A Phase I, First-In-Human, Multicenter, Open Label, and Dose-Escalation Study of TT-01488, Administered Orally in Adult Patients With B-Cell Malignancies
Overview
- Phase
- Phase 1
- Intervention
- TT-01488
- Conditions
- B-Cell Malignancies
- Sponsor
- TransThera Sciences (Nanjing), Inc.
- Enrollment
- 37
- Locations
- 2
- Primary Endpoint
- Dose-Limiting Toxicity (DLT) of TT-01488
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a first-in-human (FIH), 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.
Detailed 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Men and women ≥ 18 years of age with histologically or cytologically confirmed R/R B-NHL, including but not limited to chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), Waldenström macroglobulinemia (WM), follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large-b-cell lymphomas (DLBCL), and transformed lymphoma who failed or are intolerant to ≥ 1 prior standard of care regimens.
- •Patients with prior treatment of BTK inhibitors are eligible
- •Patients with low grade lymphoma must be progressing and requiring treatment:
- •Patients with CLL must have disease requiring treatment as specified in 2018 IWCLL Guidelines (Appendix 5)
- •Patients with B-cell NHL must have measurable disease per 2014 Lugano Classification (Appendix 6)
- •Patients with WM must have minimum serum immunoglobulin M (IgM) level of ≥ 2 times the upper limit of normal (ULN)
- •Body weight ≥ 40 kg
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- •Adequate organ function, defined by the following laboratory parameters:
- •Hematologic:
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)
- •A life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of TT-01488, or put the study outcomes at undue risk
- •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 including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, and corrected QT interval using Fridericia's Formula (QTcF) \> 470 msec, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
- •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
- •Any immunotherapy, , radiotherapy (limited-field radiation for palliation within 7 days), or experimental therapy within 4 weeks, or 5-half lives for chemotherapy and small molecule agents (whichever is shorter), before first dose of study drug (corticosteroids for disease-related symptoms allowed but require 1-week washout before study drug administration)
- •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;
Arms & Interventions
Dose Escalation for TT-01488
TT-01488 tablets will be administered once daily in a 28-day cycle in increasing strength in order to determine the recommended dose for dose expansion.
Intervention: TT-01488
Dose Expansion for TT-01488
TT-01488 tablets will be administered once daily in 28-day cycles to verify the safety and preliminary efficacy as observed in the dose escalation cohorts.
Intervention: TT-01488
Outcomes
Primary Outcomes
Dose-Limiting Toxicity (DLT) of TT-01488
Time Frame: Up to 28 days after first dose
Safety and tolerability of TT-01488 as a single agent
Dose recommend for dose expansion (DRDE)
Time Frame: 1 - 1.5 years
Safety and tolerability of TT-01488 as a single agent
Maximum Tolerated Dose (MTD), if reached, of TT-01488
Time Frame: Up to 28 days after first dose
Safety and tolerability of TT-01488 as a single agent
Secondary Outcomes
- Overall survival (OS)(1 - 1.5 years)
- Disease Control Rate (DCR)(1 - 1.5 years)
- Recommended Phase 2 dose (RP2D)(1 - 1.5 years)
- Objective Response Rate (ORR)(1 - 1.5 years)
- Maximum plasma concentration (Cmax)(1 - 1.5 years)
- Time to Maximum Plasma Concentration (Tmax)(1 - 1.5 years)
- Half-life (T1/2)(1 - 1.5 years)
- Number of participants with treatment-related adverse events (AEs)(1 - 1.5 years)
- Duration of Response (DOR)(1 - 1.5 years)
- Progression free survival (PFS)(1 - 1.5 years)
- Area under the concentration time curve (AUC 0-last)(1 - 1.5 years)
- Volume of Distribution (Vd)(1 - 1.5 years)
- Mean Residence Time (MRT)(1 - 1.5 years)