A Biomarker-Directed Phase 2 Trial of SY-1425 in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to determine the activity of SY-1425 in relapsed/refractory acute myeloid leukemia (AML) patients (SY-1425 administered as a monotherapy or in combination with azacitidine), relapsed/refractory higher-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy or in combination with daratumumab), newly diagnosed treatment naïve AML patients who are unlikely to tolerate standard intensive chemotherapy (SY-1425 administered as a monotherapy or in combination with azacitidine), or lower-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy).

Detailed Description
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This is a phase 2, multi-center, open-label study exploring the activity of SY-1425 in patients with relapsed or refractory non-APL AML, relapsed or refractory higher-risk MDS, newly diagnosed treatment naïve AML, or transfusion dependent, lower-risk MDS. All patients must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway biomarker at the time of the study screening evaluation. Patients will accrue to each of the six arms based on diagnosis, prior treatment, risk group, and investigator choice of treatment (SY-1425 single agent or in combination with azacitidine or daratumumab). SY-1425 will be administered at 6 mg/m2/day orally divided in two doses. SY-1425 will be given on a 28-day treatment cycle and dosing will be continuous. For those newly diagnosed treatment naïve and relapsed refractory AML patients receiving the combination of SY-1425 and azacitidine, azacitidine will be administered at 75 mg/m2/day IV or SC days 1-7, and SY-1425 will be administered at 6 mg/m2/day orally divided in two doses days 8-28 on a 28-day treatment cycle. For those relapsed or refractory non-APL AML and relapsed or refractory higher-risk MDS patients receiving the combination of SY-1425 and daratumumab, SY-1425 daily dosing (dose level described above) will begin with a 7-day lead-in followed by continuous dosing on a 28-day treatment cycle. Daratumumab will be administered at a dose of 16 mg/kg starting on Cycle 1 Day 1 weekly for 8 weeks (8 dose total), followed by dosing every 2 weeks for 16 weeks (8 doses total), followed by dosing every 4 weeks. Dosing will continue unless: the patient experiences unacceptable toxicity, disease progression/relapse, pursues post-remission therapy other than SY-1425 (single agent or in combination with azacitidine or daratumumab), or the Investigator determines it is in the best interest of the patient to discontinue treatment. Newly diagnosed AML patients who achieve a CR/CRi or PR while on SY-1425 single agent treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing at least 4 cycles of SY-1425 single agent treatment, are eligible to receive SY-1425 in combination with azacitidine. Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at least a minor erythroid response. Lower-risk MDS patients who in the opinion of the investigator are receiving clinical benefit, but do not meet the minor erythroid response criteria can remain on study with sponsor approval. Lower-risk MDS patients who continue past week 24 will continue to receive treatment until erythroid relapse, disease progression, or unacceptable toxicity. An end of treatment visit will be conducted for all AML and higher-risk MDS patients within 30 days of the last dose of study drug, but prior to the start of any subsequent therapies to monitor for safety and resolution of adverse events. For lower-risk MDS patients, the end of treatment visit will also be the end of study visit which will be conducted 30 days after the last dose of study drug. All AML and higher-risk MDS patients will be followed every three months for survival for up to 2 years and patients who are withdrawn prior to relapse will also follow-up for event free survival.

Official Title
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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)

