Phase II Cohort A: Relapsed or Refractory Mantle Cell Lymphoma, Phase II Cohort B: Relapsed or Refractory Chronic Lymphocytic Leukemia, Phase I: Relapsed or Refractory B-cell Malignancies
Conditions
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.
Interventions
DRUGAcalabrutinib
Acalabrutinib 100 mg orally twice daily
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose administration up to 30 days following the date of last dose of study treatment, approximately 25 months. | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. A SAE is an AE occurring during any study phase, that fulfils 1 or more of the following criteria: death, life-threatening, in-participant hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital abnormality or birth defect, and an important medical event that may jeopardize the participant or may require medical treatment to prevent 1 of the outcomes listed above. AEs leading to discontinuation of acalabrutinib were those with action taken was 'Drug Permanently Discontinued' for acalabrutinib. |
| Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | 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 | Blood samples were collected to determine the AUCinf of acalabrutinib and ACP-5862 in plasma. The AUCinf was determined using non-compartmental method. |
| 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 | Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1 | Blood samples were collected to determine the AUC0-12 of acalabrutinib and ACP-5862 in plasma. The AUC0-12 was determined using non-compartmental method. |
| 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 | 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 | Blood samples were collected to determine the AUClast of acalabrutinib and ACP-5862 in plasma. The AUClast was determined using non-compartmental method. |
| Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the Cmax of acalabrutinib and ACP-5862 in plasma. The Cmax was determined using non-compartmental method. |
| Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the tmax of acalabrutinib and ACP-5862 in plasma. The tmax was determined using non-compartmental method. |
| Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib | 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 | Urine samples were collected to determine the CL/F of acalabrutinib. The CL/F was determined using non-compartmental method. |
| Phase I: Apparent Volume of Distribution (Vz/F) of Acalabrutinib Post Single Dose of Acalabrutinib | 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 | Blood samples were collected to determine the Vz/F of acalabrutinib in plasma. The Vz/F was determined using non-compartmental method. |
| Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | 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 | Blood samples were collected to determine the λz of acalabrutinib and ACP-5862 in plasma. The λz was determined using non-compartmental method. |
| Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | 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 | Blood samples were collected to determine the t1/2λz of acalabrutinib and ACP-5862 in plasma. The t1/2λz was determined using non-compartmental method. |
| Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the MRCmax of acalabrutinib and ACP-5862 in plasma. The MRCmax was determined using non-compartmental method. |
| Phase I: Metabolite/Parent Drug AUC Ratio (MRAUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | 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 | Blood samples were collected to determine the MRAUCinf of acalabrutinib in plasma. The MRAUCinf was determined using non-compartmental method. |
| Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the AUCτ of acalabrutinib and ACP-5862 in plasma. The AUCτ was determined using non-compartmental method. |
| Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the Cmin of acalabrutinib and ACP-5862 in plasma. The Cmin was determined using non-compartmental method. |
| Phase I: Metabolite/Parent Drug AUCτ Ratio (MRAUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the MRAUCτ of acalabrutinib and ACP-5862 in plasma. The MRAUCτ was determined using non-compartmental method. |
| Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the TCP of acalabrutinib and ACP-5862 in plasma. The TCP in systemic exposure was calculated as AUCτ (steady state)/AUCinf (first dose). The TCP was determined using non-compartmental method. |
| Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the Rac AUC of acalabrutinib and ACP-5862 in plasma. The Rac AUC was calculated as AUCτ (steady state)/AUCτ (first dose). The Rac AUC was determined using non-compartmental method. |
| Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 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 | Blood samples were collected to determine the Rac Cmax of acalabrutinib and ACP-5862 in plasma. The Rac Cmax was calculated as Cmax (steady state)/Cmax (first dose). The Rac Cmax was determined using non-compartmental method. |
| Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) | 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. | The ORR \[based on International workshop on chronic lymphocytic leukemia (iwCLL) 2018 criteria as assessed by the BICR\] was defined as the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi), nodular partial response (nPR), and partial response (PR). The ORR and the corresponding 95% 2-sided confidence interval (CI) of ORR were presented based on Clopper-Pearson exact method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | 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 | The BOR is best response a participant has had following first dose date but prior to starting any subsequent anticancer therapy up to and including progression or last evaluable assessment in absence of progression. The CR: No lymph nodes \>=1.5 centimeters. The CRi: Participants who fulfill all criteria for CR but have a persistent anemia, thrombocytopenia or neutropenia apparently unrelated to CLL but related to drug toxicity. The nPR: Participants who were in a complete remission but bone marrow nodules can be identified histologically. The PR: Disease \>=50% from baseline. Partial response with lymphocytosis (PRL): Presence of lymphocytosis plus \>=50% reduction in lymphadenopathy and/or in spleen or liver enlargement plus 1 of PR criteria for platelets or hemoglobin must be met. Stable disease (SD): Change of -49% to +49% in lymph nodes. PD: Increase \>=50% from baseline or from response. |
| Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL | 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 | The BOR is best response a participant has had following first dose date but prior to starting any subsequent anticancer therapy up to and including progression or last evaluable assessment in absence of progression. CR: No lymph nodes \>=1.5 centimeters. PR: Disease \>=50% from baseline. SD: Change of -49% to +49% in lymph nodes. PD: Increase \>=50% from baseline or from response. |
| Phase II: ORR Assessed by Investigator | 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. | The ORR (based on iwCLL 2018 criteria as assessed by the Investigator) was defined as the percentage of participants who achieved a CR, CRi, nPR, and PR. The ORR and the corresponding 95% 2-sided CI of ORR were presented based on Clopper-Pearson exact method. |
| Phase II: Duration of Response (DoR) Assessed by BICR and Investigator | 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. | The DoR (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval from the first documentation of objective response to the earlier of the first documentation of objective PD or death from any cause. The DoR was calculated using Kaplan-Meier technique. |
| Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator | 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. | The PFS (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval from the start of acalabrutinib therapy to the earlier of the first documentation of objective PD or death from any cause. The PFS was calculated using Kaplan-Meier technique. |
| Phase II: Time to Response (TTR) Assessed by BICR and Investigator | 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. | The TTR (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval between the date of first dose and the date of initial documentation of a response. |
| Phase II CLL Only: Time to Next Treatment (TTNT) | Response evaluations performed every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023. | The TTNT was defined as the interval from the start of acalabrutinib therapy to institution of non-protocol specified anticancer treatment for CLL or death due to any cause, whichever came first. The TTNT was calculated using Kaplan-Meier technique. |
| Phase II CLL Only: Percentage of Participants With Minimal Residual Disease (MRD) Negativity | At screening (-28 days) and end of treatment visit. Assessed until 18 December 2023. | The MRD negative rate was defined as the percentage of participants with MRD-negativity (\<1 CLL cell per 10000 leukocytes) measured in the peripheral blood by flow cytometry. |
| Phase II: Percentage of Participants With Overall Survival (OS) at Month 6 | From the first dose administration up to Month 6 | The OS was defined as the interval from the start of acalabrutinib therapy to death from any cause. The OS was calculated using Kaplan-Meier technique. |
| Phase II: Plasma Concentration of Acalabrutinib | At 1, 2 and 4 hours post-dose on Day 8, 15 and 22 of Cycle 1 | Blood samples were collected to determine the plasma concentration of acalabrutinib. |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORJun Zhu, Prof
Peking University Cancer Hospital & Institute
Participant flow
Recruitment details
This Phase I/II open-label study was conducted in participants with relapsed/refractory (R/R) mantle cell lymphoma (MCL), R/R chronic lymphocytic leukemia (CLL) or other B-cell malignancies at 20 study centers in China. The Phase II CLL results are reported for analysis with assessment until data cut-off (DCO) date of 18 December 2023. PD= Progressive disease.
