Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
AML, MDS, non-acute promyelocytic leukemia (non-APL), lower-risk myelodysplastic syndrome (LR-MDS)
Brief summary
The purpose of this study is to determine the activity of tamibarotene in participants with relapsed/refractory (R/R) AML (administered as a monotherapy or in combination with azacitidine), R/R higher-risk MDS (HR-MDS) (administered as a monotherapy or in combination with daratumumab), newly diagnosed treatment naïve AML participants who are unlikely to tolerate standard intensive chemotherapy (administered as a monotherapy or in combination with azacitidine), or lower-risk MDS (LR-MDS) (administered as a monotherapy).
Interventions
DRUGTamibarotene
Administered as oral tablets
DRUGAzacitidine
Administered via intravenous (IV) or subcutaneous (SC) infusion
DRUGDaratumumab
Administered via IV infusion
Sponsors
Syros Pharmaceuticals
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
Key Inclusion Criteria: 1. Must have: 1. Relapsed and/or refractory non-APL AML that has failed to achieve a complete remission (CR) or partial remission (PR) following standard induction therapy, or has relapsed after any duration of CR or PR i. Must have measurable disease with bone marrow blasts ≥5%at screening 2. Relapsed and/or refractory HR-MDS (High / Very High Risk, as defined by the Revised International Prognostic Scoring System (IPSS-R)) that has failed to achieve a CR or PR, or any hematologic improvement (HI, per IWG 2006 criteria) after standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has relapsed after any duration of CR or PR or HI i. Must have measurable disease with bone marrow blasts \>5% at screening 3. Newly diagnosed, treatment-naïve non-APL AML in participants who, at the time of study entry are unlikely to tolerate standard intensive chemotherapy due to age, performance status, or comorbidities based on at least one of the following criteria: * i. Age ≥ 75 years old * ii. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 3 * iii. Cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤ 50% * iv. Pulmonary disease with diffusing capacity of lung for carbon monoxide ≤ 65% or Forced Expiratory Volume in 1 Second ≤ 65% * v. Creatinine clearance ≥ 30 milliliter (mL)/minute (min) to \< 45 mL/min * vi. Hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 x upper limit of normal (ULN) * vii. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the Sponsor prior to enrollment 4. Transfusion-dependent LR-MDS without the del 5q abnormality, in participants refractory to erythropoietin treatment or unlikely to respond to erythropoietin treatment (EPO \>500). * i. LR-MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R. * ii.Red blood cell (RBC) transfusion-dependent anemia defined as no eight consecutive weeks without RBC transfusions within the 16 weeks prior to study entry, or ≥4 RBC transfusions within the 8 weeks prior to study entry. * iii.Refractory to or ineligible for erythropoiesis-stimulating agents (ESAs) is defined as RBC-Transfusion Dependence despite ESA treatment of ≥40,000 units/week recombinant human erythropoietin for 8 weeks or an equivalent dose of darbepoetin (150 µg/week) or serum EPO level \>500 milliunits (mU)/mL in participants not previously treated with ESAs. 2. Participants must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway associated biomarker at the time of study screening. a. Participants treated with tamibarotene monotherapy and in combination with daratumumab, and R/R AML participants treated with tamibarotene in combination with azacitidine must be positive as defined by a pre-determined cut-off 3. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study. 4. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML participants \< 75 years of age, ECOG 0-3; for ≥ 75 years of age, ECOG 0-2. 5. Adequate organ function as defined by: 1. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), unless suspected to have Gilbert's disease. For newly diagnosed AML participants \< 75 years of age, total bilirubin ≤ 3 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN. 2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia cells 3. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 45 mL/min based on the Cockroft-Gault glomerular filtration rate estimation. For newly diagnosed AML participants \< 75 years of age, creatinine clearance ≥ 30 mL/min; for ≥ 75 years of age, creatinine clearance ≥ 45 mL/min. 6. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea. 7. No investigational agents within 2 weeks prior to first study treatment. 8. No strong inducers of CYP3A4 within 2 weeks prior to first study treatment. 9. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE severity. Key
Exclusion criteria
1. Acute promyelocytic leukemia (APL, M3 subtype of AML) or participants with a t(9:22) cytogenetic translocation. 2. Hyperleukocytosis (leukocytes ≥25 x 109/L) at study entry. The participants may be treated with hydroxyurea according to routine practice, and enroll in the study when the leukocyte count falls below 25 x 109/L. 3. Participants known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a participant who refuses blood product support. 4. Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the treatment of hematologic malignancy. 5. Tamibarotene and daratumumab combination only - Prior or concurrent exposure to daratumumab or other CD38 therapies. 6. Tamibarotene and daratumumab combination only - Participant has either of the following: 1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is \<50% of predicted normal. 2. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study. 7. Participants with active malignancy (not including basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone therapy). Participants with history of other cancers should be free of disease for at least 2 years. 8. Participants with hypertriglyceridemia defined as \>1000 mg/dL (CTCAE Grade 4). 9. Participants with clinically significant cardiac disease including one of the following currently or in the previous 6 months: myocardial infarction, unstable cardiac function due to unstable angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or significant ventricular arrhythmias. 10. Participants with known active uncontrolled central nervous system (CNS) leukemia. 11. Participants taking Vitamin A supplements (\>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Up to 48 months | ORR was defined as: AML: number of participants with complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), partial remission(PR), or morphologic leukemia-free state (MLFS) determined by the investigator per revised International Working Group (IWG) AML criteria. HR-MDS: the number of participants with CR, PR, marrow CR (mCR), or HI determined by the investigator per revised IWG MDS criteria. |
| Transfusion Independence Rate (TIR) for LR-MDS Participants Treated With Tamibarotene Monotherapy | Up to 48 months | TIR was defined as the number of participants who achieved transfusion independence defined as 8 consecutive weeks of red blood cell (RBC) transfusion independence. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treated With Tamibarotene in Combination With Daratumumab | Up to 48 months | A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. A TEAE was any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the study drug. A serious TEAE resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant who received study drug or other important medical events. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR for AML or HR-MDS Participants Treated With Tamibarotene in Combination With Daratumumab | Up to 48 months | ORR was defined as: AML: the number of participants with CR, CRi, CRh, PR, or MLFS as determined by the investigator per the revised IWG AML criteria. HR-MDS: the number of participants with CR, PR, mCR, or HI as determined by the investigator per the revised IWG MDS criteria. |
| Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | Up to 48 months | EFS was defined as time from first treatment until date of documentation of disease relapse following CR, CRi, or death, whichever occurred first. If the participant did not achieve a CR, EFS was defined as the point of progression or death, whichever occurred first. Per prespecified analysis, data were not collected for the Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy arm as there were fewer than 5 participants in the arm. Additionally, per prespecified analysis, data were not collected for this Outcome Measure for the LR-MDS: Tamibarotene Monotherapy arm. Data are presented per specifications in the statistical analysis plan. All-cause mortality is reported in the Reported Adverse Events module. |
| Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine | Up to 48 months | DOR was defined as time from first date of response CR, CRi, CRh, MLFS or PR until the date of relapse. As prespecified, data were not collected for this Outcome Measure for any of the Tamibarotene Monotherapy arms, or R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab arm. Data is presented as specified in the statistical analysis plan. |
| ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | Up to 48 months | ORR was defined as: AML: the number of participants with CR, CRi, CRh, PR, or MLFS as determined by the investigator per the revised IWG AML criteria. Per prespecified analysis, data were not collected for this Outcome Measure for the R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy arm, the Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy arm, and the R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab arm as there were fewer than 5 responders per arm. Data are presented per specifications in the statistical analysis plan. |
| Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | Up to 48 months | HI was defined according to the modified IWG response criteria for MDS as the number of participants with a response (lasting at least 8 weeks) after first treatment, including erythroid response, platelet response, or neutrophil response. Data are presented per specifications in the statistical analysis plan. |
| Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Up to 48 months | A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. A TEAE was any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the study drug. A serious TEAE resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant who received study drug or other important medical events. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
| Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | Up to 48 months | OS was defined as the time from first treatment until death from any cause. Per planned analysis, data were not collected for this Outcome Measure for the Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy arm as there were fewer than 5 participants in the study arm. Additionally, per prespecified analysis, data were not collected for this Outcome Measure for the LR-MDS: Tamibarotene Monotherapy arm. Data is presented as specified in the statistical analysis plan. All-cause mortality is reported in the Reported Adverse Events module. |
| ORR in AML Participants Positive for the Interferon Regulatory Factor 8 (IRF8) Biomarker and Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | Up to 48 months | ORR was defined as: AML: number of participants with CR, CRi, CRh, PR, or MLFS determined by the investigator per the revised IWG AML criteria. Per prespecified analysis, data were collected for this Outcome Measure only for the arm that enrolled the IRF8-positive participants and that included 5 or more responders. Data are presented per specifications in the statistical analysis plan. |
| ORR in AML Participants Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | Up to 48 months | ORR was defined as: AML: the number of participants with CR, CRi, CRh, PR, or MLFS as determined by the investigator per the revised IWG AML criteria. Per prespecified analysis, data were collected for this Outcome Measure only for the arm that enrolled the RARA-negative participants and that included 5 or more responders. Data are presented per specifications in the statistical analysis plan. |
Countries
France, United States
Participant flow
Pre-assignment details
Screening assessments were conducted within 30 days of dosing.
