Burkitt Lymphoma, CLL, Follicular Lymphoma (FL), Hairy Cell Leukemia, Hodgkin Lymphoma, Indolent Non Hodgkin Lymphoma, Mantle Cell Lymphoma (MCL), Marginal Zone Lymphomas, Mediastinal Large B Cell Lymphoma, Multiple Myeloma, Richter's Syndrome, Small Lymphocytic Lymphoma (SLL), Waldenström Macroglobulinemia
Conditions
Keywords
Bruton tyrosine kinase inhibitor, Btk, B-Cell Malignancies, Mantle Cell, Multiple Myeloma, CLL, SLL, DLBCL, Follicular, Waldenstrom, Burkitt lymphoma, marginal zone lymphomas, hairy cell leukemia, B cell acute lymphoid leukemia, Acalabrutinib, ACP-196
Brief summary
This study is evaluating the safety, pharmacodynamics (PD), and efficacy of acalabrutinib and pembrolizumab in hematologic malignancies.
Detailed description
This is a Phase 1b/2, open-label, nonrandomized study that will be conducted in 2 stages. In the first stage, Part 1 of the study will determine the safety and preliminary efficacy of acalabrutinib and pembrolizumab in a limited group of B-cell malignancies. In the second stage, Part 2 allows for possible expansion cohorts into a wider range of B-cell malignancies, and Part 3 will evaluate the combination in subjects with myelofibrosis (MF).
Interventions
DRUGPembrolizumab
Intravenous Administered (IV)
DRUGAcalabrutinib
Orally Administered (PO)
Sponsors
Acerta Pharma BV
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Diagnosis of a hematologic malignancy as documented by medical records and with histology based on criteria established by the World Health Organization (WHO). * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. * Agreement to use contraception during the study and for 90 days after the last dose of ACP-196 or 120 days after the last dose of pembrolizumab, if sexually active and able to bear or beget children. * Completion of all therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥ 4 weeks before the start of study therapy. * ANC ≥ 0.5 x 10\^9/L or platelet count ≥ 50 x 10\^9/L unless due to disease involvement in the bone marrow. Main
Exclusion criteria
* A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of study drugs, or put the study outcomes at undue risk. * Central nervous system (CNS) involvement by lymphoma/leukemia * Any therapeutic antibody within 4 weeks of first dose of study drugs. * Total bilirubin \> 1.5 x ULN; and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3.0 x ULN. * Estimated creatinine clearance of \< 30 mL/min, calculated using the formula of Cockcroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Study Drug-Related SAE | 104 weeks | Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. Drug-related AEs were those assessed by investigator as related to study treatment. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) | 104 weeks | Treatment-emergent AEs were defined as those events that occurred on or after the first dose of study drug, through the treatment phase, and within 30 days following the last dose of study drug. |
| Number of Participants With Grade 3-4 Adverse Events | 104 weeks | Severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 |
| Number of Participants With Grade 5 Adverse Events | 104 weeks | Number of participants with CTCAE Grade 5 (fatal) adverse events |
| Number of Participants With Any Study-Drug Related AE | 104 weeks | Study drug-related AEs were those assessed by investigator as related to study treatment. |
| Number of Participants With Grade 3-4 Study-Drug Related AE | 104 weeks | The severity of the AEs was assessed by NCI CTCAE Version 4.03 or higher. Drug-related AEs were those assessed by investigator as related to study treatment. |
| Number of Participants With Grade 5 Study-Drug Related AE | 104 weeks | Grade 5 (fatal) AEs assessed by investigator as related to study treatment. |
| Number of Participants With Any SAE | 104 weeks | Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. |
| Number of Participants With Grade 3-4 Any SAE | 104 weeks | Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. The severity of the AEs was assessed by NCI CTCAE Version 4.03 or higher. |
| Number of Participants With Grade 5 Any SAE | 104 weeks | Grade 5 events were fatal events. Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. |
| Number of Participants With Any Grade 3-4 Study Drug-Related SAE | 104 weeks | Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. The severity of the AEs was assessed by NCI CTCAE Version 4.03 or higher. Drug-related AEs were those assessed by investigator as related to study treatment. |
| Number of Participants With Any Grade 5 Study Drug-Related SAE | 104 weeks | Grade 5 AEs were fatal events. Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. Drug-related AEs were those assessed by investigator as related to study treatment. |
| Number of Participants With AE Leading to Study Drug Discontinuation, Modification or Delay | 104 weeks | AEs that discontinuation of study treatment, or a reduction in dosage, or a delay (temporary withholding) in treatment. |
