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

On the 24^th October 2019, the company announced the updated clinical data of a phase II trial NCT02807558 evaluating 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).¹ The data was presented at the 5^th European School of Haematology (ESH) International Conference Acute Myeloid Leukemia, Estoril, PT.²  

Patient population¹  

• 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

Treatment¹

All patients received intravenous or subcutaneous administration of azacitidine (75 mg/m²) for seven days, then oral administration of SY-1425 (6 mg/m²/day), that was divided into two doses for each 28-day cycle.

Results²

• 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 independence³
• Duration of response was up to 334 days for RARα-positive patients vs 168 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

17

13

ORR

9 (53)

8 (62)

CR/CRi

8 (47)

8 (62)

CR

7 (41)

7 (54)

CRm

3 (18)

3 (23)

CRc

3 (18)

3 (23)

CRi

1 (6)

1 (8)

Safety¹

• 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

Conclusion

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.