Pre-assignment details
This study was divided into 2 parts: Phase I portion (participants with R/R B-cell malignancies) and Phase II portion (participants with R/R MCL and R/R CLL). Study consists of screening period (28 days), treatment period until PD and a safety and survival follow-up period. A total of 105 unique participants were enrolled in the study, 12 participants in Phase I, 33 participants in Phase II MCL, 60 participants in Phase II CLL. One participant from Phase I entered Phase II MCL reporting group.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Participants received single dose of acalabrutinib 100 mg capsule orally on Day 1 Cycle 0 and followed by 2 days washout period and then received acalabrutinib 100 mg capsule orally twice daily in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 12 |
| Phase II MCL Participants received acalabrutinib 100 mg capsule orally twice daily in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 33 |
| Phase II CLL Participants received acalabrutinib 100 mg capsule orally twice daily in 28-day cycle until PD or specific treatment discontinuation criteria were met. | 60 |
| Total | 105 |
Baseline characteristics
| Characteristic | Phase I | Phase II MCL | Phase II CLL | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 11 Participants | 23 Participants | 39 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 22 Participants | 37 Participants | 66 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 33 Participants | 60 Participants | 105 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 19 Participants | 30 Participants |
| Sex: Female, Male Male | 5 Participants | 29 Participants | 41 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 7 / 34 | 2 / 60 |
| other Total, other adverse events | 12 / 12 | 28 / 34 | 56 / 60 |
| serious Total, serious adverse events | 2 / 12 | 6 / 34 | 21 / 60 |
Outcome results
Primary
Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the Rac AUC of acalabrutinib and ACP-5862 in plasma. The Rac AUC was calculated as AUCτ (steady state)/AUCτ (first dose). The Rac AUC was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | Acalabrutinib | 1.048 ratio | Geometric Coefficient of Variation 37.97 |
| Phase I | Phase I: Accumulation Ratio of AUCτ (Rac AUC) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | ACP-5862 | 1.348 ratio | Geometric Coefficient of Variation 41.64 |
Primary
Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the Rac Cmax of acalabrutinib and ACP-5862 in plasma. The Rac Cmax was calculated as Cmax (steady state)/Cmax (first dose). The Rac Cmax was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | Acalabrutinib | 0.8218 ratio | Geometric Coefficient of Variation 59.99 |
| Phase I | Phase I: Accumulation Ratio of Cmax (Rac Cmax) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | ACP-5862 | 1.130 ratio | Geometric Coefficient of Variation 70.23 |
Primary
Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib
Urine samples were collected to determine the CL/F of acalabrutinib. The CL/F was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib | Post single dose | 74.01 liter per hour | Geometric Coefficient of Variation 36.77 |
| Phase I | Phase I: Apparent Total Body Clearance of Drug (CL/F) of Acalabrutinib Post Single and Multiple Dose of Acalabrutinib | Post multiple dose | 72.81 liter per hour | Geometric Coefficient of Variation 45.25 |
Primary
Phase I: Apparent Volume of Distribution (Vz/F) of Acalabrutinib Post Single Dose of Acalabrutinib
Blood samples were collected to determine the Vz/F of acalabrutinib in plasma. The Vz/F was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I | Phase I: Apparent Volume of Distribution (Vz/F) of Acalabrutinib Post Single Dose of Acalabrutinib | 171.3 liter | Geometric Coefficient of Variation 105.5 |
Primary
Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the AUCτ of acalabrutinib and ACP-5862 in plasma. The AUCτ was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | Acalabrutinib | 1373 h*ng/mL | Geometric Coefficient of Variation 43.62 |
| Phase I | Phase I: Area Under the Plasma Concentration-Time Curve Across the Dosing Interval (AUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | ACP-5862 | 2707 h*ng/mL | Geometric Coefficient of Variation 28.61 |
Primary
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
Blood samples were collected to determine the AUC0-12 of acalabrutinib and ACP-5862 in plasma. The AUC0-12 was determined using non-compartmental method.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 12 hours postdose on Cycle 0 Day 1
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | 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 | Acalabrutinib | 1310 h*ng/mL | Geometric Coefficient of Variation 50.39 |
| Phase I | 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 | ACP-5862 | 2008 h*ng/mL | Geometric Coefficient of Variation 37.76 |
Primary
Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the AUCinf of acalabrutinib and ACP-5862 in plasma. The AUCinf was determined using non-compartmental method.
