, histologically confirmed diagnosis of conventional chondrosarcoma of any grade
  22. 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 defined below:
      • Relapsed disease: a patient who previously achieved a CR or PR, but after a period of 6 months or more demonstrates evidence of progression
      • Refractory disease: treatment failure or disease progression within 6 months of the last anti-leukemia therapy
    • :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:
      • Absolute neutrophil count ≥ 1000/μL
      • Platelet counts ≥ 75,000/μL; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet counts below 75,000/μL should be discussed and reviewed with Medical Monitor for enrollment consideration
      • Total hemoglobin ≥9 g/dL (without transfusion support within 2 weeks of screening)
      • Adequate liver function as indicated by a total bilirubin, aspartate transaminase (AST), and alanine transaminase (ALT) ≤ 2x the institutional upper limit of normal (ULN) value unless directly attributed to the patient’s CLL
      • 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
Exclusion Criteria
  1. Pregnancy or breastfeeding
  2. Prior DR5 agonist therapy
  3. Prior Bcl-family inhibitor therapy
  4. Concomitant use of agents well known to cause liver toxicity
  5. Current treatment with medications that are well known to prolong the QT interval
    • Patients deemed to be clinically stable per the judgement of the investigator based on length of time on medications and baseline QTcF results being within normal limits are eligible
  6. History of severe allergic or anaphylactic reactions to antibody therapy (or recombinant antibody-related fusion proteins)
  7. Palliative radiation to bone metastases within 2 weeks prior to Day 1
  8. Major surgical procedure within 4 weeks prior to Day 1
  9. Known active bacterial, viral (including COVID-19), fungal, mycobacterial, parasitic, or other infection (including HIV and atypical mycobacterial disease but excluding fungal infections of the nail beds) at study enrollment or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1
  10. Patients with active Hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening
    • Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible
    • HBV DNA should be obtained in these patients prior to study treatment administration
  11. Patients with active Hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA testing at screening
    • Patients who are positive for HCV antibody are eligible only if Polymerase Chain Reaction (PCR) is negative for HCV RNA.
  12. Evidence of significant uncontrolled concomitant diseases, such as cardiovascular disease (including stroke, New York Heart Association Class III or IV cardiac disease or myocardial infarction within 6 months prior to screening, unstable arrhythmias, and unstable angina); pulmonary, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders; autoimmune disease, or a serious nonhealing wound or fracture
  13. History or presence of an abnormal ECG that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree atrioventricular heart block, or evidence of prior myocardial infarction
  14. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
  15. Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low grade localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ (CIS) of the breast, or Stage I uterine cancer
  16. 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, provided that they meet all of the following criteria:
    • Evaluable or measurable disease outside the CNS
    • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
    • The screening CNS radiographic study is ≥ 8 weeks since completion of radiotherapy and ≥ 4 weeks since the discontinuation of corticosteroids and anticonvulsants
  17. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
  18. 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.
  19. For bevacizumab (and approved biosimilars)-containing chemotherapy cohorts only:
    • Recent history of hemoptysis of ≥1/2 teaspoon of red blood
  20. For chemotherapy combination dose expansion cohort only:
    • Neuroendocrine histology
  21. 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
    • History of cranial nerve palsy
    • Uncontrolled hypertension defined as blood pressure > 160/100 mmHg without medication, or not controlled despite medications
    • 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
    • Clinically significant pulmonary illness resulting in grade ≥ 2 hypoxia per Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) or any requirement for supplemental oxygen, or pulse oximetry less than 88% saturation on room air
    • Chondrosarcoma Cohort: Mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes
  22. 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
    • Prior use of any monoclonal antibody within 8 weeks prior to first dose of study treatment
    • Prior use of any chemotherapeutic agent or small molecule inhibitors within 2 weeks or 5 half-lives, whichever is shorter, prior to first dose of study treatment
    • 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 7 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
  23. Inability to comply with study and follow-up procedures

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT04553692

Contact Us About This Trial

Reach out to us by sharing your info in the form below or give us a call at 972-566-3000.

Re: MC# 21-36