A Phase 1 Study to Evaluate the Safety and Tolerability of TT-01488 in Patients With B-Cell Malignancies

Official title

A Phase I, Multicenter, Open Label, and Dose-Escalation Study of TT-01488, Administered Orally in Adult Patients With B-Cell Malignancies

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.

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.

Interventions

• Drug TT-01488 Tablets
  TT-01488 tablet will be administered orally once daily per protocol defined schedule.

Primary outcome measures

• Dose-Limiting Toxicity (DLT) of TT-01488 [Time frame: Up to 28 days after first dose]
• Dose recommend for dose expansion (DRDE) [Time frame: 3 years]
• Maximum Tolerated Dose (MTD), if reached, of TT-01488 [Time frame: Up to 28 days after first dose]

Secondary outcome measures (12)

• Number of participants with treatment-related adverse events (AEs) [Time frame: 3 years]
• Area under the concentration time curve (AUC 0-t) [Time frame: 3 years]
• Maximum plasma concentration (Cmax) [Time frame: 3 years]
• Time to Maximum Plasma Concentration (Tmax) [Time frame: 3 years]
• Half-life (T1/2) [Time frame: 3 years]
• Mean Residence Time (MRT) [Time frame: 3 years]
• Apparent volume of distribution associated with the terminal phase (Vz/F) [Time frame: 3 years]
• Apparent clearance (CL/F) [Time frame: 3 years]
• Objective Response Rate (ORR) [Time frame: 3 years]
• Disease Control Rate (DCR) [Time frame: 3 years]
• Duration of Response (DOR) [Time frame: 3 years]
• Progression free survival (PFS) [Time frame: 3 years]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital with Nanjing Medical University — Nanjing

Identifiers

NCT: NCT05683717 · TT01488CN02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