This study is being done to test the safety and efficacy of an investigational drug called AZD6738, when taken alone and when taken in combination with another investigational drug called acalabrutinib (also known as ACP-196).
- Conditions
- Relapsed or Refractory High-risk Chronic Lymphocytic LeukemiaMedDRA version: 21.0Level: LLTClassification code 10009310Term: CLLSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2016-003737-15-PL
- Lead Sponsor
- Acerta Pharma BV
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 50
Eligible subjects will be considered for inclusion in Parts 1 and 2 of this study if they meet all of 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:
For Arm A part 1:
a. Presence of 17p del
b. Presence of TP53 mutation
c. Presence of 11q del
For 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.
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 independent of transfusion
and growth factor support for =14 days before screening,defined as:
a. Absolute neutrophil count (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. Serum aspartate aminotransferase (AST)/ serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (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 <1.5 x
ULN)
f. Albumin >33 g/L.
g. Alkaline phosphatase <2.5 x ULN
h. Estimated creatinine clearance using standard methodology (ie, eGFR using Cockcroft-Gault) =45 mL/min.
5. Active disease meeting =1 of the following IWCLL 2008 criteria for requiring treatment:
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL and/or thrombocytopenia (platelets >75,000 cells/mm3 (75 x 109/L)
b. Massive (ie, =6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
c. Massive nodes (ie, =10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
d. Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of
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 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 (GI) 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) <55%
18. Mean resting corrected QT interval (QTc) calculated using Fridericia's formula (QTcF) >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 unexplained sudden death under 40 years of age
21.Patien
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method