Relapsed or Refractory High-risk Chronic Lymphocytic Leukemia MedDRA version: 21.0 Level: LLT Classification code 10009310 Term: CLL System Organ Class: 100000004864
Conditions
Sponsors
Acerta Pharma BV
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: The Eligible subjects will be considered for inclusion in Parts 1 and 2 of the study if they meet all the following criteria: 1. Diagnosis of relapsed or refractory CLL that meets published diagnostic criteria (International Workshop on Chronic Lymphocytic Leukemia [IWCLL] Hallek 2008) and supported/documented by medical records: a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing =B-cell marker (CD19, CD20, or CD23) and CD5. b. Prolymphocytes may comprise = 55% of blood lymphocytes. c. Presence of = 5 x 109 B-lymphocytes/L (5000µL) in the peripheral blood (at any point since diagnosis). 2. Provision of signed, written, and dated informed consent form (ICF) 3. CLL subjects must have = 1 of the following high risk prognostic factors to be considered eligible for the study: From Arm A Part 1: a. Presence of 17p del b. Presence of TP53 mutation c. Presence of 11q del From Arm B Part 1 and 2: a. Presence of 11q del and be deemed suitable to receive a BTK inhibitor and ceralasertib per investigator’s clinical opinion Note: Initially the subject population for Arm B Parts 1 and 2 will be restricted to those subjects with 11q del only, but the population may be expanded to include those with 17p del and TP53 mutation. This decision will be made between investigators and sponsor based on emerging data and the decision agreed at an SRC meeting and documented in writing. Subjects will be eligible based on local laboratory karyotyping and fluorescence in situ hybridization (FISH) results and these results will also be retrospectively confirmed by a central laboratory. Where testing cannot be performed locally for any reason, central laboratory results will be required to confirm eligibility prior to enrollment. Note: For bothArm A, Part 1 and Part 2 of the study, subjects must be R/R high -risk CLL and have exhausted other therapeutic options according to local/regional standard of care . For Arm B, Part 1, and Arm B, Part 2 of the study, subjects must be R/R high-risk CLL (11q del) and be suitable for treatment with a BTK inhibitor and ceralasertib per investigator’s clinical opinion. Subjects with 17p deletions and/or TP53 mutations may be enrolled into the study at a later point in time after evaluation of activity of the combination in subjects with 11q deletions. Enrollment of these subjects will require approval from the Sponsor. 4. Meet the following laboratory parameters: Adequate hematologic function defined as independent of transfusion and growth factor support for =14 days before screening, : a. ANC >1500 cells/mm3 (1.5 x 109/L) b. Platelet count >75,000 cells/mm3 (75 x 109/L) c. Hemoglobin =9.0 g/dL d. AST (SGOT) ALT (SGPT) =2.5 x upper limit of normal (ULN). e. Total bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin in which case direct bilirubin should be 33 g/L. g. Alkaline phosphatase 75,000 cells/mm3 (75 x 109/L) b. Massive (ie, =6 cm below the left costal margin), progressive, or symptomatic splenomegaly
Exclusion criteria
Exclusion criteria: Subjects will be ineligible for this study (both parts) if they meet any of the following criteria: 1. A diagnosis of ataxia telangiectasia 2. Any prior exposure to an ATR inhibitor or known hypersensitivity to an excipient of the product 3. History of prior malignancy except for the following: a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician b. Adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer c. Adequately treated carcinoma in situ without current evidence of disease 4. As judged by the investigator, any evidence of severe or uncontrolled systemic disease 5. Known history of infection with human immunodeficiency virus (HIV) 6. Serologic status reflecting active hepatitis B or C infection 7. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris,etc 8. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass 9. History of CNS lymphoma, leptomeningeal disease or spinal cord compression 10. History of severe allergic or anaphylactic reactions to kinase inhibitors or history of hypersensitivity to active or inactive excipients of ceralasertib or acalabrutinib or drugs with a similar chemical structure or class to ceralasertib or acalabrutinib 11. Presence of a GI ulcer diagnosed by endoscopy within 3 months before screening 12. Any clinically significant pre-existing renal disease or high risk of developing renal impairment. 