Acute Myeloid Leukemia (AML)
Conditions
Keywords
Tolero, Phase 2, AML, Relapsed, Refractory, Alvocidib, Venetoclax
Brief summary
This study will evaluate the safety and efficacy of alvocidib in patients with AML who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine.
Interventions
DRUGAlvocidib (flavopiridol) and cytarabine (Ara-C)
Alvocidib (flavopiridol), administered intravenously, + cytarabine (Ara-C), administered by subcutaneous injection
DRUGAlvocidib (flavopiridol)
Administered intravenously
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, Two-stage
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be ≥18 years of age. 2. Have an established, pathologically confirmed diagnosis 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. Have received initial induction therapy with venetoclax in combination with azacytidine or decitabine (with or without other investigational agents as part of a clinical trial; requires Medical Monitor review) and were either refractory (failed to achieve a CR/CRi or achieved a CR/CRi with duration \<90 days) or have relapsed (reoccurrence of disease following a CR/CRi with duration ≥90 days). 4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2. 5. Have a glomerular filtration rate (GFR) ≥30 mL/min using the Cockcroft-Gault equation. 6. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN). 7. Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia). 8. Be infertile 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 prior to study entry, for the duration of study participation, and for at least 3 months (males) and 6 months (females) after the last dose of study drug. 9. Be able to comply with the requirements of the entire study. 10. Provide written informed consent prior to any study related procedure: in the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.
Exclusion criteria
1. Received any previous treatment with alvocidib or any other CDK inhibitor or received prior anti-leukemic therapy other than first-line venetoclax in combination with azacytidine or decitabine. 2. 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. 3. Received an allogeneic stem cell transplant within 60 days of the start of study treatment. Patients who received an allogeneic stem cell transplant must be off all immunosuppressants at the time of study treatment 4. Are receiving or have received systemic therapy for graft-versus-host disease. 5. Have a peripheral blast count of \>30,000/mm3 (may use hydroxyurea as in #2 above). 6. Received antileukemic therapy within the last 2 weeks or 3-5 half lives of the prior therapy (with the exception of hydroxyurea or if the patient has definite refractory disease), whichever is less. Refractory patients who received therapy within the last 2 weeks may be eligible with prior approval of the Medical Monitor. 7. Diagnosed with acute promyelocytic leukemia (APL-M3). 8. Have active central nervous system (CNS) leukemia. 9. Have evidence of uncontrolled disseminated intravascular coagulation. 10. Have an active, uncontrolled infection. 11. Have other life-threatening illness. 12. Have other active malignancies requiring treatment or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia. 13. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol. 14. Are pregnant and/or nursing. 15. Have received any live vaccine within 14 days prior to first study drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Complete Remission | Response assessments were measured from date of first dose through End of Treatment date, an average of 3 months. | Rate of combined complete remission (complete remission (CR) + CR with incomplete hematological recovery (CRi)), as defined by the International Working Group Criteria and 2017 European LeukemiaNet). Combined complete remissions (patients with a best response of CR or CRi), complete remissions, composite complete remissions (patients with a best response of CR, CRi or CRh), and combined responses (patients with a best response of CR, CRi, CRh, MLFS or PR) will be summarized by observed response rates and estimated 95% CIs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | Percentage of patients achieving complete response (CR) whose bone marrow is determined to be negative for minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry \[MPFC\] and molecular testing including next generation sequencing \[NGS\] |
| Composite CR Rate | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | Patients with a best response of CR + CRi + CRh (CR + partial recovery of both blood cell types) |
| Combined Response Rate | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | Combined Percentage of Patients Achieving One of the Following: CR \< CRi, CRh, MLFS, PR Morphologic leukemia-free state (MLFS) = Bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required; Partial Response (PR) = Meets all hematologic values required for CR but with a decrease of at least 50% in the percentage of blasts to ≥5% to ≤25% in bone marrow |
| Median Overall Survival | From first dose until disease progression or death; through study termination, an average of 10 months | Time from treatment (Day 1) until death from any cause |
| Duration of Composite Complete Remission (CR) | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | Duration of Composite CR, defined as the time from first documented response of CR, CRi or CRhi to relapse or death from any cause |
| Transfusion Independence | Transfusion dependence was measured from 28 days prior to first dose through 56 days after last dose, an average of 6 months | Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of patients who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, and neither RBC nor PLT transfusions for 28 and 56 days; comprised of 6 secondary endpoints |
| Event Free Survival (EFS) | From first dose until disease progression or death; through study termination, an average of 10 months | Event Free Survival - time from first treatment (D1) until (a) treatment failure, (b) relapse after CR/Cri or CRh, or (c) death from any cause, whichever occurs first |
Countries
United States
Participant flow
Recruitment details
Eleven subjects were enrolled between January 2020 and November 2020
Pre-assignment details
A safety lead-in cohort comprised of 6 patients (3 patients in each treatment arm) were treated and evaluated for dose-limiting toxicities (DLTs) prior to enrolling patients in Stage 1. (Seven patients were enrolled but only 6 were considered evaluable.) If a DLT was observed, dose de-escalation occurred, and if no DLTs were observed, randomization into Stage 1 would commence.
