ACP-196 (Acalabrutinib) in Combination With Pembrolizumab, for Treatment of Hematologic Malignancies

Study Overview
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Brief Summary
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This study is evaluating the safety, pharmacodynamics (PD), and efficacy of acalabrutinib and pembrolizumab in hematologic malignancies.

Detailed Description
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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).

Official Title
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A Phase 1b/2 Proof-of-Concept Study of the Combination of ACP-196 (Acalabrutinib) and Pembrolizumab in Subjects With Hematologic Malignancies

Conditions
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CLL, Follicular Lymphoma (FL), Small Lymphocytic Lymphoma (SLL), Richter's Syndrome, Mantle Cell Lymphoma (MCL), Indolent Non Hodgkin Lymphoma, Waldenström Macroglobulinemia, Multiple Myeloma, Hodgkin Lymphoma, Burkitt Lymphoma, Marginal Zone Lymphomas, Mediastinal Large B Cell Lymphoma, Hairy Cell Leukemia

Intervention / Treatment
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* Drug: Acalabrutinib
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib plus Pembrolizumab<br>A nonrandomized study that will be conducted in 2 stages. In the first stage, (Safety), subjects will receive Acalabrutinib Dose A orally administered (PO) twice daily (BID) in combination with Pembrolizumab Dose B administered every 3 weeks (Q3W). The second stage was an expansion of Cohorts with the same dose regimen as the first stage. An additional expansion in subjects with Myelofibrosis was planned but not conducted. | Drug: Acalabrutinib<br>* Orally Administered (PO)<br>* Other names: ACP-196;Drug: Pembrolizumab<br>* Intravenous Administered (IV)<br>* Other names: KEYTRUDA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 104 weeks | 
| 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 | 104 weeks | 
| Number of Participants With Grade 5 Adverse Events | Number of participants with CTCAE Grade 5 (fatal) adverse events | 104 weeks | 
| Number of Participants With Any Study-Drug Related AE | Study drug-related AEs were those assessed by investigator as related to study treatment. | 104 weeks | 
| 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. | 104 weeks | 
| Number of Participants With Grade 5 Study-Drug Related AE | Grade 5 (fatal) AEs assessed by investigator as related to study treatment. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| 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. | 104 weeks | 
| Number of Participants With AE Leading to Study Drug Delay | An adverse event that caused a temporary withholding of study treatment. | 104 weeks | 
| 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. | 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The percentage of subjects who achieve a partial response or complete response | 104 weeks | 
| 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 | 104 weeks | 
| 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 | 104 weeks | 
| Overall Survival | The time from the first dose date of acalabrutinib or pembrolizumab until date of death due to any cause | 104 weeks | 
| 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 | 104 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Follicular, Waldenstrom, Burkitt lymphoma, Bruton tyrosine kinase inhibitor, Btk, B-Cell Malignancies, Mantle Cell, Multiple Myeloma, CLL, SLL, DLBCL, marginal zone lymphomas, hairy cell leukemia, B cell acute lymphoid leukemia, Acalabrutinib, ACP-196