Acute Myeloid Leukemia
Conditions
Keywords
AML, Relapsed/Refractory Acute Myeloid Leukemia, IDH
Brief summary
The purpose of the clinical trial is to identify the maximum tolerated dose of MEN1703 and to further investigate its safety profile in participants with acute myeloid leukemia (AML).
Detailed description
Phase I/II, open-label, multi-center, dose escalation study to estimate the maximum tolerated dose of MEN1703 in participants with acute myeloid leukemia. The clinical trial will investigate the safety profile and anti-leukemic activity of MEN1703 in participants with AML and that have no standard therapeutic options available. The clinical trial encompasses 2 parts: * Part 1: Ascending dose levels - the main purpose of this part of the clinical trial is to determine the highest dose of MEN1703 considered to be well tolerated. * Part 2: Expansion cohort - the main purpose of this part of the clinical trial is to assess the safety and anti-leukemia activity of MEN1703 given at the highest tolerated dose in participant with relapsed/refractory acute myeloid leukemia, either all comers as well as harboring isocitrate dehydrogenase (IDH1/IDH2) mutations. Participants participating to the clinical trial will take the study drug as oral capsules once daily for 14 consecutive days over a 21-day treatment cycle.
Interventions
DRUGMEN1703
MEN1703 given as oral capsules once daily for 14 consecutive days over a 21-day treatment cycle.
Sponsors
Medpace, Inc.
Theradex
Menarini Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with diagnosis of AML, all comers or bearing IDH1 or IDH2 mutation (completed) * Participant has no standard therapeutic options available and has either relapsed AML unsuitable for intensive chemotherapy, with no standard therapeutic options and/or not eligible for any approved targeted therapy or primary refractory AML unsuitable for intensive chemotherapy, with no standard therapeutic options and/or not eligible for any approved targeted therapy
Exclusion criteria
* Anti-cancer treatments (including cytotoxic chemotherapy, radiotherapy, hormonal therapy, biologic, immunotherapy or investigational drugs) received within 14 days or 5 half-lives for targeted therapies (whichever is shorter) before first dose of study drug (to be supplemented)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | Up to 21 months | An adverse event (AE) was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the investigational medicinal product. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse events module. |
| Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | Day 1 through Day 21 (first treatment cycle) | AEs were graded according to the National Cancer Institute common terminology criteria for adverse events, version 4.03. The following AEs were considered as DLT unless they were clearly and incontrovertibly attributable to the underlying disease or to an extraneous cause: Grade 5 toxicity; Grade 4 neutropenia lasting ≥42 days from the start of the therapy cycle in absence of evidence of active acute myeloid leukemia (AML) (\<5% blasts); Grade 3 or 4 non-hematologic toxicity (with protocol-define exceptions). Only clinically significant abnormalities in laboratory findings, physical examination, vital signs, weight, or electrocardiogram were considered for DLT assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and Part 2: Duration of Response (DoR) | Up to 32 months | DoR was defined as the time from the date of first CR, CRi, CRh, CR without minimal residual disease (CRMRD-), MLFS or PR until the date of documented relapse of any type, progressive disease or death due to disease progression for participants who achieve CR, CRi, CRh, CRMRD-, MLFS or PR. Results are reported in days. |
| Part 1 and Part 2: Relapse Free Survival (RFS) | Up to 32 months | RFS was defined as the time from the date of first CR, CRi, CRh, or CRMRD- until the date of documented relapse or death from any cause. Results are reported in days. |
| Part 1 and Part 2: Overall Survival (OS) | Up to 32 months | OS was defined as the number of days between the first study drug administration and death from any cause. Results are reported in days. |
| Part 1 and Part 2: Event Free Survival (EFS) | Up to 32 months | EFS was defined as the time from the date of first study drug intake until the date of documented relapse, treatment failure, or death from any cause. Results are reported in days. |
| Part 1 and Part 2: Transfusion Conversion Rate | Up to 21 months | Transfusion conversion rate was defined as the percentage of participants who were transfusion dependent at baseline but became transfusion independent post-baseline. Participants were classified as baseline transfusion independent if there were no red blood cells (RBC) or platelet transfusions at baseline; otherwise, the participant was considered as baseline transfusion dependent. Participants were classified post-baseline transfusion independent in the event of 56 consecutive days without any RBC or platelet transfusion post-baseline; otherwise, the participant was considered post-baseline transfusion dependent. |
