Clinical trial NCT04660045: Early Intervention With Acalabrutinib in Patients With High Risk CLL
Official title: A Phase II Trial of Early Intervention With Acalabrutinib in Patients With CLL at High Risk for Richter's Transformation
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
CLL/SLL
Keywords: CLL
untreated
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2020-12-09
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study evaluates the effectiveness of acalabrutinib treatment in patients with chronic lymphocytic leukemia (CLL) deemed at high risk for Richter's Transformation (RT). This is a single arm study. Enrolled patients will initiate therapy with acalabrutinib and will dose continuously. While on study, subjects will be monitored monthly for the first 3 months, then every three months thereafter until disease progression, discontinuation due to toxicity, death, or study completion.

Detailed description: This is a multi-center, single arm, Phase II clinical trial to investigate the effectiveness of acalabrutinib treatment within 6 months of chronic lymphocytic leukemia (CLL) diagnosis for patients with CLL deemed at high risk for Richter's Transformation (RT).

Eligibility criteria: Inclusion Criteria:

* Subject must be able to voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
* The time from diagnosis to consent should be ≤6 months.
* Subject must be ≥ 18 years of age.
* Subject must have diagnosis of CLL/SLL based upon 2018 iwCLL Guidelines.
* Rai stage 0-2 disease without indication for treatment as defined by the 2018 iwCLL guidelines
* Subject must have high risk CLL as defined by any one of the following:

  * NOTCH1 mutated (classic frameshift mutation only)
  * Unmutated V4-39 B cell receptor usage
  * Pathogenic c-MYC mutations
  * Complex karyotype, (by CpG/oligodeoxynucleotide stimulation)
  * Deletion 17p, or presence of TP53 mutation
* Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
* PT/PTT/INR within 1.5 x the ULN
* Adequate renal function defined by serum creatinine less than 2 x ULN
* Adequate hepatic function:

  * ALT/AST less than 2x ULN
  * Tbili less than 1.5 X ULN unless bilirubin elevation is due to Gilbert's syndrome (total bilirubin \<3)
* Subject must have adequate bone marrow function.

  * Absolute neutrophil count ≥1.0 x103/μL
  * Hemoglobin ≥ 11.0 g/dL
  * Platelets ≥ 100 x 103/μL

Exclusion Criteria:

* Previous exposure to any systemic anti-cancer therapy as a treatment for CLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, or investigational therapy. Note, patients treated with chemotherapy for a prior non-hematologic malignancy if more than 5 years earlier are eligible.
* Subject with a history of malignancy except for non-melanoma skin cancers. Subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll.
* Subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry.
* Subjects with a history of autoimmune hemolytic anemia or immune thrombocytopenia purpura.
* Subject has prolymphocytic leukemia.
* Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
* Subject requires warfarin or equivalent vitamin K antagonist
* Uncontrolled or active significant infection,
* History of or suspected or confirmed PML
* Clinically 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. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
* Patients with stroke or CNS hemorrhage within 6 months
* Pregnant or breastfeeding

  * Women of childbearing potential (WCBP) who are sexually active with heterosexual partners must agree to use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib.
* Major surgical procedure within 28 days of first dose of study drug. If a subject had surgery, they must have recovered adequately from any toxicity or complications before the first dose of study drug.
* Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication.
* Subject is known to be positive for human immunodeficiency virus (HIV)
* Active hepatitis C, as confirmed by being positive for Hep C RNA by PCR
* Active hepatitis B infection documented by a positive PCR for Hep B DNA. If hepatitis B serology is positive for hepatitis B core antibody, but Hep B DNA PCR is negative, patient is eligible to enroll.
* Subject requires strong CYP 3A4/5 inhibitors or inducers (Appendix B).
* Subject requires proton pump inhibitors. (Subjects that can transition to an H2 antagonist are allowed to enroll.)

Primary outcomes:
measure: Percentage of subjects who do not develop Richter's Transformation (RT) within 5 years of study drug administration
timeFrame: 5 years
Secondary outcomes:
measure: Event-free survival
timeFrame: 5 years
measure: Progression-free survival
timeFrame: 5 years
measure: Progression-free survival in patients with TP53 disruption
timeFrame: 5 years
measure: Overall survival
timeFrame: 5 years
measure: Percentage of subjects who do not develop Richter's Transformation within 2 years of study drug administration
timeFrame: 2 years
measure: Median time to development of RT
timeFrame: 5 years
measure: Safety of early interventional acalabrutinib in patients with chronic lymphocytic leukemia (CLL) at high risk for Richter's Transformation
timeFrame: 5 years
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: John N Allan, M.D.
role: PRINCIPAL_INVESTIGATOR
References: