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New data from phase II trial of SY-1425 combined with azacitidine in newly diagnosed, unfit patients with AML

Nov 12, 2019

On the 24 thOctober 2019, the company announced the updated clinical data of a phase II trial NCT02807558evaluating the efficacy of SY-1425 (a first in-class selective retinoic acid receptor alpha (RARα)) combined with azacitidine for the treatment of newly diagnosed, unfit patients with acute myeloid leukemia (AML). 1The data was presented at the 5 thEuropean School of Haematology (ESH) International Conference Acute Myeloid Leukemia, Estoril, PT. 2 

Patient population 1 

  • Patients were enrolled if they were newly diagnosed with AML (excluding promyelocytic leukemia patients) and if they were ineligible for standard intensive chemotherapy
  • Forty newly diagnosed patients with AML were evaluated for safety
  • Thirty-five patients were assessed for efficacy with the following biomarkers:
    • Thirteen were positive for RARα
    • Twenty-two were negative for RARα
    • 4/35 patients were positive for interferon regulatory factor 8 (IRF8)
  • Median age was 76 years

Treatment 1

All patients received intravenous or subcutaneous administration of azacitidine (75 mg/m 2) for seven days, then oral administration of SY-1425 (6 mg/m 2/day), that was divided into two doses for each 28-day cycle.

Results 2

  • Majority of responses were observed in the first assessment. Response assessments were done on Day 1 of Cycle 1, 2, 4, and then every third cycle
  • 82% (9/11) of patients that were RARα-positive demonstrated prolonged transfusion independence 3
  • Duration of response was up to 334 days for RARα-positive patients vs168 days for RARα-negative patients
    • 3/8 patients achieved a lasting response beyond the data cut-off of seven months
  • Patients who were positive for IRF8 and negative for RARα (n= 4) achieved CR/Cri rate of 0%
Table 1.Responses of biomarker stratified patients

CR, complete response; CRc, cytogenetic CR; CRi, CR with incomplete hematologic recovery; CRm, molecular CR (minimal residual disease negative by flow cytometry or molecular techniques); ORR, overall response rate. As defined by revised International Working Group (IWG) criteria

Best IWG Response

RARα/IRF8 Positive n (%)

RARα Positive n (%)

Response Evaluable




9 (53)

8 (62)


8 (47)

8 (62)


7 (41)

7 (54)


3 (18)

3 (23)


3 (18)

3 (23)


1 (6)

1 (8)

Safety 1

  • The SY-1425 and azacitidine combination was well tolerated with no observed incidence of increased toxicities, in comparison to either SY-1425 or azacitidine alone
  • Myelosuppression rates such as neutropenia, were comparable to treatment with azacitidine alone
  • The most common grade 3 or higher adverse events (AEs) were thrombocytopenia (25%), anemia (23%), and febrile neutropenia (23%)
  • Most non-hematologic AEs were low grade with nausea (38%), decreased appetite (38%), constipation (33%), fatigue (33%), and peripheral edema (30%)
  • Myelosuppression rates, such as neutropenia, were equal to that observed in single-agent azacytidine treatment


The authors concluded that in comparison to treatment with SY-1425 or azacitidine alone, combination treatment demonstrated increased efficacy, an acceptable tolerability safety profile with a high CR rate (54%), and prompt onset of action in newly diagnosed, RARα-positive, unfit patients with AML. Response rates in patients that were negative for RARα were comparable to response rates with single-agent azacitidine. This trial shows promising results in RARα-positive patient population and warrants further evaluation.

  1. SYROS. Syros Announces New Data from Phase 2 Trial of SY-1425 in Combination with Azacitidine Demonstrating High Response Rates, Rapid Onset of Action and Favorable Tolerability Profile in RARA-Positive Newly Diagnosed Unfit AML Patients[Accessed November 07 2019]
  2. De Botton S et al. SY-1425, a Potent and Selective RARα Agonist, in Combination with Azacitidine Demonstrates High Response Rates and a Rapid Onset of Clinical Responses
    in RARA-Positive Newly Diagnosed Unfit AML. Abstract 16081. Poster presented at European School of Haematology; October 24-26, 2019; Estoril, PT
  3. Kahl K.L. MJH Life Sciences. SY-1425 Combination Shows Promise in Acute Myeloid Leukemia Subgroup[Accessed November 07 2019]