| Part 1 and Part 2: Overall Response Rate (ORR) | Up to 32 months | ORR was defined as the percentage of participants who had a complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh), or morphologic leukemia-free state (MLFS) response to therapy. |
| Part 1 and Part 2: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Rate | Up to 21 months | Allogeneic HSCT rate was defined as the percentage of participants undergoing allogeneic stem cell transplant during the study period of each participant. |
| Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction | Up to 20 months | Bone marrow aspirates/biopsies were taken at designated timepoints for evaluation of leukemic blast proportion in the bone marrow. A reduction in bone marrow blast proportion indicates increased anti-leukemic activity of the study drug. |
| Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Day 1 and Day 14 of Cycle 1 (pre-dose, up to 120 hours post dose) (21 days/cycle) | Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. Results are reported as nanograms/milliliter (ng/mL). Standard error not reported, arithmetic coefficient of variation (CV%) reported instead. |
| Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | Day 1 of Cycle 1 (pre-dose, up to 24 hours post dose) (21 days/cycle) | Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. AUClast was calculated by the linear trapezoidal rule. Results are reported in hour times nanograms/milliliter (h\*ng/mL). Standard error not reported, arithmetic CV% reported instead. |
| Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703 | Day 14 of Cycle 1 (pre-dose, up to 120 hours post dose) (21 days/cycle) | Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. AUC0-24 was calculated by the linear trapezoidal rule. Results are reported in h\*ng/mL. Standard error not reported, arithmetic CV% reported instead. |
| Part 1 and Part 2: Transfusion Maintenance Rate | Up to 21 months | Transfusion maintenance rate was defined as the percentage of participants who were transfusion independent at baseline and still maintained to be transfusion independent post-baseline. Participants were classified as baseline transfusion independent if there were no RBC or platelet transfusions at baseline; otherwise, the participant was considered as baseline transfusion dependent. Participants were classified post-baseline transfusion independent in the event of 56 consecutive days without any RBC or platelet transfusion post-baseline; otherwise, the participant was considered post-baseline transfusion dependent. |
| Part 1 and Part 2: Partial Remission (PR) Rate | Up to 32 months | PR rate was defined as the percentage of participants who had a partial remission response to therapy. |
Countries
Italy, Poland, Spain, United States
Participant flow
Recruitment details
Participants were screened across 4 countries: Unites States, Italy, Spain, and Poland.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (25 mg) Participants received MEN1703 (25 mg) orally once daily for 14 consecutive days in cycles of 21 days. | 2 |
| Cohort 2 (50 mg) Participants received MEN1703 (50 mg) orally once daily for 14 consecutive days in cycles of 21 days. | 3 |
| Cohort 3 (75 mg) Participants received MEN1703 (75 mg) orally once daily for 14 consecutive days in cycles of 21 days. | 3 |
| Cohort 4 (100 mg) Participants received MEN1703 (100 mg) orally once daily for 14 consecutive days in cycles of 21 days. | 6 |
| Cohort 5 (125 mg) Participants received MEN1703 (125 mg) orally once daily for 14 consecutive days in cycles of 21 days. | 55 |
| Cohort 6 (150 mg) Participants received MEN1703 (150 mg) orally once daily for 14 consecutive days in cycles of 21 days. | 4 |
| Total | 73 |
Baseline characteristics
| Characteristic | Cohort 1 (25 mg) | Cohort 2 (50 mg) | Cohort 3 (75 mg) | Cohort 4 (100 mg) | Cohort 5 (125 mg) | Cohort 6 (150 mg) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 47.50 years STANDARD_DEVIATION 31.82 | 71.00 years STANDARD_DEVIATION 5 | 75.33 years STANDARD_DEVIATION 8.963 | 65.67 years STANDARD_DEVIATION 18.726 | 65.55 years STANDARD_DEVIATION 12.06 | 63.50 years STANDARD_DEVIATION 7.047 | 65.58 years STANDARD_DEVIATION 12.923 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 53 Participants | 4 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 3 Participants | 4 Participants | 51 Participants | 4 Participants | 66 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 24 Participants | 1 Participants | 33 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 31 Participants | 3 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 3 / 3 | 3 / 3 | 1 / 6 | 35 / 55 | 4 / 4 |
| other Total, other adverse events | 2 / 2 | 3 / 3 | 3 / 3 | 6 / 6 | 52 / 55 | 4 / 4 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 | 3 / 3 | 6 / 6 | 35 / 55 | 4 / 4 |
Outcome results
Primary
Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events
An adverse event (AE) was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the investigational medicinal product. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse events module.
