Study of Acalabrutinib in Chinese Adult Subjects With Relapsed or Refractory Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia or Other B-cell Malignancies

Study Overview
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Brief Summary
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This is an open-label, two-part study to assess the safety, tolerability, pharmacokinetics and clinical efficacy of acalabrutinib in Chinese adult subjects with R/R MCL, CLL and other B-cell malignancies. The study is divided into 2 parts: Phase 1 portion and Phase 2 portion.

Official Title
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A Phase 1/2 Open Label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Acalabrutinib in Chinese Adult Subjects With Relapsed or Refractory Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia or Other B-cell Malignancies

Conditions
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Phase I: Relapsed or Refractory B-cell Malignancies, Phase II Cohort A: Relapsed or Refractory Mantle Cell Lymphoma, Phase II Cohort B: Relapsed or Refractory Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Chinese subjects at least 18 years of age at the time of study entry. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 Adequate hematological and organ function. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy. Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14) (q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (eg, CD5, CD19, CD20, PAX5). Disease had relapsed after or been refractory to previous treatment. Diagnosis of CLL that meets published diagnostic criteria. Must have received ≥ 1 prior systemic therapies for CLL. Active disease per iwCLL 2018 criteria that requires treatment. (CLL only) Other relapsed/refractory B-cell malignancies without stand of care (phase 1 only). Exclusion criteria Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject had been disease free for ≥2 years or which would not have limited survival to <2 years. Significant cardiovascular disease. Known central nervous system involvement of lymphoma/leukemia or leptomeningeal disease. Known history of HIV, serologic status reflecting active hepatitis B or C infection. Major surgery within 4 weeks before first dose of study drugs. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. Required or received anticoagulation with warfarin or equivalent vitamin K antagonist (eg, phenprocoumon). Prior exposure to a BCR or BCL-2 inhibitor. Use of a strong inhibitor or inducer of CYP3A. Breastfeeding or pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib<br>Acalabrutinib will be orally administered until disease progression or unacceptable toxicity. | Drug: Acalabrutinib<br>* Acalabrutinib 100 mg orally twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of participants with Adverse Events (AEs) |  | approximately 2 years. | 
| Phase 2: Overall Response Rate (ORR) |  | up to 3 years | 
| Phase 1: Pharmacokinetics Characterization after single dose, AUC (Area under the plasma concentration-time curve (from zero to infinity) ) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, AUC0-12 (Area under the plasma concentration-time curve (from zero to 12 hours)) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, AUC0-t (Area under the plasma concentration-time curve (from zero to the time of the last measurable concentration)) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, Cmax (Maximum observed plasma concentration) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, tmax (Time to maximum concentration) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, CL/F (Oral clearance) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, Vz/F (Volume of distribution) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, λz (Terminal rate constant) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, t1/2 (Terminal half life) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, MR_Cmax (metabolite-to-parent ratio, Maximum observed plasma concentration) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after single dose, MR_AUC (metabolite-to-parent ratio, Area under the plasma concentration-time curve (from zero to infinity)) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, AUCτ,ss (Area under the plasma concentration-time curve across the dosing interval at steady state) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, Cmax,ss (Maximum observed plasma concentration at steady state) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, Cmin,ss (Minimum observed plasma drug concentration at steady state) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, tmax,ss (Time to maximum concentration at steady stage) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, CLss/F (Oral clearance at steady stage) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, MR_ AUCτ (metabolite-to-parent ratio, Area under the plasma concentration-time curve across the dosing interval) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, TCP (Temporal change parameter in systemic exposure (also known as: time dependency, temporal parameter change, linearity index); calculated as AUCτ(steady state)/AUC(first dose)) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, Rac(AUC) (Accumulation ratio calculated as AUCτ(steady state)/AUCτ(first dose)) |  | approximately 1 month. | 
| Phase 1: Pharmacokinetics Characterization after multiple doses, Rac(Cmax) (Accumulation ratio calculated as Cmax,ss/Cmax) |  | approximately 1 month. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Tumor response (number of patients with Complete Response (CR), Partial Response (PR), Stable Diseaase (SD), Progression of Disease (PD)) |  | up to 2 years. | 
| Phase 2: Number of participants with Adverse Events (AEs) |  | approximately 2 year. | 
| Phase 2: Plasma concentration of acalabrutinib and its major metabolite (sparse sampling) |  | up to 1 month. | 
| Phase 2: Progression free survival (PFS) |  | up to 3 years | 
| Phase 2: Duration of Response (DoR) |  | up to 3 years | 
| Phase 2: Time To Response (TTR) |  | up to 3 years | 
| Phase 2: Overall Survival (OS) |  | up to 3 years | 
| Phase 2: Time to Next Treatment (for R/R CLL only) |  | up to 3 years | 
| Phase 2: Minimum Residual Disease Rate (for R/R CLL only) |  | up to 3 years |