| Number of Participants With AE Leading to Study Drug Discontinuation | 104 weeks | An adverse event that resulted in the permanent discontinuation of study treatment in the study. |
| Number of Participants With AE Leading to Study Drug Delay | 104 weeks | An adverse event that caused a temporary withholding of study treatment. |
| Number of Participants With AE Leading to Study Drug Modification | 104 weeks | An adverse event that resulted in a reduction in the dosage of study treatment for that participant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 104 weeks | The percentage of subjects who achieve a partial response or complete response |
| Duration of Response | 104 weeks | The interval from the first documentation of response to the earlier of the first documentation of definitive disease progression or death from any cause |
| Progression-free Survival | 104 weeks | The interval from the first dose date of acalabrutinib or pembrolizumab to the earlier of the first documentation of objective disease progression or death from any cause |
| Overall Survival | 104 weeks | The time from the first dose date of acalabrutinib or pembrolizumab until date of death due to any cause |
| Time to Next Treatment | 104 weeks | The time from the first dose date of acalabrutinib or pembrolizumab to the start of the next treatment other than the study treatment |
Countries
United States
Contacts
STUDY_DIRECTORAstraZeneca Clinical Study Information Center
1-877-240-9479 - information.center@astrazeneca.com
Participant flow
Pre-assignment details
For the ACE-LY-005 program, Study Terminated by Sponsor refers to the following: Patients receiving treatment benefits will continue to be provided with study medication in the Post Final Analysis Management of the trial. No further data collection for analysis and reporting will be completed after the final Analysis
Participants by arm
| Arm | Count |
|---|---|
| Acalabrutinib + Pembrolizumab All participants in this study received both study drugs and were therefore analysed together as a single treatment arm.
Participants receiving the different regimens were not analysed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
The study included N=161 participants who received both acalabrutinib and pembrolizumab and are summarized together (from First stage safety lead-in and Second stage expansion). Stage 3 (additional expansion in subjects with Myelofibrosis) was planned but not conducted. | 161 |
| Total | 161 |
Baseline characteristics
| Characteristic | Acalabrutinib + Pembrolizumab |
|---|---|
| Age, Continuous | 62.4 Years STANDARD_DEVIATION 14.6 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 11 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 148 Participants |
| Race/Ethnicity, Customized Not Reported | 2 Participants |
| Race/Ethnicity, Customized White | 141 Participants |
| Region of Enrollment USA | 161 Participants |
| Sex: Female, Male Female | 63 Participants |
| Sex: Female, Male Male | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 69 / 161 |
| other Total, other adverse events | 157 / 161 |
| serious Total, serious adverse events | 75 / 161 |
Outcome results
Primary
Number of Participants With AE Leading to Study Drug Delay
An adverse event that caused a temporary withholding of study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With AE Leading to Study Drug Delay | 71 Number of participants |
Primary
Number of Participants With AE Leading to Study Drug Discontinuation
An adverse event that resulted in the permanent discontinuation of study treatment in the study.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With AE Leading to Study Drug Discontinuation | 45 Number of participants |
Primary
Number of Participants With AE Leading to Study Drug Discontinuation, Modification or Delay
AEs that discontinuation of study treatment, or a reduction in dosage, or a delay (temporary withholding) in treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With AE Leading to Study Drug Discontinuation, Modification or Delay | 83 Number of participants |
Primary
Number of Participants With AE Leading to Study Drug Modification
An adverse event that resulted in a reduction in the dosage of study treatment for that participant.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With AE Leading to Study Drug Modification | 9 Number of participants |
Primary
Number of Participants With Any Grade 3-4 Study Drug-Related SAE
Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. The severity of the AEs was assessed by NCI CTCAE Version 4.03 or higher. Drug-related AEs were those assessed by investigator as related to study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Any Grade 3-4 Study Drug-Related SAE | 30 Number of participants |
Primary
Number of Participants With Any Grade 5 Study Drug-Related SAE
