| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myeloid Leukemia (AML) |
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| E.1.1.1 | Medical condition in easily understood language |
| Acute Myeloid Leukemia (AML) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to characterize the clinical activity of tamibarotene 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. |
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| E.2.2 | Secondary objectives of the trial |
• 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 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
• Characterize the pharmacokinetics (PK) of SY-1425 after single and multiple doses
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 CR or PR following standard induction therapy, or has relapsed after any duration of CR or PR, or
b. Relapsed and/or refractory higher-risk MDS (High / Very High Risk, as defined by the Revised International Prognostic Scoring System (IPSS-R)) patients that have failed to achieve a CR or PR, or any HI (per IWG 2006 criteria) after standard therapy with hypomethylating agents (eg, azacitidine, decitabine), or have relapsed after any duration of CR or PR or HI, or
c. Newly diagnosed, treatment-naïve non-APL AML in patients ≥ 60 years of age who, at the time of study entry are unlikely to respond to or tolerate standard therapy due to age, performance status, and/or adverse risk factor based on at least one of the following criteria associated with increased 8-week induction mortality (Kantarjian et al, 2006), or
i. Age ≥ 75-years-old
ii. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2
iii. Complex karyotype / Poor risk cytogenetic and molecular abnormalities:
1. Complex (≥ 3 clonal chromosomal abnormalities)
2. Monosomal karyotype (-5, 5q-, -7, 7q-)
3. 11q23 – non t(9,11)
4. Inv (3), t(3;3)
5. t(6;9)
6. Normal cytogenetics: with FLT3-ITD mutation
iv. Antecedent hematologic disorder ≥ 12 months
v. Creatinine > 1.3 mg/dL
d. Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients refractory to erythropoietin treatment or unlikely to respond to EPO 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 g/week) or serum EPO level >500 mU/mL in patients not previously treated with ESAs.
3. 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.
4. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
5. ECOG Performance Status (PS) of 0, 1 or 2.
6. 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
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 ≥ 40 mL/min based on the Cockroft-Gault GFR estimation.
7. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea.
8. No investigational agents within 2 weeks prior to first study treatment.
9. No strong inducers of CYP3A4 (see Appendix 5) within 2 weeks prior to first study treatment.
10. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE severity.
11. Serum/urine pregnancy test (for females of childbearing potential) that is negative at screening and immediately prior to initiation of treatment (first dose).
12. Willingness and ability to comply with the scheduled study visits, treatment plans, laboratory tests and other procedures.
13. Fully-executed, signed and dated Institutional Review Board (IRB) approved informed consent document.
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| E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. APL (M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation.
2. Hyperleukocytosis (leukocytes ≥ 25 x 109/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 109/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. 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.
6. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE v4.03 Grade 4).
7. Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsades de pointes or clinically-significant ventricular arrhythmias.
8. QTc interval >480 msec based on triplicate ECG readings using the Fridericia (QTcF), with the exception of patients with Right Bundle Branch Block or Left Bundle Branch Block.
9. Patients with an active, life-threatening or clinically-significant uncontrolled systemic infection.
10. Patients with known active uncontrolled central nervous system (CNS) leukemia.
11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness or hepatitis B or hepatitis C infection.
12. Known malabsorption syndrome or other condition that may impair absorption of study medication (eg, gastrectomy).
13. Major surgery within 4 weeks prior to starting study treatment.
14. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A.
15. Concurrent treatment with any investigational or approved oncology agents (unless specified in the protocol, such as hydroxyurea) or herbal preparations.
16. Current illicit drug or alcohol abuse.
17. Other severe acute or chronic medical 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 and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
18. 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 and birth control pills are not barrier methods, but are highly effective especially when combined with a barrier method (eg, latex condom or a diaphragm or cervical cap) while taking study drug (SY-1425 and azacitidine) 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.
a. Non-childbearing potential is defined as menopausal for at least 2 years or documented oophorectomy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• ORR for patients with AML or higher-risk MDS (Arms 1, 2A, 2B)
• TIR for patients with lower-risk MDS (Arm 3)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
In AML and higher-risk MDS patients, response will be measured by changes from baseline in peripheral blood counts and bone marrow aspirates. Bone marrow aspirates will be collected to measure response on Day 1 of Cycles 2, 3 (if CR/CRi was not achieved on C2D1), and 4, followed by every third cycle, with additional bone marrow aspirates analyzed as clinically indicated based upon changes in peripheral blood counts, or when it is needed to establish either CR or disease progression.
In lower-risk MDS patients, response will be measured by changes from baseline in transfusion requirements and peripheral blood counts, which will be evaluated at each study visit.
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| E.5.2 | Secondary end point(s) |
• ORR for AML or higher-risk MDS patients positive for the RARA super-enhancer associated biomarker (Arms 1, 2A and 2B)
• TIR for lower-risk MDS patients positive for the RARA super-enhancer associated biomarker (Arm 3)
• Response rate (ORR + TIR) for patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker treated with SY-1425 as a single agent (Arms 1, 2A and 3)
• ORR for AML or higher-risk MDS patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker (Arms 1, 2A and 2B)
• TIR for lower-risk MDS patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker (Arm 3)
• Clinical activity as measured by EFS, RFS, DOR, OS, and HI in Arms 1, 2A, 2B
• Clinical activity as measured by DOR and HI in Arm 3
• Proportion of patients requiring supportive measures secondary to cytopenias, as measured by changes in transfusion rates, incidence and duration of growth factor support and antibiotics use, and number of hospitalizations associated with febrile neutropenia and/or thrombocytopenic bleeding
• Characterize the safety and tolerability of SY-1425 by assessing the type and frequency of AEs and SAEs using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03, as well as changes in clinically significant clinical laboratory values, electrocardiogram (ECG) parameters and vital sign measurements
• PK parameters of SY-1425, as single agent and in combination with azacitidine, after single and multiple doses by performing PK analysis to define time to maximum concentration (tmax), Cmax, minimum plasma concentration (Cmin), AUC, total body clearance (CL/F) and half-life (t1/2), where the data permits
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
In AML and higher-risk MDS patients, response will be measured by changes from baseline in peripheral blood counts and bone marrow aspirates. Bone marrow aspirates will be collected to measure response on Day 1 of Cycles 2, 3 (if CR/CRi was not achieved on C2D1), and 4, followed by every third cycle, with additional bone marrow aspirates analyzed as clinically indicated based upon changes in peripheral blood counts, or when it is needed to establish either CR or disease progression.
In lower-risk MDS patients, response will be measured by changes from baseline in transfusion requirements and peripheral blood counts, which will be evaluated at each study visit.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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