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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
B-Cell Malignancies

Intervention / Treatment
-----------------
* Drug: TT-01488 Tablets


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation for TT-01488<br>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. | Drug: TT-01488 Tablets<br>* TT-01488 tablet will be administered orally once daily per protocol defined schedule.<br>|
| Experimental: Dose Expansion for TT-01488<br>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. | Drug: TT-01488 Tablets<br>* TT-01488 tablet will be administered orally once daily per protocol defined schedule.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Limiting Toxicity (DLT) of TT-01488 | Safety and tolerability of TT-01488 as a single agent | Up to 28 days after first dose | 
| Dose recommend for dose expansion (DRDE) | Safety and tolerability of TT-01488 as a single agent | 3 years | 
| Maximum Tolerated Dose (MTD), if reached, of TT-01488 | Safety and tolerability of TT-01488 as a single agent | Up to 28 days after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events (AEs) | Safety and tolerability of TT-01488 as a single agent. AEs will be assessed per CTCAE v5.0 or 2018 IWCLL and may include, but is not limited to, clinically abnormal laboratory tests, physical exams, vital signs, electrocardiograms, and ECOG performance status. | 3 years | 
| Area under the concentration time curve (AUC 0-t) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Maximum plasma concentration (Cmax) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Time to Maximum Plasma Concentration (Tmax) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Half-life (T1/2) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Mean Residence Time (MRT) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Apparent volume of distribution associated with the terminal phase (Vz/F) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Apparent clearance (CL/F) | Pharmacokinetic (PK) profile of TT-01488 as a single agent | 3 years | 
| Objective Response Rate (ORR) | Preliminary efficacy profile of TT-01488 as a single agent | 3 years | 
| Disease Control Rate (DCR) | Preliminary efficacy profile of TT-01488 as a single agent | 3 years | 
| Duration of Response (DOR) | Preliminary efficacy profile of TT-01488 as a single agent | 3 years | 
| Progression free survival (PFS) | Preliminary efficacy profile of TT-01488 as a single agent | 3 years | 
| Overall survival (OS) | Preliminary efficacy profile of TT-01488 as a single agent | 3 years |