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

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

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.

Study Overview

• Status: Recruiting
• Conditions: B-Cell Malignancies
• Intervention / Treatment: Drug: TT-01488 Tablets

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.

• Study Type: Interventional
• Enrollment (Estimated): 37
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sun Caixia, PhD; Phone Number: 025-58216298; Email: clinicaltrial@transtherabio.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • The First Affiliated Hospital with Nanjing Medical University
      • Contact: Jianyong Li, M.D.; Email: lijianyonglm@126.com
      • Contact: Wei Xu, M.D.; Email: xuwei10000@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: TT-01488 Tablets; TT-01488 tablet will be administered orally once daily per protocol defined schedule.
Experimental: 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.	Drug: TT-01488 Tablets; TT-01488 tablet will be administered orally once daily per protocol defined schedule.

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
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
Dose recommend for dose expansion (DRDE)	Safety and tolerability of TT-01488 as a single agent	3 years

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

Collaborators and Investigators

• Sponsor: TransThera Sciences (Nanjing), Inc.
• Investigators: Principal Investigator: Li Jianyong, The First Affiliated Hospital with Nanjing Medical University; Principal Investigator: Xu Wei, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 30, 2028

Study Registration Dates

• First Submitted: January 4, 2023
• First Submitted That Met QC Criteria: January 4, 2023
• First Posted (Actual): January 13, 2023

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: TT01488CN02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No