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

Acute Myeloid Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02807558
• Other study ID #: SY-1425-201
• Secondary ID: 2017-000783-14
• Status: Completed
• Phase: Phase 2
• Start date: September 20, 2016
• Est. completion date: January 25, 2023

Study information

• Verified date: January 2024
• Source: Syros Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: January 25, 2023
• Est. primary completion date: January 25, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 micrometer (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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Tamibarotene
Administered as oral tablets
• Azacitidine
Administered via intravenous (IV) or subcutaneous (SC) infusion
• Daratumumab
Administered via IV infusion

Locations

Country	Name	City	State
France	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	Vandoeuvre les nancy
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Syros Pharmaceuticals

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate (ORR) in AML or HR-MDS participants treated with tamibarotene monotherapy or in combination with azacitidine	Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria	Up to 48 months
Primary	Transfusion independence rate (TIR) for LR-MDS participants treated with tamibarotene monotherapy	Number of participants who achieve transfusion independence defined as 8 consecutive weeks of red blood cell (RBC) transfusion independence	Up to 48 months
Primary	Safety and tolerability in AML and MDS participants treated with tamibarotene in combination with daratumumab: Number of Participants with Adverse Events		Up to 48 months
Secondary	ORR in AML or HR-MDS participants positive for the RARA super-enhancer associated biomarker treated with tamibarotene monotherapy or in combination with azacitidine	Response to treatment assessed by the site investigators using IWG response criteria	Up to 48 months
Secondary	TIR for LR-MDS participants positive for the RARA super-enhancer associated biomarker treated with tamibarotene monotherapy	Number of participants who achieve transfusion independence defined as 8 consecutive weeks of RBC transfusion independence	Up to 48 months
Secondary	Response rate (ORR +TIR) in participants positive for the Interferon Regulatory Factor 8 (IRF8) biomarker and negative for the RARA super-enhancer associated biomarker treated with tamibarotene monotherapy	Response to treatment assessed by the site investigators using IWG response criteria	Up to 48 months
Secondary	ORR in AML or HR-MDS participants positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker treated with tamibarotene monotherapy or in combination with azacitidine	Response to treatment assessed by the site investigators using IWG response criteria	Up to 48 months
Secondary	TIR in LR-MDS participants positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker treated with tamibarotene monotherapy	Number of participants who achieve transfusion independence defined as 8 consecutive weeks of RBC transfusion independence	Up to 48 months
Secondary	ORR in AML participants treated with tamibarotene in combination with azacitidine	Response to treatment assessed by the site investigators using IWG response criteria	Up to 48 months
Secondary	ORR in AML or HR-MDS participants treated with tamibarotene in combination with daratumumab	Response to treatment assessed by the site investigators using IWG response criteria	Up to 48 months
Secondary	Event-free survival in AML and HR-MDS participants treated with tamibarotene monotherapy, or in combination with azacitidine or daratumumab	Time from first treatment until date of documentation of disease relapse following complete response/complete remission, or death, whichever comes first	Up to 48 months
Secondary	Relapse-free survival in AML and HR-MDS participants treated with tamibarotene monotherapy, or in combination with azacitidine or daratumumab	Time from first objective documentation of complete response/complete remission until the date of first objective documentation of disease relapse or death due to any cause, whichever occurs first	Up to 48 months
Secondary	Duration of response in AML, HR-MDS and LR-MDS participants treated with tamibarotene monotherapy, or in combination with azacitidine or daratumumab	Time from first date of response (complete response/complete remission, partial response, or hematologic improvement) until date of relapse	Up to 48 months
Secondary	Overall survival in AML and HR-MDS participants treated with tamibarotene monotherapy, or in combination with azacitidine or daratumumab	Time from first treatment until death from any cause	Up to 48 months
Secondary	Hematologic Improvement in AML, HR-MDS and LR-MDS participants treated with tamibarotene monotherapy, or in combination with azacitidine or daratumumab	Hematologic response as measured by the site investigators using the modified IWG response criteria	Up to 48 months
Secondary	Number of participants requiring supportive measures secondary to cytopenias	Supportive measures secondary to cytopenias as measured by changes in transfusion rates, incidence and duration of use for growth factor support and antibiotics, and number of hospitalizations associated with febrile neutropenia and/or thrombocytopenic bleeding	Up to 48 months
Secondary	Number of Participants with Adverse Events in AML and MDS participants treated with tamibarotene monotherapy or in combination with azacitidine		Up to 48 months