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)
You are being asked to take part in this study because you have acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and the standard drugs to treat the disease are no longer effective, treatment was not effective for your type of disease, or the standard treatments are not suitable for you. The goal of this clinical research study is to learn if an investigational drug SY-1425 (sometimes known as tamibarotene), when given alone or in combination with azacitidine (Vidaza) or daratumumab (Darzalex), can help to control AML or MDS in patients who have certain biomarkers. Biomarkers are found in the blood/tissue and may be related to your reaction to SY-1425. Researchers want to learn if patients who have the biomarkers being studied will respond to SY-1425 better than patients who do not have them. The safety of this drug will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Tamibarotene
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Syros Pharmaceuticals, Inc.
Primary The primary objectives are: Characterize the clinical activity of SY-1425 by the overall response rate (ORR) in patients in Arms 1, 2A and 2B, and by the transfusion independence rate (TIR) in patients in Arm 3 Characterize the safety and tolerability of the combination of SY-1425 and daratumumab in Arm 4 Secondary The secondary objectives are: Characterize the clinical activity of SY-1425 in patients positive for the RARA super-enhancer associated biomarker by the ORR in Arms 1, 2A, 2B and by TIR in Arm 3 Characterize the clinical activity of SY-1425 in patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker by the ORR in Arms 1, 2A, 2B and by TIR in Arm 3 Characterize the clinical activity of the combination of SY-1425 and daratumumab by overall response rate (ORR) in Arm 4 Characterize the clinical activity by patients in Arms 1, 2A, 2B and 3, based on event-free survival (EFS), relapse-free survival (RFS), duration of response (DOR), overall survival (OS), hematologic improvement (HI) For all patients, evaluate the requirement for supportive measures secondary to cytopenias Characterize the safety and tolerability of SY-1425 as a single agent in Arms 1, 2A and 3, and in combination with azacitidine in Arm 2B Characterize the PK of SY-1425 after single and multiple doses Exploratory The exploratory objectives are: Assess factors associated with the ORR, including but not limited to arm and diagnosis, RARA super-enhancer associated biomarker and/or IRF8 biomarker status, dehydrogenase/reductase (SDR family) member 3 (DHRS3) induction, myeloid differentiation, induction of CD38 expressionand other potential predictors of success including genotype and mutation status Evaluate changes in health related quality of life (HRQOL). Establish pharmacokinetic (PK)/PD relationships based on PD markers in leukemic cells from repeat peripheral blood samples. Characterize the PK of daratumumab in combination with SY-1425. Characterize the relationship between SY-1425 activity and baseline tumor biomarker levels (RARa mRNA or IRF8 mRNA) Characterize expression of myeloid differentiation markers, including CD38, over time Explore the potential role of additional genes alterations (e.g. expression or mutation) in sensitivity and/or resistance to SY-1425 using multiplex platform such as, but not limited to ChIP-seq analysis.
IRB Review and Approval Date: 11/28/2016
Recruitment Status: Open
Projected Accrual: 112
1) Patients must be at least 18 years of age
2) Patients must have:a) 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) Patients must have measurable disease with bone marrow blasts >/=5% at screening. b) Relapsed and/or refractory higher-risk 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) after standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has relapsed after any duration of CR or PR or HI; i) Patients must have measurable disease with bone marrow blasts>/=5% at screening. c) Newly diagnosed, treatment-naïve non-APL AML in patients 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:
3) **continued from above: 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 DLCO </= 65% of FEVI </= 65%; v. Creatinine clearance >/= 30 mL/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) *continued from above: d) Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients refractory to erythropoietin treatment or unlikely to respond to erythropoietin treatment (EPO >500); i. Lower-risk MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R; ii. Red blood cell (RBC) transfusion dependent anemia defined as no 8 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 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 ug/week) or serum EPO level >500 mU/mL in patients not previously treated with ESAs.
5) Patients must be positive for the RARA super-enhancer associated biomarker or IRF8 biomarker as measured by RT-qPCR as defined by a predetermined inclusion criterion cutoff based on centralized testing of peripheral blood at the time of study screening.
6) Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
7) ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 years of age, ECOG 0 to 3; for >/= 75 years of age, ECOG 0 to 2.
8) Adequate organ function as defined by: a) Total bilirubin </= 1.5 x the upper limit of normal (ULN), unless suspected to have Gilbert’s disease. For newly diagnosed AML patients < 75 years of age, total bilirubin </= 3.0 x ULN; for >/= 75 years of age, total bilirubin </= 1.5 x ULN; b) ALT and AST </= 3 x ULN or </= 5 x ULN if documented liver infiltration with leukemia cells; c) Serum creatinine </= 2.0 x ULN or calculated creatinine clearance >/= 45 mL/min based on the Cockroft-Gault GFR estimation. For newly diagnosed AML patients < 75 years of age, creatinine clearance >/= 30 mL/min; for >/= 75 years of age, creatinine clearance >/= 45 mL/min.
9) Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea.
10) No investigational agents within 2 weeks prior to first study treatment.
11) No strong inducers of CYP3A4 within 2 weeks prior to first study treatment.
12) Resolved acute effects of any prior AML/MDS therapy to baseline or </= Grade 1 CTCAE severity.
13) Serum/urine pregnancy test (for females of childbearing potential) that is negative at screening and immediately prior to initiation of treatment (first dose).
14) Willingness and ability to comply with the scheduled study visits, treatment plans, laboratory tests and other procedures.
15) Fully-executed, signed and dated Institutional Review Board (IRB) approved informed consent document.
1) APL (M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation.
2) Hyperleukocytosis (leukocytes >/=25 x 10(9)/L) at study entry. These patients may be treated with hydroxyurea according to routine practice, and enroll in the study when the leukocyte count falls below 25 x 10(9)/L.
3) Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
4) Prior treatment with ATRA or systemic retinoid for the treatment of hematologic malignancy.
5) ARM 4 ONLY: Prior or ocncurrent exposure to daratumumab or other CD38 therapies
6) ARM 4 ONLY: Subject has either of the following: a. 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 subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal. b. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
7) Patients with other active malignancy (not including basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone therapy). Patients with history of other cancers should be free of disease for at least 2 years.
8) Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Version 4.03 Grade 4).
9) Any 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 clinically-significant ventricular arrhythmias.
10) QTc interval >480 msec based on triplicate ECG readings using the Fridericia (QTcF), with the exception of patients with Right Bundle Branch Block (RBBB) or Left Bundle Branch Block (LBBB).
11) Patients with an active, life-threatening or clinically-significant uncontrolled systemic infection.
12) Patients with known active uncontrolled central nervous system (CNS) leukemia.
13) Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness or hepatitis B or hepatitis C infection.
14) Known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).
15) Major surgery within 4 weeks prior to starting study treatment.
16) Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A.
17) Concurrent treatment with any investigational or approved oncology agents (unless specified in the protocol, such as hydroxyurea) or herbal preparations.
18) ARM 4 ONLY: Known allergies, hypersensitivity, or intolerance to mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products.
19) ARM 4 ONLY: Vaccination with live attenuated vaccines within 4 weeks of first study drug administration.
20) Current illicit drug or alcohol abuse.
21) Other severe acute or chronic medical condition such as refractory congestive heart failure, pulmonary disease associated with dyspnea at rest or requiring oxygen therapy, kidney dialysis, liver cirrhosis (Child B or C), or psychiatric condition or laboratory abnormality that may increase the risk to the patient associated with study participation or investigational product administration or which may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
22) Pregnant females; breastfeeding females; and males and females of childbearing potential not willing to use two highly effective methods of birth control, one being barrier method. Intrauterine Devices (IUD) and birth control pills are not barrier methods, but are highly effective especially when combined with a barrier method (e.g. latex condom or a diaphragm or cervical cap) while taking study drug (SY-1425, azacitidine and daratumumab) and continuing contraception use for at least 90 days after the last dose of study drug. Men/women should not donate sperm or ova during this timeframe. Non-childbearing potential is defined as menopausal for at least 2 years or documented oophorectomy.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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