Time frame: Up to 21 months
Population: Safety population: all participants that received at least 1 dose of MEN1703.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | 2 Participants |
| Cohort 2 (50 mg) | Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | 3 Participants |
| Cohort 3 (75 mg) | Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | 3 Participants |
| Cohort 4 (100 mg) | Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | 6 Participants |
| Cohort 5 (125 mg) | Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | 54 Participants |
| Cohort 6 (150 mg) | Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events | 4 Participants |
Primary
Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT)
AEs were graded according to the National Cancer Institute common terminology criteria for adverse events, version 4.03. The following AEs were considered as DLT unless they were clearly and incontrovertibly attributable to the underlying disease or to an extraneous cause: Grade 5 toxicity; Grade 4 neutropenia lasting ≥42 days from the start of the therapy cycle in absence of evidence of active acute myeloid leukemia (AML) (\<5% blasts); Grade 3 or 4 non-hematologic toxicity (with protocol-define exceptions). Only clinically significant abnormalities in laboratory findings, physical examination, vital signs, weight, or electrocardiogram were considered for DLT assessment.
Time frame: Day 1 through Day 21 (first treatment cycle)
Population: Safety Population: all participants that received at least one dose of MEN1703. Here, 'Overall Number of Participants Analyzed' signifies those participants from Part 1 who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | 1 Participants |
| Cohort 2 (50 mg) | Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | 0 Participants |
| Cohort 3 (75 mg) | Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | 0 Participants |
| Cohort 4 (100 mg) | Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | 0 Participants |
| Cohort 5 (125 mg) | Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | 1 Participants |
| Cohort 6 (150 mg) | Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT) | 3 Participants |
Secondary
Part 1 and Part 2: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Rate
Allogeneic HSCT rate was defined as the percentage of participants undergoing allogeneic stem cell transplant during the study period of each participant.
Time frame: Up to 21 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure. Data was collected only for Cohort 5 for this end point as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Rate | 2.7 percentage of participants |
Secondary
Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703
Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. AUC0-24 was calculated by the linear trapezoidal rule. Results are reported in h\*ng/mL. Standard error not reported, arithmetic CV% reported instead.
Time frame: Day 14 of Cycle 1 (pre-dose, up to 120 hours post dose) (21 days/cycle)
Population: Pharmacokinetics (PK) Population: all participants who received any dose of MEN1703 and had at least 1 measurable drug concentration. Here, 'Overall Number of Participants Analyzed' signifies those participants in Cohorts 2-6 who were evaluable for this outcome measure at the specified time point. Data was not collected for Cohort 1 for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703 | 1330.03 h*ng/mL |
| Cohort 2 (50 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703 | 2885.33 h*ng/mL |
| Cohort 3 (75 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703 | 5574.10 h*ng/mL |
| Cohort 4 (100 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703 | 9224.62 h*ng/mL |
| Cohort 5 (125 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703 | 15769.60 h*ng/mL |
Secondary
Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703
Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. AUClast was calculated by the linear trapezoidal rule. Results are reported in hour times nanograms/milliliter (h\*ng/mL). Standard error not reported, arithmetic CV% reported instead.
Time frame: Day 1 of Cycle 1 (pre-dose, up to 24 hours post dose) (21 days/cycle)
Population: Pharmacokinetics (PK) Population: all participants who received any dose of MEN1703 and had at least 1 measurable drug concentration. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | 152.17 h*ng/mL |
| Cohort 2 (50 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | 490.37 h*ng/mL |
| Cohort 3 (75 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | 729.48 h*ng/mL |
| Cohort 4 (100 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | 1016.62 h*ng/mL |
| Cohort 5 (125 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | 1936.61 h*ng/mL |
| Cohort 6 (150 mg) | Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703 | 2608.31 h*ng/mL |
Secondary
Part 1 and Part 2: Duration of Response (DoR)
DoR was defined as the time from the date of first CR, CRi, CRh, CR without minimal residual disease (CRMRD-), MLFS or PR until the date of documented relapse of any type, progressive disease or death due to disease progression for participants who achieve CR, CRi, CRh, CRMRD-, MLFS or PR. Results are reported in days.
Time frame: Up to 32 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Duration of Response (DoR) | NA days |
| Cohort 3 (75 mg) | Part 1 and Part 2: Duration of Response (DoR) | 79.0 days |
| Cohort 4 (100 mg) | Part 1 and Part 2: Duration of Response (DoR) | NA days |
| Cohort 5 (125 mg) | Part 1 and Part 2: Duration of Response (DoR) | 63.0 days |
| Cohort 6 (150 mg) | Part 1 and Part 2: Duration of Response (DoR) | NA days |
Secondary
Part 1 and Part 2: Event Free Survival (EFS)
EFS was defined as the time from the date of first study drug intake until the date of documented relapse, treatment failure, or death from any cause. Results are reported in days.
Time frame: Up to 32 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Event Free Survival (EFS) | 15.0 days |
| Cohort 3 (75 mg) | Part 1 and Part 2: Event Free Survival (EFS) | 14.0 days |
| Cohort 4 (100 mg) | Part 1 and Part 2: Event Free Survival (EFS) | 14.0 days |
| Cohort 5 (125 mg) | Part 1 and Part 2: Event Free Survival (EFS) | 43.0 days |
| Cohort 6 (150 mg) | Part 1 and Part 2: Event Free Survival (EFS) | 15.0 days |
Secondary
Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703
Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. Results are reported as nanograms/milliliter (ng/mL). Standard error not reported, arithmetic coefficient of variation (CV%) reported instead.
Time frame: Day 1 and Day 14 of Cycle 1 (pre-dose, up to 120 hours post dose) (21 days/cycle)
Population: Pharmacokinetics (PK) Population: all participants who received any dose of MEN1703 and had at least 1 measurable drug concentration. Here, 'Number Analyzed' signifies those participants who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 1 | 8.77 ng/mL |
| Cohort 2 (50 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 1 | 33.58 ng/mL |
| Cohort 2 (50 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 14 | 74.32 ng/mL |
| Cohort 3 (75 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 1 | 60.55 ng/mL |
| Cohort 3 (75 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 14 | 167.08 ng/mL |
| Cohort 4 (100 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 1 | 73.25 ng/mL |
| Cohort 4 (100 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 14 | 294.25 ng/mL |
| Cohort 5 (125 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 1 | 152.94 ng/mL |
| Cohort 5 (125 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 14 | 507.18 ng/mL |
| Cohort 6 (150 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 14 | 759.36 ng/mL |
| Cohort 6 (150 mg) | Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703 | Cycle 1 Day 1 | 249.00 ng/mL |
Secondary
Part 1 and Part 2: Overall Response Rate (ORR)
ORR was defined as the percentage of participants who had a complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh), or morphologic leukemia-free state (MLFS) response to therapy.
Time frame: Up to 32 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this Outcome Measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Overall Response Rate (ORR) | 0 percentage of participants |
| Cohort 3 (75 mg) | Part 1 and Part 2: Overall Response Rate (ORR) | 50.0 percentage of participants |
| Cohort 4 (100 mg) | Part 1 and Part 2: Overall Response Rate (ORR) | 0 percentage of participants |
| Cohort 5 (125 mg) | Part 1 and Part 2: Overall Response Rate (ORR) | 13.5 percentage of participants |
| Cohort 6 (150 mg) | Part 1 and Part 2: Overall Response Rate (ORR) | 0 percentage of participants |
Secondary
Part 1 and Part 2: Overall Survival (OS)
OS was defined as the number of days between the first study drug administration and death from any cause. Results are reported in days.
Time frame: Up to 32 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Overall Survival (OS) | 43.0 days |
| Cohort 3 (75 mg) | Part 1 and Part 2: Overall Survival (OS) | 138.5 days |
| Cohort 4 (100 mg) | Part 1 and Part 2: Overall Survival (OS) | NA days |
| Cohort 5 (125 mg) | Part 1 and Part 2: Overall Survival (OS) | 144.0 days |
| Cohort 6 (150 mg) | Part 1 and Part 2: Overall Survival (OS) | 42.5 days |
Secondary
Part 1 and Part 2: Partial Remission (PR) Rate
PR rate was defined as the percentage of participants who had a partial remission response to therapy.
