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Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients (ASSURE)

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ClinicalTrials.gov Identifier: NCT04008706
Recruitment Status : Not yet recruiting
First Posted : July 4, 2019
Last Update Posted : July 4, 2019
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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 600 participants with chronic lymphocytic leukemia (CLL). Participants will be enrolled into 4 cohorts: treatment-naive (TN), relapsed/refractory (R/R), prior Bruton tyrosine kinase inhibitor (BTKi) therapy, and concomitant vitamin K antagonists. Participants will remain on study treatment until completion of 48 cycles (28 days per cycle), disease progression, toxicity requiring discontinuation, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor whichever occurs first. 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 (the amount of time will vary by participant).

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Acalabrutinib Phase 3

Detailed Description:
This is a Phase 3b, multicenter, open-label, single-arm study to evaluate the safety and efficacy of acalabrutinib 100 mg bid in approximately 600 participants with chronic lymphocytic leukemia (CLL). Participants will be enrolled into 4 cohorts: treatment-naive (TN) (minimum of 300 participants), relapsed/refractory (R/R) (approximately 200 participants), prior bruton tyrosine kinase inhibitor (BTKi) therapy (up to 70 participants), and concomitant vitamin K antagonists (up to 30 participants). Ten participants will initially be enrolled in the concomitant vitamin K antagonist cohort in a staggered enrollment. Participants enrolled in this cohort will be monitored for adverse events (AEs) and laboratory assessments, including prothrombin time/ international normalized ratio (PT/INR). If >8 of the 10 participants enrolled demonstrate no clinically meaningful major hemorrhage as assessed in the first 6 months by a safety monitoring committee including internal and external members, up to an additional 20 participants with concomitant vitamin K antagonist therapy will be enrolled. If participants do not complete 6 months of study treatment for any reason other than clinically meaningful major hemorrhage, they may be replaced by another participant. Assessment of response and progression 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. Study treatment (acalabrutinib 100 mg bid) will be administered until disease progression, unacceptable toxicity, 48 cycles of study treatment, withdrawal of consent, loss to follow-up, death, or study termination by the sponsor, whichever comes first (each cycle is 28 days). In-clinic visits will occur every cycle for the first 6 cycles, and then every 3 cycles for the next 6 cycles. After 12 cycles "in-clinic visits" will occur 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, they will continue to be provided with study treatment. This may include, but not be limited to, transition to a long-term extension trial, continuous supply in this trial (for eg in countries where regulatory approval is not obtained, or drug is not reimbursed) or switching to commercial drug as permitted by local regulations. Participants who remain in the trial after the completion of 48 cycles will be followed for disease progression, description of all subsequently administered anticancer therapies, and IWCLL indication for initiation of subsequent anticancer therapies q24w via standard practice until transition to regulatory approved off-study acalabrutinib, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor. Participants 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single arm study in which participants will be enrolled into 4 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 70 participants with Prior BTKi therapy will be enrolled. In the concomitant vitamin K antagonists cohort, up to 30 participants with concomitant vitamin K antagonists will be enrolled.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects With Chronic Lymphocytic Leukemia.
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : August 24, 2025
Estimated Study Completion Date : August 24, 2025


Arm Intervention/treatment
Experimental: Acalabrutinib
Participants will be enrolled into 4 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 70 participants with Prior BTKi therapy will be enrolled. In the concomitant vitamin K antagonists cohort, up to 30 participants with concomitant vitamin K antagonists will be enrolled.
Drug: Acalabrutinib
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: 1 year after initial dose of study drug ]
    To evaluate the investigator-assessed ORR in participants receiving acalabrutinib monotherapy.

  2. 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.

  3. 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.


Other Outcome Measures:
  1. Number of participants with Adverse events [ Time Frame: From screening to safety follow-up period (approximately 30 days from last dose) ]
    To evaluate safety and tolerability of acalabrutinib monotherapy in participants with concomitant vitamin K antagonist.

  2. Overall survival (OS) [ Time Frame: Up to 48 Cycles (each cycle is 28 days) or as long as participant remains on the study (maximum up to 1 year) ]
    To evaluate OS in participants receiving acalabrutinib monotherapy.

  3. 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 investigator-assessed event-free survival (EFS).

  4. 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.

  5. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women ≥18 years of age.
  2. Diagnosis of CLL that meets published diagnostic criteria:

    1. 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.
    2. Prolymphocytes may comprise <55% of blood lymphocytes.
    3. Presence of ≥5 × 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis).
  3. Active disease per IWCLL 2018 criteria that requires treatment.

    1. 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).
    2. Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
    3. Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
    4. 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 participants with initial blood lymphocyte counts of <30x109/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.
    5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
    6. B-symptoms documented in the participants chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs:

      • Unintentional weight loss ≥10% within the previous 6 months before screening.
      • Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance status ≥2; inability to work or perform usual activities).
      • Fevers higher than 100.5°F or 38.0°C for ≥2 weeks before screening without evidence of infection.
      • Night sweats for ≥1 month before screening without evidence of infection.
  4. 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 BTKi therapy (i.e., defined as a participant who discontinued a BTKi for any reason except disease progression) for CLL.

    d. Have either TN or R/R CLL and are receiving concomitant vitamin K antagonists (e.g., coumadin).

  5. ECOG performance status of ≤2.
  6. Female participants 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. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide during the study.
  7. Fluorescence in situ hybridization (FISH) results within 60 days before screening 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. Participants must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
  8. Participants 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.

Exclusion Criteria:

  1. Participants who have had disease progression while on a BTKi for any malignant or nonmalignant condition.
  2. 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 participant has been disease-free for ≥2 years.
  3. History of confirmed progressive multifocal leukoencephalopathy.
  4. 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: participants with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
  5. Malabsorption syndrome, disease significantly affecting gastrointestinal 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.
  6. 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.
  7. Central nervous system (CNS) involvement by CLL.
  8. 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 participants who are on ongoing anti-infective treatment and participants who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.

    1. Participants 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.
    2. Participants who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded.
  9. 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).
  10. History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment.
  11. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
  12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before Screening.
  13. Major surgical procedure within 4 weeks before first dose of study treatment. Note: Participants 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.
  14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
  15. All participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment except those participants who will be enrolled into the vitamin K antagonist cohort.
  16. Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion.
  17. Total bilirubin >1.5 x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0 x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a participants total bilirubin is elevated secondary to Gilbert's, the participant 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.
  18. 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).
  19. Breastfeeding or pregnant.
  20. Received any chemotherapy, external beam radiation, investigational drug, or any other anti-CLL therapy within 30 days before first dose of study treatment.
  21. Concurrent participation in another therapeutic clinical study.

Information from the National Library of Medicine

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


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

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Sponsors and Collaborators
AstraZeneca
Parexel
Investigators
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Study Director: Dr. Siddhartha H Patel, MD Acerta Pharma, a member of the AstraZeneca Group
Principal Investigator: Dr. Carsten Niemann, MD Rigshospitalet, Denmark

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04008706     History of Changes
Other Study ID Numbers: D8220C00008
First Posted: July 4, 2019    Key Record Dates
Last Update Posted: July 4, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by AstraZeneca:
Chronic lymphocytic leukemia
Acalabrutinib

Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell