Overview
This is a multicenter, open-label Phase I dose escalation study to evaluate the safety and preliminary efficacy of the TT-01488 tablet, a non-covalent reversible BTK inhibitor, for the treatment of adult patients with B-cell malignancies.
Description
The study will consist of two parts, dose escalation and dose expansion. A modified 3+3 design will be used to guide the dose escalation and the determination of the dose recommended for dose expansion (DRDE). A sentinel cohort comprising of one subject will be enrolled at a starting dose of 50 mg q.d. Subsequently, patients will be enrolled according to the standard 3+3 dose escalation design to determine the DRDE. Once the DRDE has been selected, TT-01488 of DRDE will be further tested in the dose expansion cohort to verify the safety and preliminary efficacy as observed in the dose escalation cohorts. A recommended Phase II dose (RP2D) may be determined based on the totality of safety, pharmacokinetics, and efficacy data from the dose escalation cohorts and dose expansion cohort.
Eligibility
Inclusion Criteria:
- Participants with histologically confirmed B-cell malignancy, failed or intolerant to
either ≥ 2 prior standard/common regimens given in combination or sequentially OR have
received 1 prior BTK-containing regimen, relapse/refractory, and with treatment
- indication
-
- CLL/SLL treated with prior immunochemistry or BTK inhibitor containing regimen;
- DLBCL treated with prior CD20 or anthracyclines containing regimen;
- Other types of B-cell NHL treated with prior CD20 containing regimen
- Adequate organ function, defined by the following laboratory parameters:
- Hematologic:
- Absolute neutrophil count (ANC) ≥ 0.75×10^9/L, and ≥ 0.5×10^9/L if bone marrow
involved
- Platelets ≥ 50×10^9/L without transfusion within 7 days, and ≥ 30×10^9/L if bone marrow involved
- Hemoglobin ≥ 8.0 g/dL without transfusion within 7 days, and ≥ 7.0 g/dL if bone marrow
involved
- Coagulation:
- Prothrombin time (PT) ≤ 1.5 × ULN
- Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
- Renal function:
- Creatinine clearance ≥ 30 mL/min estimated glomerular filtration rate based on
Cockcroft-Gault formula
- Liver function:
- Total bilirubin ≤ 1.5 × ULN (unless due to Gilbert's disease)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 × ULN unless disease-related
Exclusion Criteria:
- Women who are pregnant or lactating
- Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years or which will not limit survival to < 2 years (Note: these cases must be discussed with the Medical Monitor and/or Investigator)
- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or significant screening ECG abnormalities
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
- History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen
receptor-modified T-cell (CAR-T) therapy within the past 60 days or with any of the
- following
-
- Active graft versus host disease (GvHD);
- Cytopenias from incomplete blood cell count recovery post-transplant;
- Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy;
- Ongoing immunosuppressive therapy
- Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy,
including radiation