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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Richter's Syndrome, Prolymphocytic Leukemia

Intervention / Treatment
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* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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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 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. 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 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 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: 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relapsed/Refractory Cohort<br>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<br>* Participants will receive acalabrutinib as stated in the arms' description.<br>* Other names: ACP-196;|
| Experimental: Treatment-naive Cohort<br>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<br>* Participants will receive acalabrutinib as stated in the arms' description.<br>* Other names: ACP-196;|
| Experimental: Ibrutinib-intolerant Cohort<br>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<br>* Participants will receive acalabrutinib as stated in the arms' description.<br>* Other names: ACP-196;|
| Experimental: Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort<br>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<br>* Participants will receive acalabrutinib as stated in the arms' description.<br>* Other names: ACP-196;|
| Experimental: Ibrutinib Relapsed/Refractory Cohort<br>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<br>* Participants will receive acalabrutinib as stated in the arms' description.<br>* Other names: ACP-196;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | For CLL/SLL, OR is defined as complete remission (CR), CR with incomplete marrow recovery (CRi), or partial remission (PR). CR: lymphocytes (lympho) <4×10^9/L, normocellular bone marrow (BM), normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophil count (ANC) >1.5×10^9/L, platelets >100×10^9/L, hemoglobin (Hb) >11g/dL. Cri: lympho <4×10^9/L, hypocellular BM, NLN, L/S, persistent anemia, hrombocytopenia, or neutropenia. PR: >=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (<5×10^9/L or >=50% decrease from baseline) and criteria of ANC/platelets/Hb per CR or >=50% improvement over baseline. Hematology result were without exogenous growth factors/transfusion. For RS, OR as CR or PR by Cheson et al. 2014 based on PET/CT scans and bone marrow. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms and PR: >=50% decrease in sum of the product diameter of 6 largest nodal masses and no new sites of disease. | Day 1 through the final data cutoff date (approximately 7 years 6 months) | 
| Duration of Response (DOR) as Assessed by the Investigator | The DoR is defined as the time from the date of achieving the first CR, CRi, or PR to the date of progressive disease (PD) or death due to any cause, whichever occurred first. The CR, CRi, or PR are defined in the above outcome measure. For CLL/SLL, PD is defined as lympho >=50% increase from baseline with >= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or >= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of >=50% from baseline secondary to CLL or < 100,000/µL and worsening bone marrow or Hb decrease of > 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The DoR was estimated using Kaplan-Meier method. | Day 1 through the final data cutoff date (approximately 7 years 6 months) | 
| Progression Free Survival (PFS) as Assessed by the Investigator | The PFS is defined as the time from the date of first dose of study drug to the date of first PD or death due to any cause, whichever occurred first. For CLL/SLL, PD is defined as lympho >= 50 % increase from baseline with >= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or >= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of >= 50 % from baseline secondary to CLL or < 100,000/µL and worsening bone marrow or Hb decrease of > 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The PFS was estimated using Kaplan-Meier method. | Day 1 through the final data cutoff date (approximately 7 years 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton's tyrosine kinase inhibitor