Clinical Trials /

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

NCT04008706

Description:

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 3 cohorts: treatment-naive (TN), relapsed/refractory (R/R), and prior Bruton tyrosine kinase inhibitor (BTKi) therapy. 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).

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients
  • Official Title: A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects With Chronic Lymphocytic Leukemia.

Clinical Trial IDs

  • ORG STUDY ID: D8220C00008
  • NCT ID: NCT04008706

Conditions

  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
AcalabrutinibACP-196Acalabrutinib

Purpose

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 3 cohorts: treatment-naive (TN), relapsed/refractory (R/R), and prior Bruton tyrosine kinase inhibitor (BTKi) therapy. 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).

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 3 cohorts: treatment-naive
      (TN) (minimum of 300 participants), relapsed/refractory (R/R) (approximately 200
      participants), and prior bruton tyrosine kinase inhibitor (BTKi) therapy (up to 70 to 100
      participants). 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).
    

Trial Arms

NameTypeDescriptionInterventions
AcalabrutinibExperimentalParticipants 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 70 to 100 participants with Prior BTKi therapy will be enrolled.
  • Acalabrutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in
             which the study is taking place)

          2. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):

               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 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any
                  point since the initial diagnosis)

          3. Active disease as per at least 1 of the following IWCLL 2018 criteria

               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 subjects 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 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 before screening without evidence of infection o-
                  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 subject who discontinued a BTKi for
             any reason except disease progression) for CLL d. Criterion deleted.

          5. ECOG performance status of ≤2

          6. 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.

          7. Fluorescence in situ hybridization (FISH) within 60 days before or during 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. Subjects must also have molecular analysis to detect IGHV mutation status
             at any time point since diagnosis.

          8. 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.

        Exclusion Criteria:

          1. Subjects 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 subject 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: Subjects 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 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.

               1. 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.

               2. 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

          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:
             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.

         14. 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.

         15. 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.

         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 >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

         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

         22. History of interstitial lung disease

         23. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events
Time Frame:From screening to safety follow-up period (approximately 30 days from last dose)
Safety Issue:
Description:To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with TN or R/R CLL.

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:1 year after initial dose of study drug
Safety Issue:
Description:To evaluate the investigator-assessed ORR in participants receiving acalabrutinib monotherapy.
Measure: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)
Safety Issue:
Description:To evaluate the investigator-assessed DOR in participants receiving acalabrutinib monotherapy.
Measure: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
Safety Issue:
Description:To evaluate the investigator-assessed PFS in participants receiving acalabrutinib monotherapy.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Chronic lymphocytic leukemia
  • Acalabrutinib

Last Updated

January 20, 2020