Acute Myeloid Leukemia
Conditions
Keywords
Refractory AML, Relapsed AML, AML
Brief summary
The purpose of this two-stage Phase 2 study is to assess the clinical response (Complete Remission) of ACM (Alvocidib/Cytarabine/Mitoxantrone) compared to CM (Cytarabine/Mitoxantrone) treatment in refractory or relapsed AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow.
Detailed description
In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will receive treatment with ACM. In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.
Interventions
DRUGAlvocidib
DRUGCytarabine
DRUGMitoxantrone
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Be between the ages of ≥18 and ≤65 years 2. Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of \>5% blasts based on histology or flow cytometry 3. Be in first relapse (within 24 months of CR) or have failed induction therapy\* (no CR or CRi after treatment with an intensive regimen (eg, anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or cladribine). \*Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy assessment of induction therapy must be \>21 days from the start of the previous induction cycle. 4. Demonstrate MCL-1 dependence of ≥30% by mitochondrial profiling in bone marrow. 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 6. Have a serum creatinine level ≤1.8 mg/dL 7. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN) 8. Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia) 9. Have a left ventricular ejection fraction (LVEF) \>45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 10. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for at least 6 months after completion of study therapy. 11. Be able to comply with the requirements of the entire study. 12. Provide written informed consent prior to any study related procedure.
Exclusion criteria
1. Received more than 2 cycles of induction therapy for AML. Investigational agents as part of front-line therapy for AML may by acceptable following discussion with the Medical Monitor. Hydroxyurea is permitted (see #5 below). 2. Received any previous treatment with alvocidib or any other CDK inhibitor 3. Received a hematopoietic stem cell transplant within the previous 2 months 4. Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days 5. Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm. 6. Received \>360 mg/m2 equivalents of daunorubicin 7. Have a peripheral blast count of \>30,000/mm3 (may use hydroxyurea as in #5 above) 8. Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 weeks may be eligible with prior approval of the Medical Monitor. 9. Diagnosed with acute promyelocytic leukemia (APL, M3) 10. Have active central nervous system (CNS) leukemia 11. Have evidence of uncontrolled disseminated intravascular coagulation 12. Have an active, uncontrolled infection 13. Have other life-threatening illness 14. Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia 15. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol. 16. Are pregnant and/or nursing 17. Have received any live vaccine within 14 days prior to first study drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Best response after at least 1 cycle through study completion approximately 4 years | Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group (IWG) Criteria and 2010 European LeukemiaNet (EN) criteria in patients with relapsed or refractory AML with MCL-1 dependence \>30% and in Stage 2 by the 2017 ELN criteria. The study was terminated in January 2020 due to a steady and marked reduction in enrollment. Thus, the efficacy endpoints could not be analyzed. As sufficient efficacy results were not available to analyze patients based on the percentage of MCL-1 dependency the treatment efficacy was summarized by distributing the safety population into 6 groups based on whether the patients received the ACM vs CM regimen and their disease stages at study entry. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Response to Treatment | Best response after at least 1 cycle through study completion approximately 4 years | To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with MCL-1 dependence of \>30% who failed to achieve CR following 1 cycle of CM |
Countries
Canada, Spain, United Kingdom, United States
Participant flow
Recruitment details
Enrolled 104 pts from 14Mar2016 to 12Feb2020 at 22 of 40 sites. Patients were hospitalized until completion of their chemotherapy. The study terminated early in Jan2020 due to a steady and marked reduction in enrollment. The study protocol underwent a few major amendments during the course of the trial. Although the study protocol and the SAP had planned for comprehensive analysis of the efficacy data, only select efficacy analyses could be performed due to early termination of the trial.
Participants by arm
| Arm | Count |
|---|---|
| CM Relapsed/Refractory Stage 2 Relapsed/Refractory AML patients who were randomized to receive CM | 11 |
| ACM Relapsed/Refractory Relapsed/Refractory AML patients enrolled to Stage 1 and those enrolled to Stage 2 who received ACM. | 79 |
| ACM Newly Diagnosed Newly diagnosed AML patients enrolled and received ACM. | 14 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 |
| Overall Study | Death | 0 | 8 | 1 |
| Overall Study | Lack of Efficacy | 4 | 26 | 4 |
| Overall Study | Patient went to hospice | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 0 |
| Overall Study | Progressive disease following response | 0 | 4 | 2 |
| Overall Study | Protocol Deviation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 0 |
Baseline characteristics
| Characteristic | Total | ACM Newly Diagnosed | ACM Relapsed/Refractory | CM Relapsed/Refractory |
|---|---|---|---|---|
| 2017 ELN genetic risk criteria classification Adverse | 37 Participants | 3 Participants | 26 Participants | 8 Participants |
| 2017 ELN genetic risk criteria classification Favorable | 9 Participants | 1 Participants | 6 Participants | 2 Participants |
| 2017 ELN genetic risk criteria classification Intermediate | 14 Participants | 0 Participants | 13 Participants | 1 Participants |
| 2017 ELN genetic risk criteria classification Missing | 44 Participants | 10 Participants | 34 Participants | 0 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 104 Participants | 14 Participants | 79 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 4 Participants | 0 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 | 4 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 94 Participants | 13 Participants | 70 Participants | 11 Participants |
| Sex: Female, Male Female | 47 Participants | 3 Participants | 40 Participants | 4 Participants |
| Sex: Female, Male Male | 57 Participants | 11 Participants | 39 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 11 | 11 / 79 | 1 / 14 | 12 / 93 |
| other Total, other adverse events | 11 / 11 | 79 / 79 | 14 / 14 | 93 / 93 |
| serious Total, serious adverse events | 3 / 11 | 31 / 79 | 4 / 14 | 35 / 93 |
Outcome results
Primary
Complete Response (CR) Rate in Patients With Relapsed or Refractory AML
Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group (IWG) Criteria and 2010 European LeukemiaNet (EN) criteria in patients with relapsed or refractory AML with MCL-1 dependence \>30% and in Stage 2 by the 2017 ELN criteria. The study was terminated in January 2020 due to a steady and marked reduction in enrollment. Thus, the efficacy endpoints could not be analyzed. As sufficient efficacy results were not available to analyze patients based on the percentage of MCL-1 dependency the treatment efficacy was summarized by distributing the safety population into 6 groups based on whether the patients received the ACM vs CM regimen and their disease stages at study entry.
Time frame: Best response after at least 1 cycle through study completion approximately 4 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 2 CM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Not Evaluated | 0 participants |
| Stage 2 CM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Partial Remission (PR) | 0 participants |
| Stage 2 CM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | CR with Incomplete Neutrophil Recovery (Cri) | 0 participants |
| Stage 2 CM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) | 6 participants |
| Stage 2 CM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Resistant/Relapsed Disease | 5 participants |
| Stage 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Partial Remission (PR) | 0 participants |
| Stage 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Not Evaluated | 1 participants |
| Stage 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | CR with Incomplete Neutrophil Recovery (Cri) | 3 participants |
| Stage 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) | 2 participants |
| Stage 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Resistant/Relapsed Disease | 5 participants |
| Stage 1 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | CR with Incomplete Neutrophil Recovery (Cri) | 5 participants |
| Stage 1 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Not Evaluated | 6 participants |
| Stage 1 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) | 8 participants |
| Stage 1 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Resistant/Relapsed Disease | 5 participants |
| Stage 1 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Partial Remission (PR) | 1 participants |
| Stages 1 and 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Resistant/Relapsed Disease | 30 participants |
| Stages 1 and 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | CR with Incomplete Neutrophil Recovery (Cri) | 15 participants |
| Stages 1 and 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Partial Remission (PR) | 1 participants |
| Stages 1 and 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Not Evaluated | 12 participants |
| Stages 1 and 2 ACM Relapsed/Refractory | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) | 21 participants |
| Stage 1 Newly Diagnosed ACM | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Partial Remission (PR) | 1 participants |
| Stage 1 Newly Diagnosed ACM | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) | 6 participants |
| Stage 1 Newly Diagnosed ACM | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Not Evaluated | 1 participants |
| Stage 1 Newly Diagnosed ACM | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Resistant/Relapsed Disease | 4 participants |
| Stage 1 Newly Diagnosed ACM | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | CR with Incomplete Neutrophil Recovery (Cri) | 2 participants |
| All Stages and Cohorts (Including Randomized Stage): ACM Total | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Partial Remission (PR) | 2 participants |
| All Stages and Cohorts (Including Randomized Stage): ACM Total | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | CR with Incomplete Neutrophil Recovery (Cri) | 17 participants |
| All Stages and Cohorts (Including Randomized Stage): ACM Total | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) | 27 participants |
| All Stages and Cohorts (Including Randomized Stage): ACM Total | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Not Evaluated | 13 participants |
| All Stages and Cohorts (Including Randomized Stage): ACM Total | Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Resistant/Relapsed Disease | 34 participants |
Other Pre-specified
Response to Treatment
To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with MCL-1 dependence of \>30% who failed to achieve CR following 1 cycle of CM
Time frame: Best response after at least 1 cycle through study completion approximately 4 years
Population: A total 11 patients were initially randomized to the CM arm. 6 had CR from receiving CM so they did not cross over to receive ACM. Of the remaining 5 patients, only 2 crossed over to receive ACM and were included in the analysis of this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 2 CM Relapsed/Refractory | Response to Treatment | Partial Remission (PR) | 1 participants |
| Stage 2 CM Relapsed/Refractory | Response to Treatment | Not Evaluated | 1 participants |