Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients (ASSURE)
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|ClinicalTrials.gov Identifier: NCT04008706|
Recruitment Status : Active, not recruiting
First Posted : July 5, 2019
Last Update Posted : March 20, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Chronic Lymphocytic Leukemia||Drug: Acalabrutinib||Phase 3|
This is a Global, Phase 3b, multicenter, open-label, single-arm study to evaluate the safety and efficacy of acalabrutinib 100 mg bid in approximately 540 participants with CLL. Participants will be enrolled into 3 cohorts: treatment-naive (TN): participants who have had no prior treatment for CLL and who have either a score > 6 on the cumulative illness rating scale and/or have a creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation (minimum of 300 participants), relapsed/refractory (R/R): participants who have received prior treatment for CLL and who have either relapsed or refractory CLL (approximately 200 participants), and prior bruton tyrosine kinase inhibitor (BTKi) therapy: participants who have received prior ibrutinib for CLL and who discontinued the medication for any reason prior to disease progression (up to 40 participants). Overall response and progression assessments will be conducted by the investigator in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria. Overall response assessments will be based on evaluation of physical examinations, recording of symptoms, radiologic evaluations, and hematologic evaluations.
Treatment period consists of 48 cycles [each cycle is 28 days). Study treatment (acalabrutinib 100 mg bid) will be administered until disease progression, toxicity requiring discontinuation, completion of 48 cycles of study treatment, withdrawal of consent, loss to follow-up, death, or study termination by the sponsor, whichever comes first.
48 Cycles: From Cycle 1 to Cycle 6, in-clinic visits will occur every cycle and during each visit, in-clinic assessments will be carried out. From Cycle 6 to Cycle 12, in-clinic visits will occur every 3 cycles and during each visit, in-clinic assessments will be carried out. From Cycle 13 to Cycle 48, in-clinic visits will occur every 3 cycles and in-clinic assessments will be carried out every 6 cycles.
Safety follow up visits will occur approximately 30 days from the last dose of study treatment.
If a participant continues to derive benefit from treatment at the end of 48 cycles prior to the final DCO, they will continue to be provided with study treatment. Post-DCO, 2 options will be considered: patients may be transitioned to another study or may shift to a commercial supply of acalabrutinib/off-study acalabrutinib as permitted by local regulation. Subjects who switch to off-study acalabrutinib will be considered as having completed the study and therefore will not have any additional study assessments, including the disease Follow-up period.
The duration of the study will be approximately 72 months from the first participant enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per cycle); additional study time will be accrued during the Follow-up period for those participants remaining on study treatment after completion of 48 cycles prior to the final DCO (the amount of time will vary by participant).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||553 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||This is a single arm study in which participants will be enrolled into 3 cohorts. In the treatment-naive (TN) cohort, a minimum of 300 participants with treatment-naïve chronic lymphocytic leukemia will be enrolled. In the relapsed/refractory (R/R) cohort, approximately 200 participants with relapsed/refractory chronic lymphocytic leukemia will be enrolled. In the prior Bruton tyrosine kinase inhibitor (BTKi) therapy cohort, up to 40 participants with Prior BTKi therapy will be enrolled.|
|Masking:||None (Open Label)|
|Official Title:||A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects With Chronic Lymphocytic Leukemia.|
|Actual Study Start Date :||September 17, 2019|
|Estimated Primary Completion Date :||September 1, 2025|
|Estimated Study Completion Date :||September 1, 2025|
Participants will be enrolled into 3 cohorts. In the treatment-naive (TN) cohort, a minimum of 300 participants with treatment-naïve chronic lymphocytic leukemia will be enrolled. In the relapsed/refractory (R/R) cohort, approximately 200 participants with relapsed/refractory chronic lymphocytic leukemia will be enrolled. In the prior Bruton tyrosine kinase inhibitor (BTKi) therapy cohort, approximately 40 participants with Prior BTKi therapy will be enrolled.
Acalabrutinib will be administered as one 100 mg capsule taken orally, twice daily with 8 ounces (approximately 240 mL) of water.
Other Name: ACP-196
- Number of participants with adverse events [ Time Frame: From screening to safety follow-up period (approximately 30 days from last dose) ]To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with TN or R/R CLL.
- Overall response (OR) [ Time Frame: 1 year after initial dose of study drug ]To evaluate the investigator-assessed OR in participants receiving acalabrutinib monotherapy.
- Duration of response (DOR) [ Time Frame: The time from the first objective response to the time of documented disease progression or death due to any cause, whichever occurs first within the time period to complete up to 48 cycles of treatment (each cycle is 28 days) ]To evaluate the investigator-assessed DOR in participants receiving acalabrutinib monotherapy.
- Progression-free survival (PFS) [ Time Frame: The interval from the start of study treatment to completion of 48 cycles (each cycle is 28 days) or the earlier of the first documentation of disease progression or death from any cause ]To evaluate the investigator-assessed PFS in participants receiving acalabrutinib monotherapy.
- Plasma concentrations of acalabrutinib and ACP 5862 [ Time Frame: At Day 1 of Cycle 3 and Day 1 of Cycle 15 ]To characterize the pharmacokinetics of acalabrutinib and its metabolite (ACP-5862).