Time frame: 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
Population: The Pharmacokinetics (PK) analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | Acalabrutinib | 1351 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 47.99 |
| Phase I | Phase I: Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | ACP-5862 | 2421 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 29.46 |
Primary
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
Blood samples were collected to determine the AUClast of acalabrutinib and ACP-5862 in plasma. The AUClast was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | 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 | Acalabrutinib | 1343 h*ng/mL | Geometric Coefficient of Variation 48.4 |
| Phase I | 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 | ACP-5862 | 2270 h*ng/mL | Geometric Coefficient of Variation 32.82 |
Primary
Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR)
The ORR \[based on International workshop on chronic lymphocytic leukemia (iwCLL) 2018 criteria as assessed by the BICR\] was defined as the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi), nodular partial response (nPR), and partial response (PR). The ORR and the corresponding 95% 2-sided confidence interval (CI) of ORR were presented based on Clopper-Pearson exact method.
Time frame: 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.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. One participant from Phase I rolled over to Phase II MCL reporting group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) | 82.4 percentage of participants |
| Phase II CLL | Phase II: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) | 86.7 percentage of participants |
Primary
Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
Blood samples were collected to determine the Cmax of acalabrutinib and ACP-5862 in plasma. The Cmax was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post single dose: Acalabrutinib | 967.6 ng/mL | Geometric Coefficient of Variation 59.52 |
| Phase I | Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post single dose: ACP-5862 | 628.1 ng/mL | Geometric Coefficient of Variation 46.38 |
| Phase I | Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post multiple dose: Acalabrutinib | 958.2 ng/mL | Geometric Coefficient of Variation 60.99 |
| Phase I | Phase I: Maximum Observed Plasma Drug Concentration (Cmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post multiple dose: ACP-5862 | 710.0 ng/mL | Geometric Coefficient of Variation 38.08 |
Primary
Phase I: Metabolite/Parent Drug AUC Ratio (MRAUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the MRAUCinf of acalabrutinib in plasma. The MRAUCinf was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I | Phase I: Metabolite/Parent Drug AUC Ratio (MRAUCinf) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | 1.732 ratio | Geometric Coefficient of Variation 31.55 |
Primary
Phase I: Metabolite/Parent Drug AUCτ Ratio (MRAUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the MRAUCτ of acalabrutinib and ACP-5862 in plasma. The MRAUCτ was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I | Phase I: Metabolite/Parent Drug AUCτ Ratio (MRAUCτ) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | 1.906 ratio | Geometric Coefficient of Variation 33.26 |
Primary
Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
Blood samples were collected to determine the MRCmax of acalabrutinib and ACP-5862 in plasma. The MRCmax was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post single dose | 0.6276 ratio | Geometric Coefficient of Variation 37.87 |
| Phase I | Phase I: Metabolite/Parent Drug Cmax Ratio (MRCmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post multiple dose | 0.7662 ratio | Geometric Coefficient of Variation 43.08 |
Primary
Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the Cmin of acalabrutinib and ACP-5862 in plasma. The Cmin was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | Acalabrutinib | 2.443 ng/mL | Geometric Coefficient of Variation 148 |
| Phase I | Phase I: Minimum Observed Plasma Drug Concentration (Cmin) of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | ACP-5862 | 37.52 ng/mL | Geometric Coefficient of Variation 37.58 |
Primary
Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. A SAE is an AE occurring during any study phase, that fulfils 1 or more of the following criteria: death, life-threatening, in-participant hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital abnormality or birth defect, and an important medical event that may jeopardize the participant or may require medical treatment to prevent 1 of the outcomes listed above. AEs leading to discontinuation of acalabrutinib were those with action taken was 'Drug Permanently Discontinued' for acalabrutinib.
Time frame: From the first dose administration up to 30 days following the date of last dose of study treatment, approximately 25 months.
Population: The Safety analysis set included all participants who received at least 1 dose of acalabrutinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I | Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 12 Participants |
| Phase I | Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 2 Participants |
| Phase I | Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE leading to discontinuation of Acalabrutinib | 1 Participants |
| Phase I | Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE with outcome death | 0 Participants |
Primary
Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib
Blood samples were collected to determine the TCP of acalabrutinib and ACP-5862 in plasma. The TCP in systemic exposure was calculated as AUCτ (steady state)/AUCinf (first dose). The TCP was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | Acalabrutinib | 1.017 ratio | Geometric Coefficient of Variation 37.57 |
| Phase I | Phase I: Temporal Change Parameter (TCP) in Systemic Exposure of Acalabrutinib and ACP-5862 Post Multiple Dose of Acalabrutinib | ACP-5862 | 1.118 ratio | Geometric Coefficient of Variation 17.15 |
Primary
Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the λz of acalabrutinib and ACP-5862 in plasma. The λz was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | Acalabrutinib | 0.43212 1/hour | Geometric Coefficient of Variation 51.085 |
| Phase I | Phase I: Terminal Elimination Rate Constant (λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | ACP-5862 | 0.096102 1/hour | Geometric Coefficient of Variation 19.036 |
Primary
Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib
Blood samples were collected to determine the t1/2λz of acalabrutinib and ACP-5862 in plasma. The t1/2λz was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | Acalabrutinib | 1.604 hour | Geometric Coefficient of Variation 76.21 |
| Phase I | Phase I: Terminal Phase Half-Life (t1/2λz) of Acalabrutinib and ACP-5862 Post Single Dose of Acalabrutinib | ACP-5862 | 7.213 hour | Geometric Coefficient of Variation 28.03 |
Primary
Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib
Blood samples were collected to determine the tmax of acalabrutinib and ACP-5862 in plasma. The tmax was determined using non-compartmental method.
Time frame: 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
Population: The PK analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I | Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post single dose: Acalabrutinib | 0.50 hour |
| Phase I | Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post single dose: ACP-5862 | 0.88 hour |
| Phase I | Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post multiple dose: Acalabrutinib | 0.50 hour |
| Phase I | Phase I: Time to Reach Maximum Observed Concentration (Tmax) of Acalabrutinib and ACP-5862 Post Single and Multiple Dose of Acalabrutinib | Post multiple dose: ACP-5862 | 1.00 hour |
Secondary
Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL
The BOR is best response a participant has had following first dose date but prior to starting any subsequent anticancer therapy up to and including progression or last evaluable assessment in absence of progression. CR: No lymph nodes \>=1.5 centimeters. PR: Disease \>=50% from baseline. SD: Change of -49% to +49% in lymph nodes. PD: Increase \>=50% from baseline or from response.
Time frame: 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
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. Only participants with R/R MCL are analyzed in this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I | Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL | CR | 1 Participants |
| Phase I | Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL | PR | 4 Participants |
| Phase I | Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL | SD | 0 Participants |
| Phase I | Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL | PD | 3 Participants |
| Phase I | Phase I: Best Overall Response Assessed by Investigator in Participants With R/R MCL | Not evaluable | 0 Participants |
Secondary
Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL
The BOR is best response a participant has had following first dose date but prior to starting any subsequent anticancer therapy up to and including progression or last evaluable assessment in absence of progression. The CR: No lymph nodes \>=1.5 centimeters. The CRi: Participants who fulfill all criteria for CR but have a persistent anemia, thrombocytopenia or neutropenia apparently unrelated to CLL but related to drug toxicity. The nPR: Participants who were in a complete remission but bone marrow nodules can be identified histologically. The PR: Disease \>=50% from baseline. Partial response with lymphocytosis (PRL): Presence of lymphocytosis plus \>=50% reduction in lymphadenopathy and/or in spleen or liver enlargement plus 1 of PR criteria for platelets or hemoglobin must be met. Stable disease (SD): Change of -49% to +49% in lymph nodes. PD: Increase \>=50% from baseline or from response.
