ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (BTK) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia

NCT02029443 | Active Not Recruiting Phase 1 Results

• 3 other identifiers: ACE-CL-0012023-509346-35-002014-000440-15
• Study Type: interventional
• Target: 306
• Locations: 3 countries
• Sites: 12

Brief Summary

This study is evaluating the safety and efficacy of a new BTK inhibitor, acalabrutinib, for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Conditions

Small Lymphocytic Lymphoma; Richter's Syndrome; Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia

Keywords

Bruton's tyrosine kinase inhibitor

Outcome Measures

Primary Outcomes (14)

• Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1

  Participants with DLTs in Phase 1 are reported. The DLT was defined as any of the following events unless the adverse event is clearly related to disease progression or the participant's current medical history and associated comorbidities: (1) Any Grade 3 or greater nonhematologic toxicity with the exceptions of alopecia and Grade 3 nausea, vomiting, and diarrhea that respond to supportive therapy; (2) Hematologic toxicities including Grade 4 neutropenia lasting more than 5 days, Grade 4 or Grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion, Grade 3 or greater febrile neutropenia (body temperature of 38.5 degrees Celsius or more), or Grade 4 anemia, unexplained by underlying disease; or (3) Dosing delay due to toxicity for \> 7 consecutive days.

  From Day 1 to Day 28 after first dose of study drug

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

  An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

• Number of Participants With Treatment Emergent Events of Clinical Interest (ECI)

  The treatment emergent ECI included the events identified based on preclinical findings, emerging data from clinical studies relating to acalabrutinib, and pharmacological effects of approved Bruton's tyrosine kinase (BTK) inhibitors and reported after the first dose of the study drug.

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

• Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More

  Participants with clinically important laboratory abnormalities with CTCAE Grade 3 or more are reported. Laboratory analysis included hematology, clinical chemistry, amylase, lipase, cardiac troponin I, hepatitis B and C testing, and urinalysis. The CTCAE version 4.03 is a descriptive terminology is used for AE reporting. The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death related to AE.

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

• Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs

  Participants with clinically abnormal vital signs (blood pressure, respiratory rate, pulse rate, or body temperature) reported as TEAEs are reported.

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

• Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib

  The AUC0-6 of acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours postdose on Day 1 and Day 8

• Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib

  The AUC0-last of acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib

  The AUC0-inf of Acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib

  The Cmax of Acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib

  The Tmax of Acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Terminal Elimination Half-life (t1/2) of Acalabrutinib

  The t1/2 of acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Terminal Elimination Rate Constant (λz) of Acalabrutinib

  The λz of acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Apparent Oral Clearance (CL/F) of Acalabrutinib

  The CL/F of acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

• Apparent Volume of Distribution (Vz/F) of Acalabrutinib

  The Vz/F of acalabrutinib is reported.

  Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Secondary Outcomes (3)

• Percentage of Participants With Objective Response (OR) as Assessed by the Investigator

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

• Duration of Response (DOR) as Assessed by the Investigator

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

• Progression Free Survival (PFS) as Assessed by the Investigator

  Day 1 through the final data cutoff date (approximately 7 years 6 months)

Study Arms (5)

Relapsed/Refractory Cohort

EXPERIMENTAL

Phase 1 (dose-escalation) and Phase 2 (dose-expansion) will be conducted for participants with relapsed/refractory CLL or SLL. In Phase 1, participants will receive oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants will receive oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later will be switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 will be continued to receive Dose 1 BID until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Drug: Acalabrutinib

Treatment-naive Cohort

EXPERIMENTAL

Treatment-naïve participants with confirmed CLL or SLL, will receive oral acalabrutinib Dose 5 QD (Cohort 7, later will be switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Drug: Acalabrutinib

Ibrutinib-intolerant Cohort

EXPERIMENTAL

Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, will receive oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Drug: Acalabrutinib

Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort

EXPERIMENTAL

Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia (PLL) transformation, will receive oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Drug: Acalabrutinib

Ibrutinib Relapsed/Refractory Cohort

EXPERIMENTAL

Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, will receive oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Drug: Acalabrutinib

Interventions

Acalabrutinib DRUG

Participants will receive acalabrutinib as stated in the arms' description.

Also known as: ACP-196

Ibrutinib Relapsed/Refractory Cohort; Ibrutinib-intolerant Cohort; Relapsed/Refractory Cohort; Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort; Treatment-naive Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women ≥ 18 years of age with a confirmed diagnosis of CLL/SLL, which has relapsed after, or been refractory to, ≥ 2 previous treatments for CLL/SLL.
• Must have measurable CLL/SLL defined as ≥ 1 lymph node ≥ 2 cm as measured in the longest diameter.
• Active disease meeting ≥ 1 of the following International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment:
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \< 10 g/dL) and/or thrombocytopenia (platelets \< 100,000/μL).
• Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
• Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
• Progressive lymphocytosis with an increase of \> 50% over a 2-month period or a lymphocyte doubling time (LDT) of \< 6 months. The LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of \< 30 X 10\^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
• Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
• Constitutional symptoms documented in the participant's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs:
• i. Unintentional weight loss ≥ 10% within the previous 6 months before screening.
• ii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before screening without evidence of infection.
• iii. Night sweats for \> 1 month before screening without evidence of infection.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Agreement to use highly effective methods of contraception during the study and for 2 days after the last dose of study drug if sexually active and able to bear or beget children (see Section 3.7.9 for list of highly effective methods of contraception).
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

You may not qualify if:

• Prior malignancy, except for adequately treated basal cell, squamous cell skin cancer or in situ cervical cancer. Participants with other prior malignancies from which the participant has been disease free for ≥ 2 years may be included if approved by the medical monitor.
• A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) ≤ 40%.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
• Any immunotherapy within 4 weeks of first dose of study drug.
• For participants with recent chemotherapy or experimental therapy the first dose of study drug must occur after 5 times the half-life of the agent(s).
• Relapsed after, or refractory to, prior BTK inhibitor therapy (Note: Does not apply to Ibrutinib R/R or Richter's Syndrome Group).
• Any history of Richter's transformation (Note: Does not apply to Richter's Syndrome Group).
• \. Central nervous system (CNS) involvement by lymphoma. 11. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
• \. Known history of human immunodeficiency virus (HIV) or serologic status indicating active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection or any uncontrolled active systemic infection. Participants with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
• \. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (\> 20 mg daily of prednisone daily or equivalent).
• \. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
• \. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
• \. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
• \. Major surgery within 4 weeks before first dose of study drug. 18. ANC \< 0.75 x 10\^9/L or platelet count \< 50 x 10\^9/L unless there is bone marrow involvement.

Sponsors & Collaborators

• Acerta Pharma BV: lead

Study Sites (12)

Research Site

Boston, Massachusetts, 2215, United States

Location

Research Site

New Hyde Park, New York, 11042, United States

Location

Research Site

New York, New York, 10021, United States

Location

Research Site

Columbus, Ohio, 43210, United States

Location

Research Site

Fort Worth, Texas, 76104, United States

Location

Research Site

Salt Lake City, Utah, 84112, United States

Location

Research Site

Seattle, Washington, 98122, United States

Location

Research Site

Tacoma, Washington, 98405, United States

Location

Research Site

Milan, 20132, Italy

Location

Research Site

Leeds, LS9 7TF, United Kingdom

Location

Research Site

London, SE5 9RS, United Kingdom

Location

Research Site

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (8)

• Nuttall B, Karl DL, Burke K, Callahan M, Mendler K, Cingolani P, Criscione S, Naumenko S, Bibikova E, Munugalavadla V, Byrd JC, Furman RR, Brown JR, Mortlock A, Dougherty BA, Carl Barrett J, Scaltriti M, Hadfield J. Comprehensive comparison of enzymatic and bisulfite DNA methylation analysis in clinically relevant samples. Clin Epigenetics. 2025 Oct 3;17(1):156. doi: 10.1186/s13148-025-01959-0.

  PMID: 41044668 DERIVED

• Bibikova E, Parsa S, Floren M, Law B, Clevenger T, Cheung J, De Jesus G, Burke K, Gulrajani M, Yamaguchi K, Do P, Dougherty B, Whitston D, Brock G, Munugalavadla V, Frigault MM, Hartmann TN, Byrd JC, Furman RR, Brown JR, Covey T, Mortlock A. Molecular Profiling Identifies CD49d and CD79b as Predictive Markers for Acquired Acalabrutinib Resistance in Patients With Chronic Lymphocytic Leukemia. Hematol Oncol. 2025 Jan;43(1):e70008. doi: 10.1002/hon.70008.

  PMID: 39716442 DERIVED

• Alfaifi A, Bahashwan S, Alsaadi M, Ageel AH, Ahmed HH, Fatima K, Malhan H, Qadri I, Almehdar H. Advancements in B-Cell Non-Hodgkin's Lymphoma: From Signaling Pathways to Targeted Therapies. Adv Hematol. 2024 Nov 12;2024:5948170. doi: 10.1155/2024/5948170. eCollection 2024.

  PMID: 39563886 DERIVED

• Eyre TA, Schuh A, Wierda WG, Brown JR, Ghia P, Pagel JM, Furman RR, Cheung J, Hamdy A, Izumi R, Patel P, Wang MH, Xu Y, Byrd JC, Hillmen P. Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. Lancet Haematol. 2021 Dec;8(12):e912-e921. doi: 10.1016/S2352-3026(21)00305-7. Epub 2021 Nov 1.

  PMID: 34735860 DERIVED

• Byrd JC, Wierda WG, Schuh A, Devereux S, Chaves JM, Brown JR, Hillmen P, Martin P, Awan FT, Stephens DM, Ghia P, Barrientos J, Pagel JM, Woyach JA, Burke K, Covey T, Gulrajani M, Hamdy A, Izumi R, Frigault MM, Patel P, Rothbaum W, Wang MH, O'Brien S, Furman RR. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020 Apr 9;135(15):1204-1213. doi: 10.1182/blood.2018884940.

  PMID: 31876911 DERIVED

• Awan FT, Schuh A, Brown JR, Furman RR, Pagel JM, Hillmen P, Stephens DM, Woyach J, Bibikova E, Charuworn P, Frigault MM, Hamdy A, Izumi R, Linghu B, Patel P, Wang MH, Byrd JC. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019 May 14;3(9):1553-1562. doi: 10.1182/bloodadvances.2018030007.

  PMID: 31088809 DERIVED

• Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, Maddocks KJ, Cheney C, Jones JA, Flynn JM, Andritsos LA, Awan F, Fraietta JA, June CH, Maus MV, Woyach JA, Caligiuri MA, Johnson AJ, Muthusamy N, Byrd JC. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017 Aug 1;127(8):3052-3064. doi: 10.1172/JCI89756. Epub 2017 Jul 17.

  PMID: 28714866 DERIVED

• Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7.

  PMID: 26641137 DERIVED

Related Links

• Redacted SAP
• redacted CSP
• redacted CSR Synopsis

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic

Interventions

acalabrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

The Phase 2 dose was chosen on the basis of the pharmacodynamics data.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: Acerta Pharma BV

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Acerta Clinical Trials

  1-888-292-9613 acertamc@dlss.com

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2014
• First Posted: January 8, 2014
• Study Start: January 30, 2014
• Primary Completion: July 15, 2021
• Study Completion (Estimated): June 9, 2027
• Last Updated: May 5, 2026
• Results First Posted: September 10, 2022

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

US (8); IT (1); GB (3)