MC# 21-23 - A Phase I Dose-Escalation and Dose Expansion Study of TJ033721 in Subjects with Advanced or Metastatic Solid Tumors

  • Agent(s): TJ033721
  • Disease Type(s): Esophageal, Gastric, Pancreatic, Solid Tumor, Gastroesophageal Junction
  • Phase(s): I
  • Drug Classification(s): Immunotherapy, Targeted Therapy, Bispecific Antibodies
  • Molecular Target(s): 4-1BB, CLDN18.2
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Mechanism of Action

TJ033721 is a bispecific T-cell engaging antibody that binds to the Claudin 18.2 (CLDN18.2) antigen found in several cancer cells and 4-1BB, an important regulator of cytotoxic immune response found on T cells.  On binding to these specific antigens, TJ033721 increases the tumor infiltrating lymphocytes and intensifies the immune response.  Preclinical studies demonstrate that the CLDN18.2-dependent immune activation produced by TJ033721 is superior to those produced by other 4-1BB monoclonal antibodies, even at low levels of CLDN18.2.  This tumor antigen-dependent T-cell engager is designed to avoid systemic toxicity, and the immune response is seen only in the tumor microenvironment, thus minimizing the risk of liver and systemic effects.

Purpose

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

  • How much of TJ033721 can be given with an acceptable level of side effects
  • About the safety and tolerability of TJ033721
  • How much of TJ033721 is absorbed into the blood and how fast it is removed
  • How proteins that indicate the status of your disease are affected with use of TJ033721
  • If your body develops proteins that work against TJ033721
Inclusion Criteria
  1. Males or females ages 18 years or older when starting study treatment;
  2. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
  3. Willingness and ability to consent for self to participate in study and the ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
  4. Histologically confirmed advanced or metastatic solid tumor in subjects whose disease has progressed despite standard therapy, or who has no further standard therapy, or who is unsuitable for available standard treatment options.  Subjects with HER2 positive esophagogastric cancer must have received prior anti-HER2 therapy;
  5. At least one measurable lesion as defined by RECIST 1.1;
  6. For dose expansion study only:
    1. Advanced or metastatic gastric cancer, gastroesophageal junction carcinoma, esophageal adenocarcinoma, and pancreatic ductal adenocarcinoma without further standard therapy or unsuitable for available standard treatment options.  The tumor types may be subject to adjustment based on the emerging nonclinical and clinical data;
    2. CLDN18.2-positive tumor (defined as membrane intensity score of >1+ on >1% of tumor cells as determine by CLDN18.2 IHC assay
  7. A 28-day washout period after the completion of programmed death-1 (PD-1)/PD-L1 therapy;
  8. Resolution of all acute adverse events resulting from prior cancer therapies to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade ≤ 1 or baseline (except alopecia or neuropathy);
  9. Considered by the investigator to be an appropriate candidate for a Phase 1 clinical study, with a life expectancy of ≥ 12 weeks;
  10. Adequate organ function as defined by the following criteria:
    1. Absolute neutrophil count (ANC) ≥ 1500/μL (≥ 1.5 × 109/L), without growth factor support for 7 days (14 days if on pegfilgrastim) prior to study treatment;
    2. Platelets ≥ 100,000/μL (≥100 ×109/L) without transfusion support within 14 days prior to study treatment;
    3. Hemoglobin ≥ 9.0 g/dL without transfusion support within 7 days prior to study drug administration (erythropoietin or darbepoetin permitted);
    4. Prothrombin Time (PT) ≤ 1.5 times the ULN, or 11 to 15 seconds in the absence of a normal range; partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 times the ULN; and international normalized ratio (INR) ≤ 1.5 times the ULN unless the subject is receiving anticoagulant therapy;
    5. Adequate renal function and serum creatinine ≤ 1.5 times the ULN or estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault equation;
    6. Total serum bilirubin ≤ 1.5 times the ULN, unless subject has documented Gilbert’s disease in which case total bilirubin ≤ 3.0 times the ULN;
    7. Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 3 times upper limit of normal (ULN);
    8. Albumin ≥ 2.5 g/dL.
  11. Males and females subject of childbearing potential must agree to use two forms of effective contraceptive methods while participating in the study until 84 days (12 weeks) after the last dose of TJ033721.  In addition, Women of childbearing potential (WOCBP) must have a negative serum/urine pregnancy test.
Exclusion Criteria
  1. Prior exposure to CLDN18.2 -targeted therapy;
  2. Prior exposure to 4-1BB agonists;
  3. Known active or chronic Hepatitis B (HbsAg positive and HBV-DNA ≥ 1000 cps/mL or 200 IU/mL), or Hepatitis C (HCVAb and HCV-RNA positive), other hepatitides (non-alcohol steatohepatitis, alcohol or drug-related, autoimmune) serology at screening or cirrhosis;
  4. Unstable/active ulcer or digestive tract bleeding within 6 weeks;
  5. Receipt of systemic anticancer therapy, including investigational agents or approval drugs or biological products (except hormone-replacement therapy, testosterone or oral contraceptives), within 28 days prior to study treatment (Note: if anticancer therapy was given within 28 days prior to starting study treatment, subjects are not excluded if ≥ 5 times the elimination half-life of the drug has elapsed);
  6. History of a ≥ Grade 3 immune-related adverse events (irAE) with prior immunotherapy with the exception of non-clinically significant laboratory abnormalities;
  7. Has an active autoimmune disease requiring systemic treatment within the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  Chronic systemic steroid therapy (in dosing exceeding 10mg of prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug is not permitted.  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or a short course of steroids for hypersensitivity reaction to IV contrast are not considered a form of systemic treatment and is permitted;
  8. Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or immunosuppressive medications;
  9. Current treatment on another therapeutic clinical trial;
  10. Major surgical procedure or significant traumatic injury within 4 weeks prior to study treatment and have not fully recovered from any such procedure; and have a date of surgery (if applicable) or anticipated need for a major surgical procedure planned within the next 6 months;
  11. Chest radiotherapy ≤ 28 days, wide field radiotherapy ≤ 28 days (defined as > 50% of volume of pelvic bones or equivalent), or limited field radiation for palliation ≤ 14 days prior to study treatment - such subjects must have recovered adequately from any side effects of such therapy;
  12. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with previously treated brain metastases may participate provided they are clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment;
  13. Has New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, severe/unstable angina, myocardial infarction (MI), symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack (TIA), arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), deep vein thrombosis, or coronary artery bypass grafting (CABG) in the previous 6 months;
  14. QTc ≥470 msec at the initial screening visit;
  15. Has a diagnosis of immunodeficiency such HIV;
  16. Has received a live vaccine within 30 days prior to the first dose of study drug or received any vaccine within 7 days of planned first dose of study treatment;
  17. Any active infection requiring systemic treatment;
  18. Female subjects in pregnancy, breastfeeding, or having a positive pregnancy test (serum or urine) within 7 days prior to study treatment;
  19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for this study;
  20. Unwilling or unable to comply with study procedures upon Investigator’s judgement (including follow-up procedures).

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04900818

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Re: MC# 21-23