Time frame: 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
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. Only participants with R/R CLL are analyzed in this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | CR | 0 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | CRi | 0 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | nPR | 0 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | PR | 4 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | PRL | 0 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | SD | 0 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | PD | 0 Participants |
| Phase I | Phase I: Best Overall Response (BOR) Assessed by Investigator in Participants With R/R CLL | Not evaluable | 0 Participants |
Secondary
Phase II CLL Only: Percentage of Participants With Minimal Residual Disease (MRD) Negativity
The MRD negative rate was defined as the percentage of participants with MRD-negativity (\<1 CLL cell per 10000 leukocytes) measured in the peripheral blood by flow cytometry.
Time frame: At screening (-28 days) and end of treatment visit. Assessed until 18 December 2023.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase II CLL Only: Percentage of Participants With Minimal Residual Disease (MRD) Negativity | 0 percentage of participants |
Secondary
Phase II CLL Only: Time to Next Treatment (TTNT)
The TTNT was defined as the interval from the start of acalabrutinib therapy to institution of non-protocol specified anticancer treatment for CLL or death due to any cause, whichever came first. The TTNT was calculated using Kaplan-Meier technique.
Time frame: Response evaluations performed every 12 weeks +/- 7 days through Cycle 25, and then every 24 weeks +/- 7 days thereafter. Assessed until 18 December 2023.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I | Phase II CLL Only: Time to Next Treatment (TTNT) | NA months |
Secondary
Phase II: Duration of Response (DoR) Assessed by BICR and Investigator
The DoR (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval from the first documentation of objective response to the earlier of the first documentation of objective PD or death from any cause. The DoR was calculated using Kaplan-Meier technique.
Time frame: 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.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. Only participants who achieved PR or above were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I | Phase II: Duration of Response (DoR) Assessed by BICR and Investigator | BICR Assessment | NA months |
| Phase I | Phase II: Duration of Response (DoR) Assessed by BICR and Investigator | Investigator Assessment | NA months |
| Phase II CLL | Phase II: Duration of Response (DoR) Assessed by BICR and Investigator | BICR Assessment | NA months |
| Phase II CLL | Phase II: Duration of Response (DoR) Assessed by BICR and Investigator | Investigator Assessment | NA months |
Secondary
Phase II: ORR Assessed by Investigator
The ORR (based on iwCLL 2018 criteria as assessed by the Investigator) was defined as the percentage of participants who achieved a CR, CRi, nPR, and PR. The ORR and the corresponding 95% 2-sided CI of ORR were presented based on Clopper-Pearson exact method.
Time frame: 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.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. One participant from Phase I rolled over to Phase II MCL reporting group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase II: ORR Assessed by Investigator | 73.5 percentage of participants |
| Phase II CLL | Phase II: ORR Assessed by Investigator | 85.0 percentage of participants |
Secondary
Phase II: Percentage of Participants With Overall Survival (OS) at Month 6
The OS was defined as the interval from the start of acalabrutinib therapy to death from any cause. The OS was calculated using Kaplan-Meier technique.
Time frame: From the first dose administration up to Month 6
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. One participant from Phase I rolled over to Phase II MCL reporting group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Phase II: Percentage of Participants With Overall Survival (OS) at Month 6 | NA percentage of participants |
| Phase II CLL | Phase II: Percentage of Participants With Overall Survival (OS) at Month 6 | 96.7 percentage of participants |
Secondary
Phase II: Plasma Concentration of Acalabrutinib
Blood samples were collected to determine the plasma concentration of acalabrutinib.
Time frame: At 1, 2 and 4 hours post-dose on Day 8, 15 and 22 of Cycle 1
Population: The pharmacokinetics (PK) analysis set included all participants who received at least 1 dose of acalabrutinib with reportable acalabrutinib plasma concentration and PK parameter data with no important protocol deviations that may impact PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 8: 1 hour | 157.3 nanogram per milliliter | Geometric Coefficient of Variation 103.6 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 15: 1 hour | 160.3 nanogram per milliliter | Geometric Coefficient of Variation 90 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 15: 2 hour | 178.9 nanogram per milliliter | Geometric Coefficient of Variation 70.41 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 15: 4 hour | 61.31 nanogram per milliliter | Geometric Coefficient of Variation 75.6 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 22: 1 hour | 196.3 nanogram per milliliter | Geometric Coefficient of Variation 93.17 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 22: 2 hour | 121.3 nanogram per milliliter | Geometric Coefficient of Variation 87.67 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 22: 4 hour | 100.8 nanogram per milliliter | Geometric Coefficient of Variation 162.3 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 8: 2 hour | 155.0 nanogram per milliliter | Geometric Coefficient of Variation 70.33 |
| Phase I | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 8: 4 hour | 77.06 nanogram per milliliter | Geometric Coefficient of Variation 94.19 |
| Phase II CLL | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 8: 1 hour | 238.7 nanogram per milliliter | Geometric Coefficient of Variation 288.2 |
| Phase II CLL | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 15: 1 hour | 206.6 nanogram per milliliter | Geometric Coefficient of Variation 354.3 |
| Phase II CLL | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 8: 2 hour | 187.2 nanogram per milliliter | Geometric Coefficient of Variation 111.4 |
| Phase II CLL | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 15: 4 hour | 49.96 nanogram per milliliter | Geometric Coefficient of Variation 162.4 |
| Phase II CLL | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 8: 4 hour | 58.73 nanogram per milliliter | Geometric Coefficient of Variation 115.4 |
| Phase II CLL | Phase II: Plasma Concentration of Acalabrutinib | Cycle 1 Day 15: 2 hour | 195.7 nanogram per milliliter | Geometric Coefficient of Variation 152.2 |
Secondary
Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator
The PFS (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval from the start of acalabrutinib therapy to the earlier of the first documentation of objective PD or death from any cause. The PFS was calculated using Kaplan-Meier technique.
Time frame: 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.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. One participant from Phase I rolled over to Phase II MCL reporting group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I | Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator | BICR Assessment | NA months |
| Phase I | Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator | Investigator Assessment | NA months |
| Phase II CLL | Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator | BICR Assessment | NA months |
| Phase II CLL | Phase II: Progression-Free Survival (PFS) Assessed by BICR and Investigator | Investigator Assessment | NA months |
Secondary
Phase II: Time to Response (TTR) Assessed by BICR and Investigator
The TTR (based on iwCLL 2018 criteria as assessed by the BICR and Investigator) was defined as the interval between the date of first dose and the date of initial documentation of a response.
Time frame: 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.
Population: Tumour response analysis set included all participants who received at least 1 dose of acalabrutinib with an available baseline tumour assessment. Only participants with response were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I | Phase II: Time to Response (TTR) Assessed by BICR and Investigator | BICR Assessment | 1.8 months |
| Phase I | Phase II: Time to Response (TTR) Assessed by BICR and Investigator | Investigator Assessment | 1.9 months |
| Phase II CLL | Phase II: Time to Response (TTR) Assessed by BICR and Investigator | BICR Assessment | 5.06 months |
| Phase II CLL | Phase II: Time to Response (TTR) Assessed by BICR and Investigator | Investigator Assessment | 5.52 months |