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Phase III QUAZAR AML-001 trial results

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Dec 18, 2019
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During the Late Breaking Abstracts session held on Tuesday 10th December, 2019, at the 61st  American Society of Hematology (ASH) meeting in Orlando, US, Andrew Wei, The Alfred Hospital, Melbourne, AU, presented results from the phase III QUAZAR AML-001 trial.1

QUAZAR AML-001 (NCT01757535) is a phase III randomized, double-blind, placebo-controlled trial investigating the use of CC-486 as maintenance therapy for patients with acute myeloid leukemia (AML), aged 55 or over, who are in first remission after intensive induction chemotherapy (IC), regardless of whether they received consolidation therapy or not. CC-486 is an oral formulation of azacitidine, a hypomethylating agent (HMA).1 Azacitidine is approved for adult patients with AML, who are not eligible for hematopoietic stem cell transplantation (HSCT).2

Background1

Patients with AML who receive IC can achieve complete remission (CR), however in the majority of cases, patients subsequently relapse. For many patients, subsequent hematopoietic stem cell transplant (HSCT) is not possible due to comorbidities or other high-risk features. Maintenance therapy aims to suppress the growth of remaining leukemic cells and thereby delaying relapse while maintaining adequate patient quality of life (QoL). Therefore, there is a requirement to develop well-tolerated maintenance therapies that increase the long-term chance of disease control and prolong overall survival (OS).

Read more about maintenance therapy options for patients with AML, as summarized by the AML Global Portal, here.

About CC-4861

CC-486 is an orally administered HMA, which has a distinct pharmacodynamic and pharmacokinetic profile compared to injectable azacitidine. The oral administration route allows for prolonged exposure to the drug, extending the therapeutic activity.

Eligibility criteria1

  • Enrolled patients were ≥55 years old, ineligible for transplant and had:
    • De novo or secondary AML
    • Intermediate- or poor-risk cytogenetics
    • Eastern Cooperative Oncology Group (ECOG) performance status £3
    • Achieved CR or CR with incomplete count recovery (CRi) after IC, with or without consolidation chemotherapy
    • Not eligible for HSCT
    • Adequate bone marrow recovery
  • Patients were enrolled at 148 sites in 23 countries

Dosing schedule and randomization1

  • Patients (N= 472) were randomized 1:1 within four months of attaining CR/CRi to either:
    • CC-486 (n= 283): 300mg once daily for 14 days per 28-day cycle
    • Placebo (n= 234): equivalent to CC-486, once daily for 14 days per 28-day cycle
  • Patients were stratified by age (55–64 vs ≥65 years), prior myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML; yes vs no), cytogenetic risk (intermediate vs poor) and consolidation (yes vs no)

Study design1

  • Patients received 300mg of CC-486 or placebo, once daily for 14 days per 28-day cycle, with response assessed every three cycles
  • The results of the assessment determined next treatment:
    • Patients in CR/CRi continued treatment until end of study
    • Patients with 5–15% bone marrow blasts were permitted to receive optional CC-486/placebo in a 21-day dosing schedule until end of study
    • Treatment was stopped when blast level reached >15%, toxicity was unacceptable, or transplant was possible
  • Follow-up: until death, withdrawal of consent, study termination or loss to follow-up
  • Endpoints:
    • Primary: OS
    • Secondary: relapse-free survival (RFS), health-related QoL (HRQoL) and safety and tolerability
    • Exploratory analysis was conducted on measurable residual disease (MRD) status by flow cytometry with a ≥0.1% MRD-positive threshold

Patient characteristics1

  • Median patient age: 68 years (55-86)
  • Most patients had de novo AML (CC-486: 89%, placebo: 92%) , intermediate cytogenetic risk (CC-486: 85%, placebo: 87%)
  • Prior to maintenance treatment, most patients had received consolidation chemotherapy (CC-486: 78%, placebo: 82%)
  • Most patients were in CR following IC (CC-486: 79%, placebo: 84%)
  • Patient characteristics were balanced between study arms

