Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping.
- Conditions
- bloodcancerChronic Lymphocytic Leukemia10024324
- Registration Number
- NL-OMON52681
- Lead Sponsor
- Rigshospitalet/Copenhagen University hospital
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Pending
- Sex
- Not specified
- Target Recruitment
- 20
1. CLL diagnosed according to IWCLL criteria within one year prior to
randomization
2. High risk of infection and/or progressive treatment within 2 years according
to CLL-TIM
3. IWCLL treatment indication not fulfilled
4. Life expectancy > 2 years
5. Age at least 18 years
6. Ability and willingness to provide written informed consent and adhere to
study procedures and treatment
7. Adequate bone marrow function as indicated by platelets above 100 x 10E9,
hemoglobin above 10 g/dL and neutrophils above 1 x 10E9
8. Creatinine clearance above 30 mL/min directly measured with 24hr urine
collection or calculated according to the modified formula of Cockcroft and
Gault
9. Adequate liver function as indicated by a total bilirubin<= 2 x, AST or ALT <=
2.5 x the institutional ULN value, unless directly attributable to the
patient*s CLL or to Gilbert*s Syndrome.
10. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc
negative; patients positive for anti-HBc may be included if PCR for HBV DNA is
negative and HBV-DNA PCR is performed every month until 12 months after last
treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to
registration.
11. Eastern Cooperative Oncology Group Performance Status (ECOG) performance
status 0-2.
12. Woman of childbearing potential (WOCBP) who are sexually active must use
highly effective methods of contraception during treatment and for 30 days
after the last dose of investigational drugs.
13. Willing and able to participate in all required evaluations and procedures
in this study protocol including swallowing capsules without difficulty.
14. Ability to understand the purpose and risks of the study and provide signed
and dated informed consent and authorization to use protected health
information.
1. Prior CLL treatment (including monoclonal antibodies, chemotherapy, small
molecules, including CD20 antibodies, BTK inhibitors and bcl-2 inhibitors for
any indication)
2. Transformation of CLL (Richter*s transformation)
3. Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP
(idiopathic thrombocytopenic purpura) treated with immune suppression or
uncontrolled AIHA or ITP
4. History of progressive multifocal leukoencephalopathy
5. HIV infection (a negative test required)
6. Known active infection
7. Malignancies other than CLL requiring systemic therapies (except
anti-hormonal therapies) or considered to impact survival
8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or
anticoagulant therapy with vitamin K antagonists
9. History of bleeding disorders or current platelet inhibitors or
anticoagulant therapy
10. History of clinically significant cardiovascular disease such as
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 corrected QT interval (QTc) > 480 msec at
screening.
11. History of stroke or intracranial hemorrhage within 6 months prior to
registration.
12. Use of investigational agents which might interfere with the study drug
within 28 days prior to registration.
13. Vaccination with live vaccines within 28 days prior to registration.
14. Major surgery less than 30 days before start of treatment. 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.
15. Known hypersensitivity to any active substance or to any of the excipients
of one of the drugs used in the trial.
16. Pregnant women and nursing mothers (a negative pregnancy test is required
for all women of childbearing potential within 7 days before start of
treatment; further pregnancy testing will be performed regularly).
17. Fertile men or women of childbearing potential unless: surgically sterile
or >= 2 years after the onset of menopause or willing to use two methods of
reliable contraception including one highly effective contraceptive method
(Pearl Index <1) and one additional effective (barrier) method during study
treatment and for 30 days after the end of study treatment.
18. Legal incapacity.
19. Persons who are in dependence to the sponsor or an investigator
20. Persons not considered fit for the trial by the investigator
21. Malabsorption syndrome, disease significantly affecting gastrointestinal
function, or resection of the stomach or small bowel 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.
22. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x
ULN.
23. Requires treatment with proton pump inhibitors (e.g., omeprazole,
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists
or antacids are eligible for enrollment to this study.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>• Grade >=3-Infection-free survival in the treatment arm compared to the<br /><br>observation arm 12 weeks after finishing treatment, (24 weeks after treatment<br /><br>initiation). This is a non-inferiority analysis as detailed in the statistical<br /><br>analysis plan to assure safety of the combination treatment in this preemptive<br /><br>trial population.</p><br>
- Secondary Outcome Measures
Name Time Method <p>• Grade >=3-infection free and CLL-treatment-free survival at end of treatment,<br /><br>1 year and 2 years after enrollment<br /><br>• Rate of overall survival (OS) and cause of death<br /><br>• Treatment free survival<br /><br>• Rate and CTCAE V5.0 grade of infections<br /><br>• Response rate and duration according to IWCLL criteria<br /><br>• Treatment related adverse events, type, frequency and severity during and for<br /><br>2 years after treatment<br /><br>• Immune function as assessed by immune phenotyping, functional TruCulture<br /><br>assays and measurements of cytokine levels</p><br>