Participants by arm
| Arm | Count |
|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy Participants with R/R non-APL AML or R/R HR-MDS received tamibarotene at 6 mg/m\^2/day in 2 divided doses on Days 1-28 of a 28-day cycle. | 29 |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy Newly diagnosed, treatment-naive participants with non-APL AML who were unlikely to tolerate standard intensive chemotherapy received tamibarotene at 6 mg/m\^2/day in 2 divided doses on Days 1-28 of a 28- day cycle. | 2 |
| LR-MDS: Tamibarotene Monotherapy Participants with transfusion-dependent LR-MDS without the del- 5q abnormality who were refractory to EPO treatment or unlikely to respond to EPO treatment received tamibarotene at 6 mg/m\^2/day in 2 divided doses from Days 1-28 of a 28-day cycle. | 29 |
| Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine Newly diagnosed, treatment-naive participants with non-APL AML who were unlikely to tolerate standard intensive chemotherapy received tamibarotene at 6 mg/m\^2/day in 2 divided doses on Days 8-28 of a 28-day cycle, and azacitidine at 75 mg/m\^2 once daily on Days 1-7 of a 28-day cycle. | 51 |
| R/R Non-APL AML: Tamibarotene and Azacitidine Participants with R/R non-APL AML received tamibarotene at 6 mg/m\^2/day in 2 divided doses on Days 8-28 of a 28-day cycle, and azacitidine at 75 mg/m\^2 once daily on Days 1-7 of a 28-day cycle. | 28 |
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab Participants with R/R non-APL AML or R/R HR-MDS received tamibarotene at 6 mg/m\^2/day in 2 divided doses during a 7-day lead-in and on Days 1-28 of a 28-day cycle. Participants also received daratumumab at 16 mg/kg starting on Cycle 1 Day 1 once weekly for 8 weeks, followed by dosing every 2 weeks for 16 weeks, followed by dosing every 4 weeks. | 16 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 9 | 0 | 0 | 0 |
| Overall Study | Consent withdrawn by participant | 4 | 0 | 4 | 2 | 1 | 0 |
| Overall Study | Death | 23 | 2 | 3 | 43 | 24 | 15 |
| Overall Study | Lack of Efficacy | 0 | 0 | 9 | 0 | 0 | 0 |
| Overall Study | Non-compliance with Study Drug | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Other than specified | 1 | 0 | 2 | 0 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | R/R Non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab | R/R Non-APL AML: Tamibarotene and Azacitidine | Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine | LR-MDS: Tamibarotene Monotherapy | Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy |
|---|---|---|---|---|---|---|---|
| Age, Customized 85 years and over | 13 Participants | 0 Participants | 2 Participants | 5 Participants | 3 Participants | 0 Participants | 3 Participants |
| Age, Customized Adults (18-64 years) | 20 Participants | 5 Participants | 5 Participants | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Age, Customized From 65-84 years | 122 Participants | 11 Participants | 21 Participants | 43 Participants | 24 Participants | 2 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 2 Participants | 3 Participants | 6 Participants | 2 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 13 Participants | 16 Participants | 29 Participants | 25 Participants | 0 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 29 Participants | 1 Participants | 9 Participants | 16 Participants | 2 Participants | 0 Participants | 1 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 | 4 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 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 | 30 Participants | 2 Participants | 9 Participants | 15 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 109 Participants | 14 Participants | 18 Participants | 30 Participants | 22 Participants | 0 Participants | 25 Participants |
| Sex: Female, Male Female | 64 Participants | 8 Participants | 15 Participants | 19 Participants | 10 Participants | 0 Participants | 12 Participants |
| Sex: Female, Male Male | 91 Participants | 8 Participants | 13 Participants | 32 Participants | 19 Participants | 2 Participants | 17 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 | 23 / 29 | 2 / 2 | 3 / 29 | 43 / 51 | 24 / 28 | 15 / 16 |
| other Total, other adverse events | 29 / 29 | 2 / 2 | 29 / 29 | 50 / 51 | 27 / 28 | 15 / 16 |
| serious Total, serious adverse events | 16 / 29 | 2 / 2 | 15 / 29 | 43 / 51 | 20 / 28 | 12 / 16 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treated With Tamibarotene in Combination With Daratumumab
A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. A TEAE was any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the study drug. A serious TEAE resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant who received study drug or other important medical events. 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 48 months