Grade 5 AEs were fatal events. Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. Drug-related AEs were those assessed by investigator as related to study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Any Grade 5 Study Drug-Related SAE | 3 Number of participants |
Primary
Number of Participants With Any SAE
Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Any SAE | 75 Number of participants |
Primary
Number of Participants With Any Study-Drug Related AE
Study drug-related AEs were those assessed by investigator as related to study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Any Study-Drug Related AE | 142 Number of participants |
Primary
Number of Participants With Any Study Drug-Related SAE
Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. Drug-related AEs were those assessed by investigator as related to study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Any Study Drug-Related SAE | 34 Number of participants |
Primary
Number of Participants With Grade 3-4 Adverse Events
Severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Grade 3-4 Adverse Events | 105 Number of participants |
Primary
Number of Participants With Grade 3-4 Any SAE
Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment. The severity of the AEs was assessed by NCI CTCAE Version 4.03 or higher.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Grade 3-4 Any SAE | 64 Number of participants |
Primary
Number of Participants With Grade 3-4 Study-Drug Related AE
The severity of the AEs was assessed by NCI CTCAE Version 4.03 or higher. Drug-related AEs were those assessed by investigator as related to study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Grade 3-4 Study-Drug Related AE | 66 Number of participants |
Primary
Number of Participants With Grade 5 Adverse Events
Number of participants with CTCAE Grade 5 (fatal) adverse events
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Grade 5 Adverse Events | 9 Number of participants |
Primary
Number of Participants With Grade 5 Any SAE
Grade 5 events were fatal events. Serious AEs were those that resulted in death, were life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product, or were considered a significant medical event by the investigator based on medical judgment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Grade 5 Any SAE | 9 Number of participants |
Primary
Number of Participants With Grade 5 Study-Drug Related AE
Grade 5 (fatal) AEs assessed by investigator as related to study treatment.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Grade 5 Study-Drug Related AE | 3 Number of participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (AEs)
Treatment-emergent AEs were defined as those events that occurred on or after the first dose of study drug, through the treatment phase, and within 30 days following the last dose of study drug.
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the safety of the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Number of Participants With Treatment Emergent Adverse Events (AEs) | 160 Number of participants |
Secondary
Duration of Response
The interval from the first documentation of response to the earlier of the first documentation of definitive disease progression or death from any cause
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the the combination study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Duration of Response | 28.5 Months |
Secondary
Overall Response Rate
The percentage of subjects who achieve a partial response or complete response
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the the combination study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Overall Response Rate | 38.5 percent |
Secondary
Overall Survival
The time from the first dose date of acalabrutinib or pembrolizumab until date of death due to any cause
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the the combination study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Overall Survival | 50.4 Months |
Secondary
Progression-free Survival
The interval from the first dose date of acalabrutinib or pembrolizumab to the earlier of the first documentation of objective disease progression or death from any cause
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the the combination study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Progression-free Survival | 4.7 Months |
Secondary
Time to Next Treatment
The time from the first dose date of acalabrutinib or pembrolizumab to the start of the next treatment other than the study treatment
Time frame: 104 weeks
Population: All participants in this study received both study drugs and were therefore analyzed together as a single treatment arm. Participants receiving the different regimens were not analyzed separately by regimen, as the study was designed to assess the the combination study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acalabrutinib + Pembrolizumab | Time to Next Treatment | 21.1 Months |