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AzTrials

Acute Myeloid LeukemiaPhase 2NCT02807558

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

A Phase 2 study testing Tamibarotene, Azacitidine and Daratumumab in people with Acute Myeloid Leukemia and Myelodysplastic Syndrome, run by Syros Pharmaceuticals at 26 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Tamibarotene, Azacitidine and Daratumumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
155 participants
Where
26 sitesin 2 countries
Study dates
20 Sep 2016to 25 Jan 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Must have:
  • 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
  • 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
  • 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
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  • 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
  • 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.
  • Participants must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway associated biomarker at the time of study screening.
  • 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
  • Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
  • 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.
  • Adequate organ function as defined by:
  • 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.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia cells
  • 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.
  • Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea.
  • No investigational agents within 2 weeks prior to first study treatment.
  • No strong inducers of CYP3A4 within 2 weeks prior to first study treatment.
  • Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE severity.

Who cannot join

  • Acute promyelocytic leukemia (APL, M3 subtype of AML) or participants with a t(9:22) cytogenetic translocation.
  • 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.
  • Participants known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a participant who refuses blood product support.
  • Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the treatment of hematologic malignancy.
  • Tamibarotene and daratumumab combination only - Prior or concurrent exposure to daratumumab or other CD38 therapies.
  • Tamibarotene and daratumumab combination only - Participant has either of the following:
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  • 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.
  • 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.
  • 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.
  • Participants with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4).
  • 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.
  • Participants with known active uncontrolled central nervous system (CNS) leukemia.
  • 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.

Trial locations and contacts

26 sites in 2 countries.

26 sites in 2 countries

United States14 sites

  • Study site

    Allentown, Pennsylvania

  • Study site

    Ann Arbor, Michigan

  • Study site

    Boston, Massachusetts

  • Study site

    Cleveland, Ohio

  • Study site

    Durham, North Carolina

  • Study site

    Hartford, Connecticut

  • Study site

    Houston, Texas

  • Study site

    Iowa City, Iowa

  • Study site

    Miami, Florida

  • Study site

    Nashville, Tennessee

  • Study site

    New York, New York

  • Study site

    Pittsburgh, Pennsylvania

  • Study site

    Portland, Oregon

  • Study site

    Rochester, New York

Other trials in United States

France12 sites

  • CHU Amiens

    Amiens

  • Centre Hospitalier de la Côte basque

    Bayonne

  • Centre Hospitalier Universitiaire Hopital Avicenne

    Bobigny

  • Hospital Morvan

    Brest

  • Centre Hospitalier de Versailles - Hôpital André Mignot

    Le Chesnay

  • Centre hospitalier Lyon Sud

    Lyon

  • Centre Hospitalier Universitaire Nantes

    Nantes

  • Nice Hospital, Archet Hospital 1 Clinical Hematology Service

    Nice

  • Hopital Saint Louis

    Paris

  • Hôpital Haut Leveque, Centre Francois Magendie

    Pessac

  • Centre Hospitalier Universitaire Nancy

    Vandœuvre-lès-Nancy, 54511

  • Institut Gustave Roussy

    Villejuif, 94805

Other trials in France

About this study

Official title: 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).

Being tested
Tamibarotene, Azacitidine, Daratumumab
Keywords
AML, MDS, non-acute promyelocytic leukemia (non-APL), lower-risk myelodysplastic syndrome (LR-MDS)
Medical subject headings
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TamibaroteneDrug

    Also called SY-1425

    Administered as oral tablets

  • AzacitidineDrug

    Also called Vidaza

    Administered via intravenous (IV) or subcutaneous (SC) infusion

  • DaratumumabDrug

    Also called Darzalex

    Administered via IV infusion

Study groups in NCT02807558
Study groupRoleWhat they receive
R/R Non-APL AML or R/R HR-MDS: Tamibarotene MonotherapyExperimentalParticipants 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.
Receives: Drug: Tamibarotene
Newly Diagnosed Non-APL AML: Tamibarotene MonotherapyExperimentalNewly 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.
Receives: Drug: Tamibarotene
Newly Diagnosed Non-APL AML: Tamibarotene and AzacitidineExperimentalNewly 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.
Receives: Drug: Tamibarotene; Drug: Azacitidine
LR-MDS: Tamibarotene MonotherapyExperimentalParticipants 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.
Receives: Drug: Tamibarotene
R/R non-APL AML or R/R HR-MDS: Tamibarotene and DaratumumabExperimentalParticipants 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.
Receives: Drug: Tamibarotene; Drug: Daratumumab
R/R non-APL AML: Tamibarotene and AzacitidineExperimentalParticipants 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.
Receives: Drug: Tamibarotene; Drug: Azacitidine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 48 months

  2. 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.

    Measured: Up to 48 months

  3. 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.

    Measured: Up to 48 months

Secondary outcomes (9)

  1. 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.

    Measured: Up to 48 months

  2. 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.

    Measured: Up to 48 months

  3. 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.

    Measured: Up to 48 months

  4. 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.

    Measured: Up to 48 months

  5. 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.

    Measured: Up to 48 months

  6. 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.

    Measured: Up to 48 months

  7. 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.

    Measured: Up to 48 months

  8. 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.

    Measured: Up to 48 months

  9. 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.

    Measured: Up to 48 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jun 2016 (estimated)
  2. Study start20 Sep 2016
  3. Primary completion25 Jan 2023
  4. Study completion25 Jan 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
155 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02807558
Sponsor's protocol ID
SY-1425-201
Other IDs
2017-000783-14, 2017
Status last verified
Nov 2024
First submitted
13 Jun 2016
Last updated
13 Dec 2024
Data monitoring committee
No
FDA-regulated drug
Yes
Individual data sharing
No

Publications

  • de Botton S, Cluzeau T, Vigil C, Cook RJ, Rousselot P, Rizzieri DA, Liesveld JL, Fenaux P, Braun T, Banos A, Jurcic JG, Sekeres MA, Savona MR, Roboz GJ, Bixby D, Madigan K, Volkert A, Stephens K, Kang-Fortner Q, Baker K, Paul S, McKeown M, Carulli J, Eaton M, Hodgson G, Fiore C, Kelly MJ, Roth DA, Stein EM. Targeting RARA overexpression with tamibarotene, a potent and selective RARalpha agonist, is a novel approach in AML. Blood Adv. 2023 May 9;7(9):1858-1870. doi: 10.1182/bloodadvances.2022008806.

    PubMed 36477975

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tamibarotene, Azacitidine and Daratumumab in people with Acute Myeloid Leukemia and Myelodysplastic Syndrome, run by Syros Pharmaceuticals at 26 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 26 sites in United States, France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine (time frame: Up to 48 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02807558, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Dec 2024.

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