Time frame: Up to 32 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this Outcome Measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Partial Remission (PR) Rate | 0 percentage of participants |
| Cohort 3 (75 mg) | Part 1 and Part 2: Partial Remission (PR) Rate | 0 percentage of participants |
| Cohort 4 (100 mg) | Part 1 and Part 2: Partial Remission (PR) Rate | 0 percentage of participants |
| Cohort 5 (125 mg) | Part 1 and Part 2: Partial Remission (PR) Rate | 0 percentage of participants |
| Cohort 6 (150 mg) | Part 1 and Part 2: Partial Remission (PR) Rate | 0 percentage of participants |
Secondary
Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction
Bone marrow aspirates/biopsies were taken at designated timepoints for evaluation of leukemic blast proportion in the bone marrow. A reduction in bone marrow blast proportion indicates increased anti-leukemic activity of the study drug.
Time frame: Up to 20 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who had an available baseline bone marrow assessment and at least 1 post-baseline bone marrow assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction | 0 percentage of participants |
| Cohort 3 (75 mg) | Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction | 50.0 percentage of participants |
| Cohort 4 (100 mg) | Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction | 0 percentage of participants |
| Cohort 5 (125 mg) | Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction | 33.3 percentage of participants |
| Cohort 6 (150 mg) | Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction | 0 percentage of participants |
Secondary
Part 1 and Part 2: Relapse Free Survival (RFS)
RFS was defined as the time from the date of first CR, CRi, CRh, or CRMRD- until the date of documented relapse or death from any cause. Results are reported in days.
Time frame: Up to 32 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 (50 mg) | Part 1 and Part 2: Relapse Free Survival (RFS) | NA days |
| Cohort 3 (75 mg) | Part 1 and Part 2: Relapse Free Survival (RFS) | 81.0 days |
| Cohort 4 (100 mg) | Part 1 and Part 2: Relapse Free Survival (RFS) | NA days |
| Cohort 5 (125 mg) | Part 1 and Part 2: Relapse Free Survival (RFS) | 64.0 days |
| Cohort 6 (150 mg) | Part 1 and Part 2: Relapse Free Survival (RFS) | NA days |
Secondary
Part 1 and Part 2: Transfusion Conversion Rate
Transfusion conversion rate was defined as the percentage of participants who were transfusion dependent at baseline but became transfusion independent post-baseline. Participants were classified as baseline transfusion independent if there were no red blood cells (RBC) or platelet transfusions at baseline; otherwise, the participant was considered as baseline transfusion dependent. Participants were classified post-baseline transfusion independent in the event of 56 consecutive days without any RBC or platelet transfusion post-baseline; otherwise, the participant was considered post-baseline transfusion dependent.
Time frame: Up to 21 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were transfusion dependent at baseline and had transfusion status reported post baseline. Data was collected only for Cohort 5 for this end point as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Transfusion Conversion Rate | 25 percentage of participants |
Secondary
Part 1 and Part 2: Transfusion Maintenance Rate
Transfusion maintenance rate was defined as the percentage of participants who were transfusion independent at baseline and still maintained to be transfusion independent post-baseline. Participants were classified as baseline transfusion independent if there were no RBC or platelet transfusions at baseline; otherwise, the participant was considered as baseline transfusion dependent. Participants were classified post-baseline transfusion independent in the event of 56 consecutive days without any RBC or platelet transfusion post-baseline; otherwise, the participant was considered post-baseline transfusion dependent.
Time frame: Up to 21 months
Population: Efficacy Population: all participants in each cohort that have completed 1 cycle of treatment (considering both the treatment and the washout period) and have taken at least 75% of the study drug during the first cycle. Here, 'Overall Number of Participants Analyzed' signifies those participants who were transfusion independent at baseline and had transfusion status reported post baseline. Data was collected only for Cohort 5 for this end point as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (25 mg) | Part 1 and Part 2: Transfusion Maintenance Rate | 100 percentage of participants |