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

NCT ID: NCT02807558

Last Updated: 2024-12-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 155 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-20
• Study Completion Date: 2023-01-25

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)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

Administered as oral tablets

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

Administered as oral tablets

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

Administered as oral tablets

Azacitidine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

Administered as oral tablets

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

Administered as oral tablets

Daratumumab

Intervention Type: DRUG

Administered via IV infusion

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

Administered as oral tablets

Azacitidine

Intervention Type: DRUG

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

Interventions

Tamibarotene

Administered as oral tablets

Intervention Type: DRUG

Azacitidine

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

Intervention Type: DRUG

Daratumumab

Administered via IV infusion

Intervention Type: DRUG

Other Intervention Names

SY-1425; Vidaza; Darzalex

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Syros Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Syros Pharmaceuticals

Locations

Hartford, Connecticut, United States

Miami, Florida, United States

Iowa City, Iowa, United States

Boston, Massachusetts, United States

Ann Arbor, Michigan, United States

New York, New York, United States

Rochester, New York, United States

Durham, North Carolina, United States

Cleveland, Ohio, United States

Portland, Oregon, United States

Allentown, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Nashville, Tennessee, United States

Houston, Texas, United States

CHU Amiens

Amiens, , France

Centre Hospitalier de la Côte basque

Bayonne, , France

Centre Hospitalier Universitiaire Hopital Avicenne

Bobigny, , France

Hospital Morvan

Brest, , France

Centre Hospitalier de Versailles - Hôpital André Mignot

Le Chesnay, , France

Centre hospitalier Lyon Sud

Lyon, , France

Centre Hospitalier Universitaire Nantes

Nantes, , France

Nice Hospital, Archet Hospital 1 Clinical Hematology Service

Nice, , France

Hopital Saint Louis

Paris, , France

Hôpital Haut Leveque, Centre Francois Magendie

Pessac, , France

Centre Hospitalier Universitaire Nancy

Vandœuvre-lès-Nancy, , France

Institut Gustave Roussy

Villejuif, , France

Countries

United States; France

References

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.

Reference Type: DERIVED

PMID: 36477975 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-000783-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SY-1425-201

Identifier Type: -

Identifier Source: org_study_id