Acute Myeloid Leukemia
Conditions
Brief summary
The purpose of this Phase I study is to determine the safety and tolerability including the maximum dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Detailed description
Primary Objective: • To determine the safety and tolerability including the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML Secondary Objectives: * To observe patients for any evidence of antileukemic activity of alvocidib plus 7+3 using the 2017 ELN response criteria * To establish the Recommended Phase 2 Dose (RP2D) for future studies with alvocidib in combination with 7+3 Exploratory Objective: • To assess levels of minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry \[MPFC\] and next generation sequencing \[NGS\] and evaluate other potential biomarkers including, but not limited to, MCL-1 dependency.
Interventions
DRUGAlvocidib
IV bolus followed by IV infusion
DRUGCytarabine
continuous infusion
DRUGDaunorubicin
IV bolus
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* To be eligible for participation in the study, patients must meet all of the following 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 with ≥20% bone marrow blasts based on histology or flow cytometry 3. Be newly diagnosed and previously untreated 4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 5. Have a serum creatinine level ≤1.8 mg/dL 6. Have an alanine aminotransferase (ALT) and 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. Have a left ventricular ejection fraction (LVEF) \>45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 9. 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 prior to study entry, for the duration of study participation, and for at least 6 months after the last dose of study drug. 10. Be able to comply with the requirements of the entire study. 11. 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
* Patients meeting any one of these
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Alvocidib | During the first cycle | Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML |
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib | During the first cycle | Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Best response during duration of study | CR: Measurable residual disease is positive or unknown; BM blasts (bls) \<5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC \>1.0 x 109/L; platelets \>100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls \<5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by \>50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (\>15% point inc required in cases w/ \<30% bls at baseline or persistent BM bls % of \>70% over at least 3 months; without at least 100% improvement in ANC to absolute level \[\>0.5 x 109/L and/or platelet count to \>50 x 109/L non-transfused); or \>50% inc in peripheral bls to \>25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease. |
| Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3 | During Cycle 1 beginning at 1st dose of study drug through Day 50 + or - 3 days | The dose at which \< 1 of 6 patients experience a DLT during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease (MRD) Using Standardized Techniques | During duration of study | Percentage of participants with a CRMRD- response at the end of Cycle 1 |
Countries
United States
Participant flow
Recruitment details
32 patients at 3 sites; Recruitment started 25Sep2017 Recruitment ended 20Mar2020
Pre-assignment details
4 dose escalation cohorts. If 1 of 3 subjects in a cohort experienced a DLT, up to 3 additional subjects were treated at that dose level. If no DLTs observed, the alvocidib dose was escalated in a new cohort of 3 subjects. At MTD level 20 additional subjects enrolled for confirmation of safety as well as additional safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Alvocidib 20/30 mg/m2 Alvocidib 20 mg/m2 bolus followed by 30 mg/m2 IV infusion over 4 hours | 3 |
| Alvocidib 30/40 mg/m2 Alvocidib 30 mg/m2 bolus followed by 40 mg/m2 IV infusion over 4 hours | 3 |
| Alvocidib 30/50 mg/m2 Alvocidib 30 mg/m2 bolus followed by 50 mg/m2 IV infusion over 4 hours | 3 |
| Alvocidib 30/60 mg/m2 Alvocidib 30 mg/m2 bolus followed by 60 mg/m2 IV infusion over 4 hours | 23 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 2 |
| Overall Study | Insurance Company Decision | 0 | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 | 4 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 6 |
| Overall Study | Relapsed disease (following remission) | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Alvocidib 30/40 mg/m2 | Alvocidib 30/50 mg/m2 | Alvocidib 20/30 mg/m2 | Alvocidib 30/60 mg/m2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 23 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants | 20 Participants | 24 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 2 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 14 Participants | 18 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 | 0 / 3 | 0 / 3 | 0 / 3 | 2 / 23 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 23 / 23 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 5 / 23 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Alvocidib
Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Time frame: During the first cycle
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Maximum Tolerated Dose (MTD) of Alvocidib | Bolus | 30 mg/m2 |
| All Participants | Maximum Tolerated Dose (MTD) of Alvocidib | IV infusion | 60 mg/m2 |
Primary
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib
Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Time frame: During the first cycle
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib | 0 Participants |
| Alvocidib 30/40 mg/m2 | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib | 0 Participants |
| Alvocidib 30/50 mg/m2 | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib | 0 Participants |
| Alvocidib 30/60 mg/m2 | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib | 1 Participants |
Secondary
Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria
CR: Measurable residual disease is positive or unknown; BM blasts (bls) \<5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC \>1.0 x 109/L; platelets \>100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls \<5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by \>50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (\>15% point inc required in cases w/ \<30% bls at baseline or persistent BM bls % of \>70% over at least 3 months; without at least 100% improvement in ANC to absolute level \[\>0.5 x 109/L and/or platelet count to \>50 x 109/L non-transfused); or \>50% inc in peripheral bls to \>25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease.