Population: Safety population included all screened participants who received any amount of study drug (tamibarotene or combination treatment).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treated With Tamibarotene in Combination With Daratumumab | TEAE | 16 Participants |
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treated With Tamibarotene in Combination With Daratumumab | Treatment-emergent Serious Adverse Event (SAE) | 12 Participants |
Primary
Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine
ORR was defined as: AML: number of participants with complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), partial remission(PR), or morphologic leukemia-free state (MLFS) determined by the investigator per revised International Working Group (IWG) AML criteria. HR-MDS: the number of participants with CR, PR, marrow CR (mCR), or HI determined by the investigator per revised IWG MDS criteria.
Time frame: Up to 48 months
Population: Response Evaluable Population included participants who completed 1 cycle of study treatment, and had a follow-up assessment of disease status, and did not have any major protocol violations, or withdrew from the study before completion of Cycle 1 because of documented disease progression. Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | 2 Participants |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | 0 Participants |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | 4 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | 12 Participants |
Primary
Transfusion Independence Rate (TIR) for LR-MDS Participants Treated With Tamibarotene Monotherapy
TIR was defined as the number of participants who achieved transfusion independence defined as 8 consecutive weeks of red blood cell (RBC) transfusion independence.
Time frame: Up to 48 months
Population: Population evaluable for TIR, which included all participants who received at least 8 weeks of study treatment.~Here, Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Transfusion Independence Rate (TIR) for LR-MDS Participants Treated With Tamibarotene Monotherapy | 0 Participants |
Secondary
Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine
DOR was defined as time from first date of response CR, CRi, CRh, MLFS or PR until the date of relapse. As prespecified, data were not collected for this Outcome Measure for any of the Tamibarotene Monotherapy arms, or R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab arm. Data is presented as specified in the statistical analysis plan.
Time frame: Up to 48 months
Population: Response evaluable population included participants who completed 1 cycle of study treatment, and had a follow-up assessment of disease status, and did not have any major protocol violations, or withdrew from the study before completion of Cycle 1 because of documented disease progression. Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine | 5.9 months |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine | 10.8 months |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine | 4.7 months |
Secondary
Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab
EFS was defined as time from first treatment until date of documentation of disease relapse following CR, CRi, or death, whichever occurred first. If the participant did not achieve a CR, EFS was defined as the point of progression or death, whichever occurred first. Per prespecified analysis, data were not collected for the Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy arm as there were fewer than 5 participants in the arm. Additionally, per prespecified analysis, data were not collected for this Outcome Measure for the LR-MDS: Tamibarotene Monotherapy arm. Data are presented per specifications in the statistical analysis plan. All-cause mortality is reported in the Reported Adverse Events module.
Time frame: Up to 48 months
Population: Safety population included all screened participants who received any amount of study drug (tamibarotene or combination treatment). Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 2.6 months |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 3.3 months |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 1.2 months |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 8.3 months |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Negative | Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 6.6 months |
Secondary
Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab
HI was defined according to the modified IWG response criteria for MDS as the number of participants with a response (lasting at least 8 weeks) after first treatment, including erythroid response, platelet response, or neutrophil response. Data are presented per specifications in the statistical analysis plan.