- Overall survival (OS) [ Time Frame: From start of study treatment to date of death due to any cause (up to 48 cycles and then every 24 weeks for participants who remain on study drug after completion of 48 cycles until the final data cut-off (each cycle is 28 days)(up to 6 years) ]To evaluate OS in participants receiving acalabrutinib monotherapy.
- Time to next treatment [ Time Frame: From the start of study treatment to safety follow-up period (approximately 30 days from last dose) ]To evaluate the time to next treatment.
- European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [ Time Frame: Up to 48 cycles (each cycle is 28 days) ]To evaluate participant-reported symptoms and health-related quality of life following treatment with acalabrutinib monotherapy. EORTC QLQ-C30 scale scores range from 0 to 100. A higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.
- Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Up to 48 cycles (each cycle is 28 days) ]To evaluate participant-reported symptoms following treatment with acalabrutinib monotherapy using PRO-CTCAE. Patient-reported outcomes (PROs), an umbrella term referring to all outcomes and symptoms, are directly reported by the participant. Around 81 symptoms of the CTCAE v4 have been identified to be amenable to participant reporting. These symptoms have been converted to participant terms (e.g., CTCAE term "myalgia" converted to "aching muscles"). For several symptoms, like fatigue and pain, additional questions are asked about symptom frequency (never to almost constantly), severity (none to very severe, and interference with usual activities (not at all to very much). For this study, the following items are considered relevant and will be assessed: headache, diarrhea, fatigue, nausea, vomiting, abdominal pain, rash, muscle pain, nose bleed, heart palpitations, bruising, joint pain, and constipation.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years to 130 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
Diagnosis of CLL that meets all published diagnostic criteria (Hallek et al. 2018):
- Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥1 B-cell marker (CD19, CD20, and CD23) and CD5 during screening
- Prolymphocytes may comprise <55% of blood lymphocytes during screening
- Presence of ≥5 × 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis)
Active disease per at least 1 of the following iwCLL 2018 criteria
- Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/μL).
- Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
- Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy
- Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30x10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
- B-symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs: o- Unintentional weight loss ≥10% within the previous 6 months before screening o- Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance status ≥2; inability to work or perform usual activities) o- Fevers higher than 100.5°F or 38.0°C for ≥2 weeks o- Night sweats for ≥1 month before screening without evidence of infection
Must meet 1 of the following criteria:
a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria: i. A score of >6 on the Cumulative Illness Rating Scale (CIRS) ii. Creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation b. Have previously received therapy for CLL and have either refractory or relapsed CLL c. Have received prior ibrutinib therapy (i.e., defined as a subject who discontinued a ibrutinib for any reason prior to disease progression) for CLL
- ECOG performance status of ≤2
- Female subjects of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilized male partner must use ≥1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study treatment. Contraception measures and restrictions on sperm donation are not required for male subjects.
- Fluorescence in situ hybridization (FISH) for which the next-generation sequencing (NGS) method is preferred) within 60 days during screening up to before the first dose reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Subjects must also have molecular analysis to detect IGHV mutation status (NGS is the preferred method) at screening if not done at any time point before that since diagnosis.
- Each subject (or legally authorized representative if allowed per local regulations) must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.
- Subjects who have had disease progression while on a BTKi for any malignant or nonmalignant condition
- Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the subject has been disease-free for ≥2 years
- History of confirmed progressive multifocal leukoencephalopathy
- Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia's formula (QTcF) >480 msec at screening. Note: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study (For prior ibrutinib therapy cohort only).
- 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.
- Evidence of active Richter's transformation. If Richter's transformation is suspected (i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomographycomputed tomography (PET-CT) and/or biopsy according to guidelines.
- Central nervous system (CNS) involvement by CLL.
Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
- Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.
- Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enroll.lment. Those who are hepatitis C virus PCR positive will be excluded
- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks).
- History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment.
- History of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
- Major surgical procedure within 4 weeks before first dose of study treatment. Note: Subjects who have had major surgery must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study treatment.
- 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 in this study.
- All subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment. Based on the known metabolic/transport pathways involved in the disposition of acalabrutinib and the commonly known novel oral anticoagulants (eg, apixaban, rivaroxaban, and edoxaban), no clinically relevant interaction is expected following coadministration of these agents.
- Absolute neutrophil count (ANC) <0.50 x 10^9/L or platelet count <30 x 10^9/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion
- Total bilirubin >3.0x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a subject's total bilirubin is elevated secondary to Gilbert's, the subject must have a documented unconjugated bilirubin being >80% of the total bilirubin number. The investigator must also document that hemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin
- Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement)
- Breastfeeding or pregnant
- Received any chemotherapy, external beam radiation, investigational drug, or any other anti-CLL therapy within 30 days before first dose of study treatment
- Concurrent participation in another therapeutic clinical study
- History of or ongoing interstitial lung disease
- Requiring long-term (> 1 week) treatment with a strong cytochrome CYP3A inhibitor/inducer. In addition, the use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04008706
|Study Director:||Adel Habib, MD||AstraZeneca|
|Principal Investigator:||Dr. Carsten Niemann, MD||Rigshospitalet, Denmark|
|Other Study ID Numbers:||
|First Posted:||July 5, 2019 Key Record Dates|
|Last Update Posted:||March 20, 2023|
|Last Verified:||March 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.|
Statistical Analysis Plan (SAP)
|Time Frame:||AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.|
|Access Criteria:||When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Chronic lymphocytic leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Immune System Diseases