Participants by arm
| Arm | Count |
|---|---|
| Lead-In Cohort: Arm 1 ALDAC: Alvocidib administered intravenously on days 1 and 15 + cytarabine administered by subcutaneous injection days 3-12 of each 28 day cycle. Patients were stratified based on response to prior therapy (i.e. Refractory or Relapsed) | 3 |
| Lead-In Cohort: Arm 2 ALV: Alvocidib administered intravenously on days 1, 8 and 15 of each 28 day cycle. Patients were stratified based on response to prior therapy (i.e. Refractory or Relapsed) | 4 |
| Stage 1: Arm 1 ALDAC: Alvocidib administered intravenously on days 1 and 15 + cytarabine administered by subcutaneous injection days 3-12 of each 28 day cycle. Patients were stratified based on response to prior therapy (i.e. Refractory or Relapsed) | 2 |
| Stage 1: Arm 2 ALV: Alvocidib administered intravenously on days 1, 8 and 15 of each 28 day cycle. Patients were stratified based on response to prior therapy (i.e. Refractory or Relapsed) | 2 |
| Total | 11 |
Baseline characteristics
| Characteristic | Lead-In Cohort: Arm 1 | Lead-In Cohort: Arm 2 | Stage 1: Arm 1 | Stage 1: Arm 2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 5 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 | 2 / 3 | 3 / 4 | 1 / 2 | 1 / 2 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 2 / 3 | 3 / 4 | 2 / 2 | 1 / 2 |
Outcome results
Primary
Combined Complete Remission
Rate of combined complete remission (complete remission (CR) + CR with incomplete hematological recovery (CRi)), as defined by the International Working Group Criteria and 2017 European LeukemiaNet). Combined complete remissions (patients with a best response of CR or CRi), complete remissions, composite complete remissions (patients with a best response of CR, CRi or CRh), and combined responses (patients with a best response of CR, CRi, CRh, MLFS or PR) will be summarized by observed response rates and estimated 95% CIs.
Time frame: Response assessments were measured from date of first dose through End of Treatment date, an average of 3 months.
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Combined Response Rate
Combined Percentage of Patients Achieving One of the Following: CR \< CRi, CRh, MLFS, PR Morphologic leukemia-free state (MLFS) = Bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required; Partial Response (PR) = Meets all hematologic values required for CR but with a decrease of at least 50% in the percentage of blasts to ≥5% to ≤25% in bone marrow
Time frame: Response assessments were measured from date of first dose through end of treatment date, an average of 3 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Complete Response Rate
Percentage of patients achieving complete response (CR) whose bone marrow is determined to be negative for minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry \[MPFC\] and molecular testing including next generation sequencing \[NGS\]
Time frame: Response assessments were measured from date of first dose through end of treatment date, an average of 3 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Composite CR Rate
Patients with a best response of CR + CRi + CRh (CR + partial recovery of both blood cell types)
Time frame: Response assessments were measured from date of first dose through end of treatment date, an average of 3 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Duration of Composite Complete Remission (CR)
Duration of Composite CR, defined as the time from first documented response of CR, CRi or CRhi to relapse or death from any cause
Time frame: Response assessments were measured from date of first dose through end of treatment date, an average of 3 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Event Free Survival (EFS)
Event Free Survival - time from first treatment (D1) until (a) treatment failure, (b) relapse after CR/Cri or CRh, or (c) death from any cause, whichever occurs first
Time frame: From first dose until disease progression or death; through study termination, an average of 10 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Median Overall Survival
Time from treatment (Day 1) until death from any cause
Time frame: From first dose until disease progression or death; through study termination, an average of 10 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.
Secondary
Transfusion Independence
Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of patients who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, and neither RBC nor PLT transfusions for 28 and 56 days; comprised of 6 secondary endpoints
Time frame: Transfusion dependence was measured from 28 days prior to first dose through 56 days after last dose, an average of 6 months
Population: The sponsor decided not to continue the study based on the overall company strategy in AML. Data collection and analysis were not conducted.