Time frame: Up to 48 months
Population: Measured in the population evaluable for HI, which included all participants who received at least 8 weeks of study treatment.~Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 3 Participants |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 0 Participants |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 1 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 1 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Negative | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 0 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 4 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Negative | Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 3 Participants |
Secondary
Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine
A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. A TEAE was any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the study drug. A serious TEAE resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant who received study drug or other important medical events. 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 48 months
Population: Safety population included all screened participants who received any amount of study drug (tamibarotene or combination treatment).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | TEAE | 29 Participants |
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Treatment-emergent SAE | 16 Participants |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | TEAE | 2 Participants |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Treatment-emergent SAE | 2 Participants |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | TEAE | 29 Participants |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Treatment-emergent SAE | 15 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Treatment-emergent SAE | 43 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | TEAE | 51 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Negative | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | TEAE | 27 Participants |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Negative | Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine | Treatment-emergent SAE | 20 Participants |
Secondary
ORR for AML or HR-MDS Participants Treated With Tamibarotene in Combination With Daratumumab
ORR was defined as: AML: the number of participants with CR, CRi, CRh, PR, or MLFS as determined by the investigator per the revised IWG AML criteria. HR-MDS: the number of participants with CR, PR, mCR, or HI as determined by the investigator per the revised IWG MDS criteria.
Time frame: Up to 48 months
Population: Response evaluable population (which included participants who completed 1 cycle of study treatment, and had a follow-up assessment of disease status, and did not have any major protocol violations, or withdrew from the study before completion of Cycle 1 because of documented disease progression) who had evaluable data for the Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | ORR for AML or HR-MDS Participants Treated With Tamibarotene in Combination With Daratumumab | 2 Participants |
Secondary
ORR in AML Participants Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine
ORR was defined as: AML: the number of participants with CR, CRi, CRh, PR, or MLFS as determined by the investigator per the revised IWG AML criteria. Per prespecified analysis, data were collected for this Outcome Measure only for the arm that enrolled the RARA-negative participants and that included 5 or more responders. Data are presented per specifications in the statistical analysis plan.
Time frame: Up to 48 months
Population: Response evaluable population included participants who completed 1 cycle of study treatment, and had a follow-up assessment of disease status, and did not have any major protocol violations, or withdrew from the study before completion of Cycle 1 because of documented disease progression. Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | ORR in AML Participants Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | 12 Participants |
Secondary
ORR in AML Participants Positive for the Interferon Regulatory Factor 8 (IRF8) Biomarker and Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine
ORR was defined as: AML: number of participants with CR, CRi, CRh, PR, or MLFS determined by the investigator per the revised IWG AML criteria. Per prespecified analysis, data were collected for this Outcome Measure only for the arm that enrolled the IRF8-positive participants and that included 5 or more responders. Data are presented per specifications in the statistical analysis plan.
Time frame: Up to 48 months
Population: Response Evaluable Population (which included participants who completed 1 cycle of study treatment, had a follow-up assessment of disease status, did not have any major protocol violations or withdrew from study before completion of Cycle 1 because of documented disease progression) in participants who were positive for the IRF8 biomarker and negative for the RARA superenhancer associated biomarker. Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | ORR in AML Participants Positive for the Interferon Regulatory Factor 8 (IRF8) Biomarker and Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | 2 Participants |
Secondary
ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine
ORR was defined as: AML: the number of participants with CR, CRi, CRh, PR, or MLFS as determined by the investigator per the revised IWG AML criteria. Per prespecified analysis, data were not collected for this Outcome Measure for the R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy arm, the Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy arm, and the R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab arm as there were fewer than 5 responders per arm. Data are presented per specifications in the statistical analysis plan.
Time frame: Up to 48 months
Population: Response evaluable population (which included participants who completed 1 cycle of study treatment, and had a follow-up assessment of disease status, and did not have any major protocol violations, or withdrew from the study before completion of Cycle 1 because of documented disease progression) in participants who were RARA-positive. Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | 4 Participants |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine | 12 Participants |
Secondary
Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab
OS was defined as the time from first treatment until death from any cause. Per planned analysis, data were not collected for this Outcome Measure for the Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy arm as there were fewer than 5 participants in the study arm. Additionally, per prespecified analysis, data were not collected for this Outcome Measure for the LR-MDS: Tamibarotene Monotherapy arm. Data is presented as specified in the statistical analysis plan. All-cause mortality is reported in the Reported Adverse Events module.
Time frame: Up to 48 months
Population: Safety population included all screened participants who received any amount of study drug (tamibarotene or combination treatment).~Overall Number of Participants analyzed (N) = participants evaluable for this Outcome Measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy | Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 5.7 months |
| Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy | Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 5.9 months |
| R/R Non-APL AML: Tamibarotene and Azacitidine | Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 3.6 months |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Positive | Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 8.4 months |
| ND Non-APL AML: Tamibarotene and Azacitidine: RARA-Negative | Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab | 11.7 months |