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: SY-1425 (tamibarotene)
* Drug: azacitidine
* Drug: Daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be at least 18 years of age. 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, 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. 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 (Ferrara et al, 2013): 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% or 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 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 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 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 mU/mL in patients not previously treated with ESAs. Patients must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway associated biomarker at the time of study screening. a. Patients in arms 1, 2A, 3, and 4 must be positive as defined by a pre-determined cut-off Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 years of age, ECOG 0-3; for ≥ 75 years of age, ECOG 0-2. Adequate organ function as defined by: 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 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN. ALT and AST ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia cells 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. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea. No investigational agents within 2 weeks prior to first study treatment. No strong inducers of CYP3A4 (see Appendix 13.5) within 2 weeks prior to first study treatment. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE severity. Serum/urine pregnancy test (for females of childbearing potential) that is negative at screening and immediately prior to initiation of treatment (first dose). Exclusion Criteria: Acute promyelocytic leukemia (APL, M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation. 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. Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support. Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the treatment of hematologic malignancy. SY-1425 and daratumumab combination only - Prior or concurrent exposure to daratumumab or other CD38 therapies5. SY-1425 and daratumumab combination only - Subject has either of the following: 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. 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. Patients with 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. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4). Patients 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 . Patients with known active uncontrolled central nervous system (CNS) leukemia. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A. 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 investigational product (SY-1425) 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 time frame.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SY-1425 (tamibarotene)<br>Continuous days 1-28 of a 28-day cycle of SY-1425 at 6mg/m2/day orally divided into twice a day dosing. | Drug: SY-1425 (tamibarotene)<br>* Continuous days 1-28 of a 28-day cycle of SY-1425 at 6 mg/m2/day orally divided into twice a day dosing.<br>|
| Experimental: SY-1425 (tamibarotene) in combination with azacitidine<br>SY-1425 days 8-28 of a 28-day cycle at 6mg/m2/day orally divided into twice a day dosing. Azacitidine 75 mg/m2/day IV or SC days 1-7 of a 28-day cycle in combination with SY-1425. | Drug: SY-1425 (tamibarotene)<br>* Continuous days 1-28 of a 28-day cycle of SY-1425 at 6 mg/m2/day orally divided into twice a day dosing.<br>Drug: azacitidine<br>* 75 mg/m2/day IV or SC days 1-7 of a 28 day cycle in combination with SY-1425.<br>* Other names: Vidaza;|
| Experimental: SY-1425 (tamibarotene) in combination with daratumumab<br>SY-1425 during a 7-day lead-in and days 1-28 of a 28 day cycle at 6mg/m2/day orally divided into twice a day dosing. Daratumumab at 16 mg/kg/day IV starting on Cycle 1 Day 1 weekly for 8 weeks, followed by dosing every two weeks for 16 weeks, followed by dosing every 4 weeks in combination with SY-1425. | Drug: SY-1425 (tamibarotene)<br>* Continuous days 1-28 of a 28-day cycle of SY-1425 at 6 mg/m2/day orally divided into twice a day dosing.<br>Drug: Daratumumab<br>* 16 mg/kg/day IV starting on Cycle 1 Day 1 weekly for 8 weeks, followed by dosing every two weeks for 16 weeks, followed by dosing every 4 weeks in combination with SY-1425.<br>* Other names: Darzalax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) in Relapsed/Refractory AML or Higher-Risk MDS patients treated with SY-1425 as a monotherapy. | Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria | Within 20 months | 
| Overall response rate (ORR) in newly diagnosed treatment--naïve AML patients treated with SY-1425 as a monotherapy. | Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria | Within 20 months | 
| Transfusion independence rate for lower-risk MDS patients treated with SY-1425 as a monotherapy. | Proportion of patients who achieve transfusion independence defined as 8 consecutive weeks of RBC transfusion independence. | Within 20 months | 
| Overall response rate (ORR) in newly diagnosed treatment-naïve AML patients or relapsed refractory (biomarker positive) treated with SY-1425 in combination with azacitidine. | Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria. | Within 20 months | 
| Safety and tolerability of SY-1425 in combination with daratumumab | Assessed by investigator reported type and frequency of Adverse Events and Serious Adverse Events | Within 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Time from first treatment until date of documentation of disease relapse following complete response/complete remission, or death, whichever comes first. | Up to 30 months | 
| Relapse-free survival | 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 30 months | 
| Duration of response | Time from first date of response (complete response/complete remission, partial response, or hematologic improvement) until date of relapse. | Up to 20 months | 
| Overall survival | Time from first treatment until death from any cause. | Up to 30 months | 
| Hematologic Improvement | Hematologic response as measured by the site investigators using the modified International Working Group (IWG) response criteria | Within 20 months | 
| Proportion of patients requiring supportive measures | 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 20 months | 
| Number of patients with type, frequency, duration, and relatedness of adverse events. | Includes changes in clinically significant clinical laboratory values, assessments of physical exams, vital signs, and electrocardiograms (ECGs). | Up to 20 months | 
| Time to maximum plasma concentration (Tmax) |  | 4 months | 
| Peak Plasma Concentration (Cmax) |  | 4 months | 
| Trough plasma concentration (Cmin) |  | 4 months | 
| Area under the plasma concentration versus time curve (AUC) |  | 4 months | 
| Total body clearance from plasma (CL/F) |  | 4 months | 
| Terminal elimination half-life (t1/2) |  | 4 months | 
| Response Rate in patients who are positive for the RARA super-enhancer associated biomarker. | Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria to determine overall response rate for AML and higher-risk MDS patients and transfusion-independence rate for lower-risk MDS patients | Within 20 months | 
| Response Rate in patients who are positive for the RARA pathway associated biomarker, and negative for the RARA super-enhancer associated biomarker | Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria to determine overall response rate for AML and higher-risk MDS patients and transfusion-independence rate for lower-risk MDS patients | Within 20 months | 
| Overall Response Rate (ORR) in Relapsed/Refractory AML or Higher-Risk MDS patients treated with SY-1425 in combination with daratumumab | Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria | Within 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, MDS