A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or in Combination With Either Cytarabine or Azacitidine in Subjects With Acute Myeloid Leukemia
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Acute Myeloid Leukemia (AML)
- Sponsor
- Pharmacyclics LLC.
- Enrollment
- 36
- Locations
- 9
- Primary Endpoint
- Efficacy of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine Using the Overall Remission Rate (Defined as Proportion of Subjects Achieving a CR or CRi) According to the LeukemiaNet Guidelines
- Status
- Terminated
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the efficacy, safety and tolerability of ibrutinib alone or in combination with either cytarabine or azacitidine in the treatment of subjects with Acute Myeloid Leukemia (AML) who have failed standard treatment, or subjects without prior therapy who refuse standard chemotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female ≥ 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Subjects with pathologically documented AML that has failed standard treatment, or subjects without prior therapy who refuse standard treatment options
- •Bone marrow aspirate/biopsy results showing \>5% blasts
- •WBC count \<25,000 cells/mm3 (25 x 109/L)
- •Platelet count \>10,000 cells/mm3 (10 x 109/L)
- •Adequate hepatic and renal function defined as:
- •For Cohorts 1 and 2: serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3.0 x upper limit of normal (ULN); for Cohort 3: ALT ≤2.5 or AST ≤2.5 ULN.
- •Serum creatinine ≤2 mg/dL or Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault).
- •Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
Exclusion Criteria
- •Acute promyelocytic leukemia (French-American-British Class M3 AML).
- •Known active central nervous system (CNS) leukemia.
- •Known active systemic infection (Grade ≥2).
- •Active bleeding disorders or clinical signs of bleeding (Grade ≥2).
- •Prior bone marrow transplant that requires immunosuppressant therapy or presents with graft vs host disease (GVHD).
- •History of other malignancies, except:
- •Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and with low risk of recurrence by treating physician.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated carcinoma in situ without evidence of disease.
- •Prior treatment with a BTK inhibitor.
Arms & Interventions
Ibrutinib Monotherapy Cohort
Up to 33 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis.
Intervention: Ibrutinib
Ibrutinib + LD-AraC Combination Cohort
Up to 25-28 additional response evaluable subjects (for a total of 34 subjects) will receive ibrutinib 560 mg once daily on a continuous basis starting 2 days prior to first cytarabine dose (20 mg BID sc) for 10 days of a 28-day cycle.
Intervention: Ibrutinib + LD-AraC
Ibrutinib+Azacitidine Combination Cohort
Up to 34 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75mg/m2 IV once daily Days 1-7 of a 28-day cycle (with an option to increase to 100mg/m2 after 2 cycles).
Intervention: Ibrutinib+Azacitidine
Outcomes
Primary Outcomes
Efficacy of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine Using the Overall Remission Rate (Defined as Proportion of Subjects Achieving a CR or CRi) According to the LeukemiaNet Guidelines
Time Frame: When the last subject enrolled completes approximately 12 months of treatment.
Dohner's 2000 Criteria for AML: Complete Response (CR), Bone marrow blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \> 1.0 x 109/L (1000/µL); platelet count \>100 x 109/L (100 000/µL); independence of red cell transfusions; CR with Incomplete Recovery (CRi), All CR criteria except for residual neutropenia (\< 1.0 x 109/L \[1000/µL\]) or thrombocytopenia (\<100 x 109/L \[100 000/µL\]) ; Morphologic leukemia-free state, Bone marrow blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required; Partial Remission (PR), All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%; Relapse, Bone marrow blasts \> 5%; or reappearance of blasts in the blood; or development of extramedullary disease.
Safety and Tolerability of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine
Time Frame: Up to 30 days following the last dose of study drug.
Number of Participants with Adverse Events and number of patients with lab abnormalities.The safety profile of ibrutinib was evaluated based on the incidence of adverse events (AEs) as well as clinically significant laboratory abnormalities and vital signs, and other malignancies. The safety evaluations performed in this study were standard and/or were required based on the safety data available from other clinical and preclinical settings.
Secondary Outcomes
- Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS)(When the last subject enrolled completes approximately 12 months of treatment)
- Clinical Benefit Rate - as Defined as the Proportion of Subjects Who Achieve CR, CRi, Morphologic Leukemia-free State, or Partial Remission (PR)(When the last subject enrolled completes approximately 12 months of treatment)