Acute Myeloid Leukemia (AML)
Conditions
Keywords
Acute Myeloid Leukemia, AML, Ibrutinib, Cytarabine, LD-AraC, Azacitidine
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.
Interventions
DRUGIbrutinib
Subjects will receive ibrutinib 560 mg once daily on a continuing basis.
DRUGIbrutinib + LD-AraC
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.
DRUGIbrutinib+Azacitidine
Subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle (with an option to increase to 100 mg/m2 after 2 cycles).
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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). * PT/INR \<1.5 x ULN and PTT (aPTT) \<1.5 x ULN (When treated with warfarin or other vitamin K antagonists, then INR ≤3.0). * Female subjects who are of non-reproductive potential (Female subjects of reproductive potential must have a negative serum pregnancy test upon study entry). * Male and female subjects of reproductive potential agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], complete abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug.
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. * For Cohort 3 subjects, prior treatment with hypomethylating agents (eg, azacitidine, decitabine) * Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) prior to first dose of study drug. * Subject has received a monoclonal antibody for anticancer intent within 8 weeks prior to the first dose of study drug. * Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. * Recent infection requiring intravenous (IV) systemic treatment that was completed ≤14 days before the first dose of study drug. * Unresolved toxicities from prior anticancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade 0 or 1, unless otherwise defined in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS) | When the last subject enrolled completes approximately 12 months of treatment | To evaluate clinical efficacy by assessing relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS). |
| 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 | To evaluate clinical benefit defined as CR, CRi, morphologic leukemia-free state, and partial remission (PR). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib Monotherapy Cohort Up to 33 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis.
Ibrutinib: Subjects will receive ibrutinib 560 mg once daily on a continuing basis. | 7 |
| 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.
Ibrutinib + LD-AraC: 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. | 21 |
| 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).
Ibrutinib+Azacitidine: Subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle (with an option to increase to 100 mg/m2 after 2 cycles). | 8 |
| Total | 36 |
Baseline characteristics
| Characteristic | Ibrutinib Monotherapy Cohort | Ibrutinib + LD-AraC Combination Cohort | Ibrutinib+Azacitidine Combination Cohort | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 16 Participants | 2 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 6 Participants | 15 Participants |
| Age, Continuous | 67 years STANDARD_DEVIATION 11.7 | 70 years STANDARD_DEVIATION 9.1 | 58 years STANDARD_DEVIATION 12.4 | 67 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 19 Participants | 6 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 19 Participants | 8 Participants | 33 Participants |
| Region of Enrollment United States | 7 participants | 21 participants | 8 participants | 36 participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 6 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 14 Participants | 2 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 7 | 21 / 21 | 8 / 8 |
| other Total, other adverse events | 7 / 7 | 21 / 21 | 8 / 8 |
| serious Total, serious adverse events | 4 / 7 | 21 / 21 | 8 / 8 |
Outcome results
Primary
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
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.
Time frame: When the last subject enrolled completes approximately 12 months of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib Monotherapy Cohort | 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 | 0 Participants |
| Ibrutinib + LD-AraC Combination Cohort | 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 | 1 Participants |
| Ibrutinib+Azacitidine Combination Cohort | 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 | 0 Participants |
Primary
Safety and Tolerability of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine
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.
Time frame: Up to 30 days following the last dose of study drug.
Secondary
Clinical Benefit Rate - as Defined as the Proportion of Subjects Who Achieve CR, CRi, Morphologic Leukemia-free State, or Partial Remission (PR)
To evaluate clinical benefit defined as CR, CRi, morphologic leukemia-free state, and partial remission (PR).
Time frame: When the last subject enrolled completes approximately 12 months of treatment
Secondary
Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS)
To evaluate clinical efficacy by assessing relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS).
Time frame: When the last subject enrolled completes approximately 12 months of treatment