A Biomarker-Directed Phase 2 Trial of Tamibarotene (SY-1425) in Participants With Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic Acid Receptor Alpha Agonist, in Adult Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

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).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Tamibarotene; Drug: Azacitidine; Drug: Daratumumab

Detailed Description

This is a phase 2, multi-center, open-label study exploring the activity of SY-1425 in patients with relapsed or refractory non-APL AML, relapsed or refractory higher-risk MDS, newly diagnosed treatment naïve AML, or transfusion dependent, lower-risk MDS. All patients must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway biomarker at the time of the study screening evaluation. Patients will accrue to each of the six arms based on diagnosis, prior treatment, risk group, and investigator choice of treatment (SY-1425 single agent or in combination with azacitidine or daratumumab). SY-1425 will be administered at 6 mg/m2/day orally divided in two doses. SY-1425 will be given on a 28-day treatment cycle and dosing will be continuous. For those newly diagnosed treatment naïve and relapsed refractory AML patients receiving the combination of SY-1425 and azacitidine, azacitidine will be administered at 75 mg/m2/day IV or SC days 1-7, and SY-1425 will be administered at 6 mg/m2/day orally divided in two doses days 8-28 on a 28-day treatment cycle. For those relapsed or refractory non-APL AML and relapsed or refractory higher-risk MDS patients receiving the combination of SY-1425 and daratumumab, SY-1425 daily dosing (dose level described above) will begin with a 7-day lead-in followed by continuous dosing on a 28-day treatment cycle. Daratumumab will be administered at a dose of 16 mg/kg starting on Cycle 1 Day 1 weekly for 8 weeks (8 dose total), followed by dosing every 2 weeks for 16 weeks (8 doses total), followed by dosing every 4 weeks.

Dosing will continue unless: the patient experiences unacceptable toxicity, disease progression/relapse, pursues post-remission therapy other than SY-1425 (single agent or in combination with azacitidine or daratumumab), or the Investigator determines it is in the best interest of the patient to discontinue treatment. Newly diagnosed AML patients who achieve a CR/CRi or PR while on SY-1425 single agent treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing at least 4 cycles of SY-1425 single agent treatment, are eligible to receive SY-1425 in combination with azacitidine.

Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at least a minor erythroid response. Lower-risk MDS patients who in the opinion of the investigator are receiving clinical benefit, but do not meet the minor erythroid response criteria can remain on study with sponsor approval. Lower-risk MDS patients who continue past week 24 will continue to receive treatment until erythroid relapse, disease progression, or unacceptable toxicity.

An end of treatment visit will be conducted for all AML and higher-risk MDS patients within 30 days of the last dose of study drug, but prior to the start of any subsequent therapies to monitor for safety and resolution of adverse events. For lower-risk MDS patients, the end of treatment visit will also be the end of study visit which will be conducted 30 days after the last dose of study drug. All AML and higher-risk MDS patients will be followed every three months for survival for up to 2 years and patients who are withdrawn prior to relapse will also follow-up for event free survival.

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • CHU Amiens
  • Bayonne, France
    • Centre Hospitalier de la Cote Basque
  • Bobigny, France
    • Centre Hospitalier Universitiaire Hopital Avicenne
  • Brest, France
    • Hospital Morvan
  • Le Chesnay, France
    • Centre Hospitalier de Versailles - Hopital Andre Mignot
  • Lyon, France
    • Centre Hospitalier Lyon Sud
  • Nantes, France
    • Centre Hospitalier Universitaire Nantes
  • Nice, France
    • Nice Hospital, Archet Hospital 1 Clinical Hematology Service
  • Paris, France
    • Hopital Saint Louis
  • Pessac, France
    • Hôpital Haut Leveque, Centre Francois Magendie
  • Vandoeuvre les nancy, France, 54511
    • Centre Hospitalier universitaire Nancy
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• United States
  • Connecticut
    • Hartford, Connecticut, United States
  • Florida
    • Miami, Florida, United States
  • Iowa
    • Iowa City, Iowa, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Ann Arbor, Michigan, United States
  • New York
    • New York, New York, United States
    • Rochester, New York, United States
  • North Carolina
    • Durham, North Carolina, United States
  • Ohio
    • Cleveland, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Allentown, Pennsylvania, United States
    • Pittsburgh, Pennsylvania, United States
  • Tennessee
    • Nashville, Tennessee, United States
  • Texas
    • Houston, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy; Participants with R/R non-APL AML or R/R HR-MDS will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 1-28 of a 28-day cycle.	Drug: Tamibarotene; Administered as oral tablets; Other Names: SY-1425
Experimental: Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy; Newly diagnosed, treatment-naive participants with non-APL AML who were unlikely to tolerate standard intensive chemotherapy will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 1-28 of a 28-day cycle.	Drug: Tamibarotene; Administered as oral tablets; Other Names: SY-1425
Experimental: Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine; Newly diagnosed, treatment-naive participants with non-APL AML who are unlikely to tolerate standard intensive chemotherapy will receive 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.	Drug: Tamibarotene; Administered as oral tablets; Other Names: SY-1425; Drug: Azacitidine; Administered via intravenous (IV) or subcutaneous (SC) infusion; Other Names: Vidaza
Experimental: LR-MDS: Tamibarotene Monotherapy; Participants with transfusion-dependent LR-MDS without the del 5q abnormality who are refractory to erythropoietin (EPO) treatment or unlikely to respond to EPO treatment will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 1-28 of a 28-day cycle.	Drug: Tamibarotene; Administered as oral tablets; Other Names: SY-1425
Experimental: 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 will receive 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 will also receive 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.	Drug: Tamibarotene; Administered as oral tablets; Other Names: SY-1425; Drug: Daratumumab; Administered via IV infusion; Other Names: Darzalex
Experimental: R/R non-APL AML: Tamibarotene and Azacitidine; Participants with R/R non-APL AML will receive 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.	Drug: Tamibarotene; Administered as oral tablets; Other Names: SY-1425; Drug: Azacitidine; Administered via intravenous (IV) or subcutaneous (SC) infusion; Other Names: Vidaza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months
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.	Up to 48 months

Other Outcome Measures

Outcome Measure	Time Frame
Changes in total scores of patient reported health related quality of life.	Within 20 months

Collaborators and Investigators

• Sponsor: Syros Pharmaceuticals
• Investigators: Study Director: Medical Director, Syros Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2016
• Primary Completion (Actual): January 25, 2023
• Study Completion (Actual): January 25, 2023

Study Registration Dates

• First Submitted: June 13, 2016
• First Submitted That Met QC Criteria: June 16, 2016
• First Posted (Estimated): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): December 13, 2024
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: AML; MDS; non-acute promyelocytic leukemia (non-APL); lower-risk myelodysplastic syndrome (LR-MDS)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Azacitidine; Daratumumab
• Other Study ID Numbers: SY-1425-201; 2017-000783-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes