• Chronic Lymphocytic Leukemia • Richter's Syndrome • Prolymphocytic Leukemia MedDRA version: 21.0 Level: LLT Classification code 10036889 Term: Prolymphocytic leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Cla
Conditions
Interventions
Product Name: acalabrutinib
Product Code: ACP-196
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: acalabrutinib
Current Sponsor code: ACP-196
Other descriptive name: ACP-196
Concentration unit
Sponsors
Acerta Pharma, BV
Eligibility
Sex/Gender
All
Inclusion 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 IWCLL 2008 criteria for requiring treatment: o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin 50% over a 2-month period or a lymphocyte doubling time (LDT) of 1 month before screening without evidence of infection. 4. 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. 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 subject privacy regulations). Inclusion Criteria for Treatment Subgroups. Subjects meeting the following criteria will be eligible for the indicated Treatment Subgroups. In addition, Inclusion Criteria 2 to 8 from the previous apply to the Treatment Subgroups as well. 1. Treatment Naive only: Men and women = 18 years of age with confirmed diagnosis of CLL/SLL, who require treatment per National Cancer Institute 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 and Prolymphocytic Leukemia Transformation only: Men and women = 18 years of age with biopsy proven DLBCL Richter's transformation or prolymphocytic leukemia transformation. 4. 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 nonr
Exclusion criteria
Exclusion criteria: 1. 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. 2. 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. 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 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). 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). 9. Central nervous system (CNS) involvement by lymphoma. 10. Grade = 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation. 11. 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. 12. 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). 13. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug. 14. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 15. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 16. Major surgery within 4 weeks before first dose of study drug. 17. ANC 1.5 x ULN (total bilirubin = 2.5 x ULN allowed in subjects with autoimmune hemolytic anemia that is otherwise controlled); AST or ALT > 3.0 x ULN unless disease related. 19. Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN. 20. Significant screening ECG abnormalities including 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, or QTc = 480 ms. 21. Cardiac troponi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Establish the safety and the MTD of orally administered acalabrutinib in subjects with CLL/SLL • Determine the PK of orally administered acalabrutinib and identification of its major metabolite ;Secondary Objective: Secondary Objective • Evaluate tumor response by ORR, DOR and PFS. Exploratory Objective • Measure PD parameters including drug occupancy of BTK, the target enzyme, and effect on biologic markers of B-cell function;Primary end point(s): Efficacy Parameters • Overall response rate • Duration of response • Progression-free survival (with a subgroup analysis by sex, male vs female for overall response rate, duration of response) Safety Parameters • DLTs and MTD • Frequency, severity, and attribution of adverse events (AEs) Pharmacokinetic and Pharmacodynamic Parameters The occupancy of BTK by acalabrutinib will be measured in peripheral blood mononuclear cells (PBMCs) with the aid of a biotin-tagged acalabrutinib analogue probe. The effect of acalabrutinib on biologic markers of B-cell function will also be evaluated.;Timepoint(s) of evaluation of this end point: > 28 days until disease progression or an unacceptable drug-related toxicity occurs | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): None defined;Timepoint(s) of evaluation of this end point: N/A | — |
Countries
Germany, Italy, United Kingdom, United States
Contacts
Public ContactACE-CL-001 Clincial Team
Acerta Pharma, BV
Outcome results
None listed