MC# 21-15 - An Open-Label, Phase I/II Study to Evaluate Safety, Efficacy, Pharmacokinetics of EU101, an Agonistic Anti-CD137 (4-1BB) Monoclonal Antibody in Patients with Advanced Solid Tumors

  • Agent(s): EU101
  • Disease Type(s): Colorectal, Solid Tumor, Lung-NSCLC
  • Phase(s): I, II
  • Drug Classification(s): Targeted Therapy, Monoclonal Antibody
  • Molecular Target(s): CD137

Mechanism of Action

EU-101 is a human monoclonal antibody (mAb) agonist that binds to 4-1BB (also called CD137), a protein receptor expressed in many immune cells, particularly CD8+ and CD4+ T cells.  The binding of a 4-1BB agonist to CD137 is typically found to stimulate and increase the number of T cells, which strengthens anti-tumor immunity to kill cancer cells.

Purpose

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

  • How much of EU101 can be given with an acceptable level of side effects
  • About the safety and tolerability of EU101
  • How much of EU101 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from EU101
Inclusion Criteria
  1. At least 18 years of age
  2. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumors for which no standard therapy exists or standard therapy has failed because of disease progression or unacceptable toxicities.  Also includes patients who cannot be treated with standard therapy because of underlying/existing medical condition.
  3. Phase 2:
    1. Cohort 1 (colorectal cancer):
      1. CRC (including microsatellite instability-high [MSI-H] and microsatellite- stable [MSS]) regardless of RAS mutation
      2. Disease progression within 3 months after last administration of approved standard therapies
      3. Prior cytotoxic chemotherapy for metastatic disease include all the following agents: fluoropyrimidine, oxaliplatin, and irinotecan
        • Adjuvant chemotherapy-based treatments count as prior therapy, as long as relapse had occurred within 6 months of completion of such therapies
        • Prior anti-epidermal growth factor receptor (EGFR) therapy (cetuximab, panitumumab), anti-angiogenic therapy (bevacizumab, aflibercept, ramucirumab), regorafenib, and TAS-102 are allowed
      4. No more than 5 prior therapies for metastatic disease.  For patients who had disease recurrence within 6 months of completing adjuvant chemotherapy, the adjuvant regimen can be considered as 1 chemotherapy regimen for metastatic disease.
    2. Cohort 2 (NSCLC):
      1. NSCLC without known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1 genomic tumor aberrations
      2. No standard therapy exists or standard therapy has failed
      3. No more than 3 prior therapies for metastatic disease
  4. Phase 2: At least 1 measurable lesion per RECIST version 1.1
  5. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2
  6. Adequate organ and bone marrow function as defined below:
    1. Hemoglobin >9.0 g/dL (without transfusion that has occurred within 2 weeks of the hemoglobin measurement)
    2. Absolute neutrophil count ≥1,500/µL (without transfusion that has occurred within 2 weeks of the measurement)
    3. Absolute lymphocyte count ≥900 and ≤2,500/µL
    4. Platelet count ≥100,000/µL
    5. Total bilirubin ≤1.5 × ULN (except for patients with documented Gilbert’s syndrome)
    6. ALT and AST ≤2.5 × ULN (regardless of presence of liver metastases)
    7. Serum creatinine ≤1.5 × ULN or creatinine clearance >30 mL/min (creatinine clearance should be calculated using the Cockcroft-Gault formula)
    8. Prothrombin time and activated partial thromboplastin time ≤1.5 × ULN
  7. Life expectancy of at least 12 weeks
  8. Voluntarily provided a written consent to participate in the study
  9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within the 7 days before study drug administration.  A female patient is considered to be of childbearing potential after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).
  10. WOCBP and sexually active fertile male patients with partners who are WOCBP must agree to use 2 highly effective methods of contraception throughout the course of the study and for 12 weeks after the last dose of study drug.  For the definition and list of highly effective methods of contraception.
Exclusion Criteria
  1. Primary central nervous system (CNS) tumor (Phase 1), CNS metastasis, and/or carcinomatous meningitis.  Patients with prior brain metastases treated at least 4 weeks before the first dose of EU101 that are clinically stable and do not require chronic corticosteroid treatment are allowed.
  2. Received prior therapy with any anti-CD137 mAb or agent
  3. Current or history of autoimmune disease that requires immunosuppressants or systemic treatment within 2 years before the Screening Visit (patients with diabetes type 1, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
  4. Toxicity that occurred during the prior anticancer therapy that has not resolved to ≤ Grade 1 per National Cancer Institute (NCI) CTCAE 5.0 (except for clinically insignificant toxicity such as alopecia)
  5. Major surgery requiring general anesthesia within 3 weeks before first dose of EU101 or still recovering from prior surgery
  6. Active infection that is not controlled or requires intravenous (IV) antibiotics
  7. History of allogeneic tissue or organ transplant
  8. Active hepatitis B virus or hepatitis C virus infection.  Patients who have tested positive for hepatitis B surface antigen and/or hepatitis B core antibody plus have a positive hepatitis B polymerase chain reaction (PCR) assay are excluded; patients who have previously tested positive with a low or undetectable hepatitis B PCR assay are permitted with appropriate antiviral prophylaxis.  Patients who are hepatitis C antibody positive with negative PCR and have completed a full course of antiviral therapy can be included.
  9. History of any noninfectious hepatitis (ie, alcohol or nonalcoholic steatohepatitis, drug-related or autoimmune hepatitis)
  10. Human immunodeficiency virus (HIV) infection.  Patients with human immunodeficiency virus (HIV) infection with no history of acquired immunodeficiency syndrome (AIDS), no history of opportunistic infection in the past 12 months, and CD4+ T-cell (CD4+) counts ≥350 cells/uL can be included.
  11. Received systemic anticancer chemotherapy, biologics, other investigational product, or investigational device within 4 weeks before first dose of EU101 (a 2-week washout is permitted for palliative radiation to non-CNS disease)
  12. Received or receiving systemic corticosteroid therapy or any other form of systemic immunosuppressive medication 1 week before first dose of EU101 (daily prednisone at doses of ≤10 mg or prednisone equivalent dose are allowed)
  13. Known severe (≥ Grade 3) hypersensitivity reactions to antibody, or severe reaction (ie, colitis or pneumonitis) to immuno-oncology agents requiring treatment with steroids
  14. Known or suspected hypersensitivity to EU101 or any component of its formulation (eg, histidine, polysorbate 80)
  15. Current or history of interstitial lung disease, anaphylaxis, uncontrolled asthma, or pneumonitis that has required systemic corticosteroids
  16. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥3 years
  17. Clinically significant concurrent cardiovascular disease
    1. Uncontrolled hypertension (persistent systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg)
    2. Unstable angina and severe heart failure (New York Heart Association [NYHA] class III/IV) that occurred within 24 weeks before the Screening Visit
    3. Pulmonary embolism or deep venous thrombosis that occurred within 24 weeks before the Screening Visit
    4. Patients with QT interval corrected using Fridericia’s formula (QTcF) >480 msec, for males and females
  18. Pregnant women, breastfeeding women, WOCBP, or men with partners who are WOCBP who do not agree to use adequate contraceptive measures
  19. Determined as unable to participate in the study per investigator’s judgment

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City

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Re: MC# 21-15