13. Major surgical procedure within 28 days before first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug 14. Unresolved toxicities from prior anticancer therapy, = Grade 2 Common Terminology Criteria for Adverse Events (CTCAE), with the exception of alopecia 15. Cytomegalovirus (CMV) positive- CMV testing at screening must include serology testing for CMV immunoglobulin (Ig) G, CMV IgM, and CMV PCR testing 16. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 17. Cardiac dysfunction as defined as: Myocardial infarction within 6 months of study entry, NYHA class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or a known history of reduced left ventricular ejection fraction (LVEF) 470 msec obtained from 3 electrocardiograms (ECGs) in 24 hours 19. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block) 20. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplain
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 Primary Objectives: To evaluate the safety and pharmacokinetics of ceralasertib: • Arm A (discontinued): When given as monotherapy in subjects with R/R high-risk CLL who have exhausted other therapeutic options according to local/regional standard of care. • Arm B: Ceralasertib given in combination with acalabrutinib in subjects with R/R high-risk CLL who are suitable for treatment with a BTK inhibitor and ceralasertib, per investigator’s clinical opinion. Part 2 Primary Objectives: • Arm B: To explore ceralasertib in combination with acalabrutinib in subjects with R/R high-risk CLL who are suitable for treatment with a BTK inhibitor and ceralasertib per investigator’s opinion as measured by ORR (CR+partial response [PR]), CR rate, DOR, PFS, and overall survival (OS).;Secondary Objective: Part 1 Secondary Objective: • To evaluate the preliminary activity of ceralasertib when given as monotherapy and in combination with acalabrutinib, as measured by ORR (CR+PR), CR rate, DOR, PFS and OS in subjects with R/R, high-risk CLL. Part 2 Secondary Objective: • To further evaluate the safety and PK of ceralasertib given in combination with acalabrutinib in subjects with R/R, high-risk CLL.;Primary end point(s): Safety of AZD6738: Ongoing evaluation of Adverse Events throughout all study visits: Type, frequency, severity, timing of onset, duration, and relationship to study drug of any treatment-emergent adverse events (TEAEs) or abnormalities of laboratory tests, serious adverse events (SAEs), DLTs, or adverse events (AEs) leading to discontinuation of study treatment. Pharmacokinetic Data: The Sparse PK data from ceralasertib monotherapy is will be characterized using a population-based analysis. Data from other studies may also be included in this analysis. The results of any such analyses will be reported separately from the clinical study report (CSR). Rich PK sampling will be performed on all subjects receiving the ceralasertib+acalabrutinib combi | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Preliminary activity of ceralasertib measured by ORR (CR+PR), CR rate, DOR, PFS and OS as a single agent and in combination with acalabrutinib in subjects with R/R high risk CLL who have exhausted other therapeutic options according to local/regional standard of care. Safety of ceralasertib: further evaluation of safety of ceralasertib as a single agent and in combination with acalabrutinib. Pharmacokinetic Data: Further characterization of the PK profile of ceralasertib as a single agent and in combination with acalabrubitinib;Timepoint(s) of evaluation of this end point: Safety of ceralasertib: Ongoing evaluation of Adverse Events throughout all study visits Pharmacokinetic Data: Timepoints for ceralasertib monotherapy (discontinued) • Cycle 1 Days 1 and 22: Predose, 1, 4 and 8 hours postdose Timepoints for ceralasertib+acalabrutinib combination • ceralasertib: Cycle 2 Days 1 and 7: Predose, 15 mins and 1, 2, 4, 8 and 10-12 hours postdose. • Acalabrutinib: Cycle 1 Days 7 and cycle 2 days 1 and 7: predose and approximately 1, 2, 4 and 6 hours postdose. | — |
Countries
Poland, United Kingdom
Contacts
Public ContactMedical Director (Ahmed Hamdy)
Acerta Pharma
Outcome results
None listed