Phase III study of CC-486 (oral azacitidine) maintenance in newly-diagnosed AML meets primary and key secondary endpoints

Positive results from the phase III QUAZAR AML-001 study (NCT01757535) have been announced.1 The study investigated the efficacy and safety of CC‑486 – a bioavailable oral formulation of azacitidine – as maintenance therapy for patients with newly-diagnosed acute myeloid leukemia (AML) who achieved first complete response (CR) or CR with incomplete blood count recovery (CRi) with induction chemotherapy. In total, 472 patients were enrolled and randomized 1:1 to receive either CC-486 or placebo once daily for 14 days of a 28-day cycle, plus best supportive care until disease relapse.

Top-line results from the study demonstrated that maintenance with CC-486 resulted in significant improvements in overall survival (OS; primary endpoint) and relapse-free survival (RFS; secondary endpoint), compared with placebo. In addition, CC‑486 was reported to be well-tolerated with no unexpected safety events during the study.

According to the press release, the data from this phase III study will be presented at a future meeting and regulatory submissions are anticipated in the first half of 2020.

About CC-486 (azacitidine)

  •  It is a cytidine analogue that is incorporated into newly-synthesized DNA or RNA
  • It acts as a DNA methyltransferase inhibitor thus inducing DNA damage and hypomethylation
  • These effects on the DNA lead to direct cytotoxicity and eventually the death of dividing cancer cells in the bone marrow
  • CC-486 is an investigational drug with no regulatory approval for use

 About the QUAZAR AML-001 study2

  •  Multicenter, randomized, double-blind, placebo-controlled, phase III trial initiated in April 2013 and completed in August 2018
  • Patients aged 55 years with de novo  AML or AML secondary to prior diagnosis of myelodysplastic syndromes or chronic myelomonocytic leukemia
  • Patients were within 90 days of their first CR or CRi following induction therapy ± consolidation chemotherapy
  • Excluded patients:
    • With any evidence of the following abnormal karyotypes or molecular translocations inv(16), t(8;21), t(16;16), t(15;17) or t(9;22)
    • If they had previously received bone marrow or stem cell transplant
    • If they were candidates for allogeneic transplant at screening
    • If they had achieved CR/CRi with prior hypomethylating agents
  • Primary endpoint: OS
  • Secondary endpoints include: RFS, CR/CRi rate, quality of life, safety and tolerability
  • N = 472 patients were randomized 1:1 to either:
    • Oral CC-486 maintenance therapy at 300mg daily for 14 days plus best supportive care (28-day cycles)
    • Placebo maintenance daily for 14 days plus best supportive cate (28-day cycles)
  • Patients evaluated for CR/CRi status at cycle three, those who maintain a CR/Cri continue treatment with disease status assessment at the end of every third cycle
  • Patients who relapsed with >5-15% bone marrow blasts could dose escalate to 300mg of CC-486 or placebo daily for 21 days
  • Patients who relapsed with ³16% bone marrow blasts: discontinued treatment
  • The full study design has been published here2
  1. Celgene. Celgene Announces Phase 3 QUAZAR® AML-001 Study of CC-486 as Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia Met Primary and Key Secondary Endpoints; 12 September 2019; [Accessed 12th Sept 2019]
  2. Roboz, G. J. et al. (2016). Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia. Future Oncology, 12(3), 293–302. DOI:10.2217/fon.15.326

Expert Opinion

"As the PI of QUAZAR-AML, I am tremendously excited about the positive results showing that post-remission maintenance with CC-486 in newly diagnosed patients with acute myeloid leukemia leads to significant improvements in overall and relapse-free survival. Unlike for acute lymphoblastic leukemia, maintenance treatment is not currently considered standard for AML, and I anticipate that the results of this clinical trial will change current clinical practice. I am looking forward to further details and analysis of the trial results." — Gail J. Roboz from Weill Cornell Medical College 

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