Clinical trial NCT02029443: ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (BTK) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Richter's Syndrome
Prolymphocytic Leukemia
Keywords: Bruton's tyrosine kinase inhibitor
Lead sponsor: Acerta Pharma BV
Sponsor class: INDUSTRY
First posted: 2014-01-08
Enrollment: 306
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria:

1. 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.
2. Must have measurable CLL/SLL defined as ≥ 1 lymph node ≥ 2 cm as measured in the longest diameter.
3. Active disease meeting ≥ 1 of the following International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment:

   1. 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).
   2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
   3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
   4. 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.
   5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
   6. 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.
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
5. 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).
6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
7. 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 participant privacy regulations).

Inclusion Criteria for Treatment Subgroups

1. 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.
2. 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.
3. 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.
4. Ibrutinib relapsed/refractory (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 stable disease or nonresponse or who initially responded to ibrutinib therapy and now have signs of clinical progression.

Exclusion Criteria:

1. 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.
2. 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.
3. 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%.
4. 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.
5. Any immunotherapy within 4 weeks of first dose of study drug.
6. 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).
7. Relapsed after, or refractory to, prior BTK inhibitor therapy (Note: Does not apply to Ibrutinib R/R or Richter's Syndrome Group).
8. Any history of Richter's transformation (Note: Does not apply to Richter's Syndrome Group).

10. Central nervous system (CNS) involvement by lymphoma. 11. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.

12. 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.

13. 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).

14. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.

15. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

16. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.

17. 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.

19. Total bilirubin \> 1.5 x upper limit of normal (ULN) (total bilirubin ≤ 2.5 x ULN allowed in participants with autoimmune hemolytic anemia that is otherwise controlled); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3.0 x ULN unless disease related.

20. Serum amylase \> 1.5 x ULN or serum lipase \> 1.5 x ULN. 21. Significant screening electrocardiogram (ECG) abnormalities including, 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, or QTc ≥ 480 ms.

22. Cardiac troponin I levels above the limit of normal as specified by the manufacturer.

23. Breast feeding or pregnant. 24. History of bleeding diathesis (eg, hemophilia, von Willebrand disease). 25. Concurrent participation in another therapeutic clinical trial. 26. Estimated creatinine clearance of \< 30 mL/min, calculated using the formula of Cockcroft and Gault \[(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female\].

27. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1
timeFrame: From Day 1 to Day 28 after first dose of study drug
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
measure: Number of Participants With Treatment Emergent Events of Clinical Interest (ECI)
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
measure: Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
measure: Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
measure: Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours postdose on Day 1 and Day 8
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Terminal Elimination Half-life (t1/2) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Terminal Elimination Rate Constant (λz) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Apparent Oral Clearance (CL/F) of Acalabrutinib
timeFrame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
measure: Apparent Volume of Distribution (Vz/F) of Acalabrutinib
timeFrame: 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:
measure: Percentage of Participants With Objective Response (OR) as Assessed by the Investigator
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
measure: Duration of Response (DOR) as Assessed by the Investigator
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
measure: Progression Free Survival (PFS) as Assessed by the Investigator
timeFrame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New Hyde Park
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Fort Worth
country: United States
facility: Research Site
state: Texas
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Tacoma
country: United States
facility: Research Site
state: Washington
city: Milano
country: Italy
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
Study officials:
affiliation: 1-888-292-9613 acertamc@dlss.com
name: Acerta Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.