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

NCT02807558 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: SY-1425-2012017-000783-14
• Study Type: interventional
• Target: 155
• Locations: 2 countries
• Sites: 26

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).

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome

Keywords

AML; MDS; non-acute promyelocytic leukemia (non-APL); lower-risk myelodysplastic syndrome (LR-MDS)

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine

  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

  Up to 48 months

• ORR in AML Participants Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine

  Up to 48 months

• ORR for AML or HR-MDS Participants Treated With Tamibarotene in Combination With Daratumumab

  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

  Up to 48 months

Study Arms (6)

R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy

EXPERIMENTAL

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

Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy

EXPERIMENTAL

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

Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine

EXPERIMENTAL

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; Drug: Azacitidine

LR-MDS: Tamibarotene Monotherapy

EXPERIMENTAL

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

R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab

EXPERIMENTAL

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; Drug: Daratumumab

R/R non-APL AML: Tamibarotene and Azacitidine

EXPERIMENTAL

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; Drug: Azacitidine

Interventions

Tamibarotene DRUG

Administered as oral tablets

Also known as: SY-1425

LR-MDS: Tamibarotene Monotherapy; Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy; Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine; R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy; R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab; R/R non-APL AML: Tamibarotene and Azacitidine

Azacitidine DRUG

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

Also known as: Vidaza

Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine; R/R non-APL AML: Tamibarotene and Azacitidine

Daratumumab DRUG

Administered via IV infusion

Also known as: Darzalex

R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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:
• 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.

Sponsors & Collaborators

• Syros Pharmaceuticals: lead

Study Sites (26)

Unknown Facility

Hartford, Connecticut, United States

Location

Unknown Facility

Miami, Florida, United States

Location

Unknown Facility

Iowa City, Iowa, United States

Location

Unknown Facility

Boston, Massachusetts, United States

Location

Unknown Facility

Ann Arbor, Michigan, United States

Location

Unknown Facility

New York, New York, United States

Location

Unknown Facility

Rochester, New York, United States

Location

Unknown Facility

Durham, North Carolina, United States

Location

Unknown Facility

Cleveland, Ohio, United States

Location

Unknown Facility

Portland, Oregon, United States

Location

Unknown Facility

Allentown, Pennsylvania, United States

Location

Unknown Facility

Pittsburgh, Pennsylvania, United States

Location

Unknown Facility

Nashville, Tennessee, United States

Location

Unknown Facility

Houston, Texas, United States

Location

CHU Amiens

Amiens, France

Location

Centre Hospitalier de la Côte basque

Bayonne, France

Location

Centre Hospitalier Universitiaire Hopital Avicenne

Bobigny, France

Location

Hospital Morvan

Brest, France

Location

Centre Hospitalier de Versailles - Hôpital André Mignot

Le Chesnay, France

Location

Centre hospitalier Lyon Sud

Lyon, France

Location

Centre Hospitalier Universitaire Nantes

Nantes, France

Location

Nice Hospital, Archet Hospital 1 Clinical Hematology Service

Nice, France

Location

Hopital Saint Louis

Paris, France

Location

Hôpital Haut Leveque, Centre Francois Magendie

Pessac, France

Location

Centre Hospitalier Universitaire Nancy

Vandœuvre-lès-Nancy, 54511, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Related Publications (1)

• 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.

  PMID: 36477975 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

tamibarotene; Azacitidine; daratumumab

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Tiffany Crowell
• Organization: Syros Pharmaceuticals

tcrowell@syros.com

617-674-9069

Study Officials

• Medical Director

  Syros Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2016
• First Posted: June 21, 2016
• Study Start: September 20, 2016
• Primary Completion: January 25, 2023
• Study Completion: January 25, 2023
• Last Updated: December 13, 2024
• Results First Posted: December 13, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (12); US (14)