ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (Btk) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia

Sponsor

Acerta Pharma BV (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02029443

Collaborator

(none)

306

Enrollment

Locations

Arm

149.5

Anticipated Duration (Months)

25.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Richter's Syndrome Prolymphocytic Leukemia	Drug: acalabrutinib	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

306 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2, Multicenter, Open-label, and Dose-escalation Study of ACP-196 in Subjects With Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia

Actual Study Start Date :

Jan 30, 2014

Actual Primary Completion Date :

Jul 15, 2021

Anticipated Study Completion Date :

Jul 15, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: acalabrutinib	Drug: acalabrutinib

Arm

Intervention/Treatment

Experimental: acalabrutinib

Drug: acalabrutinib

Outcome Measures

Primary Outcome Measures

Determine the Maximum Tolerated Dose [Cycle 1 (28 Days)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 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. 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 subjects with initial blood lymphocyte counts of < 30 X 109/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 (e.g., infections) should be excluded.
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs:

Unintentional weight loss ≥ 10% within the previous 6 months before Screening.

Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
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.
Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Removed at Amendment 11.

Inclusion Criteria for Treatment Subgroups

Treatment Naive only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL, who require treatment per National Cancer Institute (NCI) or International Working Group guidelines and a) do not want to receive chemoimmunotherapy or b) have comorbidities that would preclude chemoimmunotherapy.
Ibrutinib Intolerant only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL who are not tolerating ibrutinib due to ibrutinib-related AEs.
Richter's Syndrome/Prolymphocytic Leukemia Transformation only: Men and women ≥ 18 years of age and biopsy proven diffuse large B cell lymphoma (DLBCL) Richter's transformation or prolymphocytic leukemia transformation.
Ibrutinib R/R only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL whose best response after 2 cycles of ibrutinib therapy was SD or nonresponse or who initially responded to ibrutinib therapy and now have signs of clinical progression.

Exclusion Criteria:

Prior malignancy, except for adequately treated basal cell, squamous cell skin cancer or in situ cervical cancer. Subjects with other prior malignancies from which the subject 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 subject'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 subjects 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. Subjects 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 AIHA or 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 (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., 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 109/L or platelet count < 50 x 109/L unless there is bone marrow involvement.
Total bilirubin > 1.5 x ULN (total bilirubin ≤ 2.5 x ULN allowed in subjects with autoimmune hemolytic anemia that is otherwise controlled); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 x ULN unless disease related.
Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN. 21. Significant screening ECG abnormalities including, 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, or QTc ≥ 480 ms.
Cardiac troponin I levels above the limit of normal as specified by the manufacturer.
Breast feeding or pregnant. 24. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease). 25. Concurrent participation in another therapeutic clinical trial.
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].
Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Boston	Massachusetts	United States	2215
2	Research Site	New Hyde Park	New York	United States	11042
3	Research Site	New York	New York	United States	10021
4	Research Site	Columbus	Ohio	United States	43210
5	Research Site	Fort Worth	Texas	United States	76104
6	Research Site	Salt Lake City	Utah	United States	84112
7	Research Site	Seattle	Washington	United States	98122
8	Research Site	Tacoma	Washington	United States	98405
9	Research Site	Milano		Italy	20132
10	Research Site	Leeds		United Kingdom	LS9 7TF
11	Research Site	London		United Kingdom	SE5 9RS
12	Research Site	Oxford		United Kingdom	OX3 7LE