Clinical trial NCT03932331: Study of Acalabrutinib in Chinese Adult Subjects With Relapsed or Refractory Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia or Other B-cell Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-04-30
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria

1. 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.
2. Chinese subjects at least 18 years of age at the time of study entry.
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
4. Adequate hematological and organ function.
5. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy.
6. 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.
7. Diagnosis of CLL that meets published diagnostic criteria. Must have received ≥ 1 prior systemic therapies for CLL.
8. Active disease per iwCLL 2018 criteria that requires treatment. (CLL only)
9. Other relapsed/refractory B-cell malignancies without stand of care (phase 1 only).

Exclusion criteria

1. 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.
2. Significant cardiovascular disease.
3. Known central nervous system involvement of lymphoma/leukemia or leptomeningeal disease.
4. Known history of HIV, serologic status reflecting active hepatitis B or C infection.
5. Major surgery within 4 weeks before first dose of study drugs.
6. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
7. Required or received anticoagulation with warfarin or equivalent vitamin K antagonist (eg, phenprocoumon).
8. Prior exposure to a BCR or BCL-2 inhibitor.
9. Use of a strong inhibitor or inducer of CYP3A.
10. Breastfeeding or pregnant.

Primary outcomes:
measure: Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose administration up to 30 days following the date of last dose of study treatment, approximately 25 months.
measure: Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
measure: Phase I: Area Under the Plasma Concentration-Time Curve From Zero to 12 Hours (AUC0-12) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1
measure: Phase I: Area Under the Plasma Concentration-Time Curve From Zero to the Time of the Last Quantifiable Concentration (AUClast) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
measure: Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
timeFrame: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
timeFrame: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib
timeFrame: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Apparent Volume of Distribution (Vz/F) of Acalabrutinib Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
measure: Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
measure: Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
measure: Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
timeFrame: Single dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1; Multiple dose: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Metabolite/Parent Drug AUC Ratio (MRAUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 0 Day 1
measure: Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Metabolite/Parent Drug AUCτ Ratio (MRAUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
timeFrame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24 and 48 hours postdose on Cycle 1 Day 8
measure: Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR)
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
Secondary outcomes:
measure: Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days thereafter or more frequently at the investigator's discretion, approximately 25 months
measure: Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days thereafter or more frequently at the investigator's discretion, approximately 25 months
measure: Phase II: ORR Assessed by Investigator
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
measure: Phase II: Duration of Response (DoR) Assessed by BICR and Investigator
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
measure: Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
measure: Phase II: Time to Response (TTR) Assessed by BICR and Investigator
timeFrame: Response evaluations performed at the end of Cycles 2, 4 and 6; and then every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
measure: Phase II CLL Only: Time to Next Treatment (TTNT)
timeFrame: Response evaluations performed every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
measure: Phase II CLL Only: Percentage of Participants With Minimal Residual Disease (MRD) Negativity
timeFrame: At screening (-28 days) and end of treatment visit. Assessed until 18 December 2023.
measure: Phase II: Percentage of Participants With Overall Survival (OS) at Month 6
timeFrame: From the first dose administration up to Month 6
measure: Phase II: Plasma Concentration of Acalabrutinib
timeFrame: At 1, 2 and 4 hours post-dose on Day 8, 15 and 22 of Cycle 1
Other outcomes:
Locations:
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Changzhou
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Fuzhou
country: China
facility: Research Site
city: Haikou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Harbin
country: China
facility: Research Site
city: Hefei
country: China
facility: Research Site
city: Hohhot
country: China
facility: Research Site
city: Nanchang
country: China
facility: Research Site
city: Nanjing
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Suzhou
country: China
facility: Research Site
city: Tianjin
country: China
facility: Research Site
city: Tianjin
country: China
facility: Research Site
city: Urumqi
country: China
facility: Research Site
city: Xining
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Jun Zhu, Prof
role: PRINCIPAL_INVESTIGATOR
References: