ACP-196 (Acalabrutinib) in Combination With Pembrolizumab, for Treatment of Hematologic Malignancies (KEYNOTE145)

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma; Hodgkin Lymphoma; Waldenström Macroglobulinemia; Burkitt Lymphoma; Small Lymphocytic Lymphoma (SLL); Hairy Cell Leukemia; CLL; Mantle Cell Lymphoma (MCL); Follicular Lymphoma (FL); Richter's Syndrome; Indolent Non Hodgkin Lymphoma; Marginal Zone Lymphomas; Mediastinal Large B Cell Lymphoma
• Intervention / Treatment: Drug: Acalabrutinib; Drug: Pembrolizumab

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).

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Research Site
  • California
    • Los Angeles, California, United States, 90095
      • Research Site
  • Colorado
    • Denver, Colorado, United States, 80218
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Research Site
  • Illinois
    • Niles, Illinois, United States, 60714
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 2215
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site
    • San Antonio, Texas, United States, 78217
      • Research Site
    • Tyler, Texas, United States, 75702
      • Research Site
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Research Site
    • Roanoke, Virginia, United States, 24014
      • Research Site
  • Washington
    • Vancouver, Washington, United States, 98684
      • Research Site
    • Yakima, Washington, United States, 98902
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Acalabrutinib plus 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.

Drug: Acalabrutinib; Orally Administered (PO); Other Names: ACP-196; Drug: Pembrolizumab; Intravenous Administered (IV); Other Names: KEYTRUDA

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Acerta Pharma BV
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: AstraZeneca Clinical Study Information Center, 1-877-240-9479 - information.center@astrazeneca.com

Publications and helpful links

Helpful Links

• Redacted CSP
• Redacted SAP

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2015
• Primary Completion (Actual): July 14, 2020
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: February 7, 2015
• First Submitted That Met QC Criteria: February 7, 2015
• First Posted (Estimated): February 12, 2015

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Multiple Myeloma; DLBCL; CLL; Bruton tyrosine kinase inhibitor; Btk; B-Cell Malignancies; Mantle Cell; SLL; Follicular; Waldenstrom; Acalabrutinib; Burkitt lymphoma; ACP-196; hairy cell leukemia; marginal zone lymphomas; B cell acute lymphoid leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms by Site; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; DNA Virus Infections; Tumor Virus Infections; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Epstein-Barr Virus Infections; Herpesviridae Infections; Leukemia, B-Cell; Lymphoma, B-Cell; Chronic Disease; Neoplasms; Lymphoma; Hematologic Neoplasms; Multiple Myeloma; Leukemia; Burkitt Lymphoma; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Hairy Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; Acalabrutinib
• Other Study ID Numbers: ACE-LY-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP