Early Intervention With Acalabrutinib in Patients With High Risk CLL
Primary Purpose
Chronic Lymphocytic Leukemia, CLL/SLL
Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Acalabrutinib
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring CLL, untreated
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.)
Sites / Locations
- Weill Cornell Medicine
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Acalabrutinib
Arm Description
Acalabrutinib 100 mg will be administered orally twice daily continuously in 28-day cycles until treatment is discontinued for any reason.
Outcomes
Primary Outcome Measures
Percentage of subjects who do not develop Richter's Transformation (RT) within 5 years of study drug administration
Secondary Outcome Measures
Event-free survival
Measured from time of study drug administration to time of progression, transformation to a more aggressive histology, treatment discontinuation due to toxicity, or death from any cause.
Progression-free survival
Measured from time of study drug administration to progression or death, measured in months.
Progression-free survival in patients with TP53 disruption
For subjects with TP53 disruption present at baseline, measured from time of study drug administration to progression or death, measured in months.
Overall survival
Measured from time of study drug administration to death from any cause, measured in months.
Percentage of subjects who do not develop Richter's Transformation within 2 years of study drug administration
Median time to development of RT
Measured from time of study drug administration
Safety of early interventional acalabrutinib in patients with chronic lymphocytic leukemia (CLL) at high risk for Richter's Transformation
Percentage of subjects who experience 1 or more adverse events.
Full Information
NCT ID
NCT04660045
First Posted
December 2, 2020
Last Updated
March 25, 2022
Sponsor
Weill Medical College of Cornell University
Collaborators
AstraZeneca
1. Study Identification
Unique Protocol Identification Number
NCT04660045
Brief Title
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
2. Study Status
Record Verification Date
March 2022
Overall Recruitment Status
Withdrawn
Why Stopped
Company supplying drug/funding ceased support.
Study Start Date
May 2022 (Anticipated)
Primary Completion Date
January 2026 (Anticipated)
Study Completion Date
June 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
AstraZeneca
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, CLL/SLL
Keywords
CLL, untreated
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Acalabrutinib
Arm Type
Experimental
Arm Description
Acalabrutinib 100 mg will be administered orally twice daily continuously in 28-day cycles until treatment is discontinued for any reason.
Intervention Type
Drug
Intervention Name(s)
Acalabrutinib
Other Intervention Name(s)
CALQUENCE, ACP-196
Intervention Description
Acalabrutinib, oral, 100 mg BID, continuous
Primary Outcome Measure Information:
Title
Percentage of subjects who do not develop Richter's Transformation (RT) within 5 years of study drug administration
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Event-free survival
Description
Measured from time of study drug administration to time of progression, transformation to a more aggressive histology, treatment discontinuation due to toxicity, or death from any cause.
Time Frame
5 years
Title
Progression-free survival
Description
Measured from time of study drug administration to progression or death, measured in months.
Time Frame
5 years
Title
Progression-free survival in patients with TP53 disruption
Description
For subjects with TP53 disruption present at baseline, measured from time of study drug administration to progression or death, measured in months.
Time Frame
5 years
Title
Overall survival
Description
Measured from time of study drug administration to death from any cause, measured in months.
Time Frame
5 years
Title
Percentage of subjects who do not develop Richter's Transformation within 2 years of study drug administration
Time Frame
2 years
Title
Median time to development of RT
Description
Measured from time of study drug administration
Time Frame
5 years
Title
Safety of early interventional acalabrutinib in patients with chronic lymphocytic leukemia (CLL) at high risk for Richter's Transformation
Description
Percentage of subjects who experience 1 or more adverse events.
Time Frame
5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John N Allan, M.D.
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Cornell Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Links:
URL
https://jcto.weill.cornell.edu/
Description
WCM Joint Clinical Trials Office
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Early Intervention With Acalabrutinib in Patients With High Risk CLL
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