Time frame: Best response during duration of study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Progressive Disease (PD) | 0 participants |
| All Participants | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Positive or Unknown (CR) | 1 participants |
| All Participants | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Not Evaluated | 0 participants |
| All Participants | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Partial Remission (PR) | 0 participants |
| All Participants | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Stable Disease | 0 participants |
| All Participants | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Negative (CRMRD-) | 2 participants |
| Alvocidib 30/40 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Partial Remission (PR) | 1 participants |
| Alvocidib 30/40 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Negative (CRMRD-) | 0 participants |
| Alvocidib 30/40 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Progressive Disease (PD) | 0 participants |
| Alvocidib 30/40 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Stable Disease | 0 participants |
| Alvocidib 30/40 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Not Evaluated | 0 participants |
| Alvocidib 30/40 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Positive or Unknown (CR) | 2 participants |
| Alvocidib 30/50 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Not Evaluated | 0 participants |
| Alvocidib 30/50 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Positive or Unknown (CR) | 0 participants |
| Alvocidib 30/50 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Stable Disease | 0 participants |
| Alvocidib 30/50 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Partial Remission (PR) | 0 participants |
| Alvocidib 30/50 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Negative (CRMRD-) | 2 participants |
| Alvocidib 30/50 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Progressive Disease (PD) | 1 participants |
| Alvocidib 30/60 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Partial Remission (PR) | 1 participants |
| Alvocidib 30/60 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Negative (CRMRD-) | 8 participants |
| Alvocidib 30/60 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Complete Remission MRD Positive or Unknown (CR) | 7 participants |
| Alvocidib 30/60 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Not Evaluated | 1 participants |
| Alvocidib 30/60 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Stable Disease | 2 participants |
| Alvocidib 30/60 mg/m2 | Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | Progressive Disease (PD) | 4 participants |
Secondary
Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3
The dose at which \< 1 of 6 patients experience a DLT during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1
Time frame: During Cycle 1 beginning at 1st dose of study drug through Day 50 + or - 3 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3 | Bolus | 30 mg/m2 |
| All Participants | Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3 | IV infusion | 60 mg/m2 |
Other Pre-specified
Minimal Residual Disease (MRD) Using Standardized Techniques
Percentage of participants with a CRMRD- response at the end of Cycle 1
Time frame: During duration of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Minimal Residual Disease (MRD) Using Standardized Techniques | 66.7 percentage of participants |
| Alvocidib 30/40 mg/m2 | Minimal Residual Disease (MRD) Using Standardized Techniques | 0 percentage of participants |
| Alvocidib 30/50 mg/m2 | Minimal Residual Disease (MRD) Using Standardized Techniques | 66.7 percentage of participants |
| Alvocidib 30/60 mg/m2 | Minimal Residual Disease (MRD) Using Standardized Techniques | 34.8 percentage of participants |