Clinical trial NCT02807558: A Biomarker-Directed Phase 2 Trial of Tamibarotene (SY-1425) in Participants With Acute Myeloid Leukemia or Myelodysplastic Syndrome
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndrome
Keywords: AML
MDS
non-acute promyelocytic leukemia (non-APL)
lower-risk myelodysplastic syndrome (LR-MDS)
Lead sponsor: Syros Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-06-21
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine
timeFrame: Up to 48 months
measure: Transfusion Independence Rate (TIR) for LR-MDS Participants Treated With Tamibarotene Monotherapy
timeFrame: Up to 48 months
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treated With Tamibarotene in Combination With Daratumumab
timeFrame: Up to 48 months
Secondary outcomes:
measure: ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine
timeFrame: Up to 48 months
measure: 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
timeFrame: Up to 48 months
measure: ORR in AML Participants Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine
timeFrame: Up to 48 months
measure: ORR for AML or HR-MDS Participants Treated With Tamibarotene in Combination With Daratumumab
timeFrame: Up to 48 months
measure: Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab
timeFrame: Up to 48 months
measure: Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine
timeFrame: Up to 48 months
measure: Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab
timeFrame: Up to 48 months
measure: Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab
timeFrame: Up to 48 months
measure: Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine
timeFrame: Up to 48 months
Other outcomes:
Locations:
city: Hartford
country: United States
state: Connecticut
city: Miami
country: United States
state: Florida
city: Iowa City
country: United States
state: Iowa
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Durham
country: United States
state: North Carolina
city: Cleveland
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Allentown
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Nashville
country: United States
state: Tennessee
city: Houston
country: United States
state: Texas
city: Amiens
country: France
facility: CHU Amiens
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte basque
city: Bobigny
country: France
facility: Centre Hospitalier Universitiaire Hopital Avicenne
city: Brest
country: France
facility: Hospital Morvan
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles - Hôpital André Mignot
city: Lyon
country: France
facility: Centre hospitalier Lyon Sud
city: Nantes
country: France
facility: Centre Hospitalier Universitaire Nantes
city: Nice
country: France
facility: Nice Hospital, Archet Hospital 1 Clinical Hematology Service
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac
country: France
facility: Hôpital Haut Leveque, Centre Francois Magendie
city: Vandoeuvre les nancy
country: France
facility: Centre Hospitalier Universitaire Nancy
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Syros Pharmaceuticals
name: Medical Director
role: STUDY_DIRECTOR
References: