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

Phase 1

Active, not recruiting

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

Interventions: Drug: Acalabrutinib
Drug: Pembrolizumab

Registration Number: NCT02362035

Lead Sponsor: Acerta Pharma BV

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).

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 161

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Acalabrutinib plus Pembrolizumab	Acalabrutinib	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.
Acalabrutinib plus Pembrolizumab	Pembrolizumab	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.

Primary Outcome Measures

Name	Time	Method
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 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 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 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 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 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 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 Grade 5 Adverse Events	104 weeks	Number of participants with CTCAE Grade 5 (fatal) adverse events
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 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 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 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.
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.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate	104 weeks	The percentage of subjects who achieve a partial response or complete response
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
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
Overall Survival	104 weeks	The time from the first dose date of acalabrutinib or pembrolizumab until date of death due to 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