Efficacy1

  • Efficacy results from the QUAZAR study are shown in Table 1 at a median follow-up of 41.2 months
  • Median OS and median RFS was improved in the CC-486 arm compared to placebo
  • Subgroup analysis showed the benefit in OS and RFS was maintained in all groups, irrespective of cytogenetic risk, consolidation cycles received and CR/CRi status
Table 1. Efficacy from QUAZAR AML-001

 

CC-486 (n= 238)

Placebo (n= 234)

HR and p values

Median OS

24.7 months

(95% CI, 18.7–30.5)

14.8 months

(95% CI, 11.7–17.6)

HR= 0.69

p= 0.0009

95% CI, 0.55–0.86

1-year survival rate

73%

(95% CI, 67–78)

56%

(95% CI, 49–62)

-

2-year survival rate

51%

(95% CI, 44–57)

37%

(95% CI, 31–43)

-

Median RFS

10.2 months

(95% CI, 7.9–12.9)

4.8 months

(95% CI, 4.6–6.4)

HR= 0.65

p= 0.0001

95% CI, 0.52–0.81

1-year relapse rate

53%

(95% CI, 46–59)

71%

(95% CI, 65–77)

-

Safety1

  • Serious AEs (CC-486 vs placebo): 34% vs 25%
  • No treatment-related deaths
  • Gastrointestinal events were predominantly during the first two treatment cycles
  • Safety was comparable to the injectable formulation of azacitidine
Table 2. AEs occurring in ≥15% of patients in either arm

 

CC-486 (n= 236)

Placebo (n= 233)

 

All grades

Grades 3–4

All grades

Grades 3–4

Patients with ≥1 AE

98%

72%

97%

63%

Gastrointestinal

Nausea

65%

3%

24%

0.4%

Vomiting

60%

3%

10%

0

Diarrhea

50%

5%

22%

1%

Constipation

39%

1%

24%

0

Hematologic

Neutropenia

45%

41%

26%

24%

Thrombocytopenia

34%

23%

27%

22%

Anemia

20%

14%

18%

13%

Other

Fatigue

30%

3%

19%

1%

Asthenia

19%

1%

6%

0.4%

Pyrexia

15%

2%

19%

0.4%

Cough

12%

0

17%

0

Ongoing treatment and discontinuations1

  • Treatment is ongoing in 45 patients in the CC-486 arm and 26 in the placebo arm
  • Discontinuations (CC-486 vs placebo): 193 vs 208 patients
    • Predominantly due to disease relapse in both arms (CC-486: 60% vs placebo: 77%)
  • Dose modifications due to AEs:
    • Interruptions (CC-486 vs placebo): 43% vs 17%
    • Reductions (CC-486 vs placebo): 16% vs 3%
    • Neutropenia was the main cause in both arms
  • Discontinuation due to AEs was infrequent (CC-486 vs placebo): 13% vs 4%
  • Median exposure to drug (CC-486 vs placebo): 12 cycles (1–80) vs 6 cycles (1–73)

Conclusion1

Currently there are few options for maintenance therapy in AML. The QUAZAR AML-001 trial is the first to demonstrate a clinically significant improvement in OS and RFS in patients with AML in first remission following induction chemotherapy, regardless of the consolidation therapy received, and across subgroups. Health-related QoL was preserved when compared to placebo, and there were no unexpected AEs. CC-486 is proposed as a new therapeutic maintenance standard for patients aged 55 or over with AML in first remission, who are not eligible for HSCT.

Expert Opinion

  1. Wei A. et al., The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission. 61st American Society of Hematology (ASH) Annual Meeting, Orlando, FL, US. 2019 Dec 10. Oral Abstract #LBA-3
  2. European Medicines Agency (EMA). Vidaza. Summary of product characteristics (SmPC). https://www.ema.europa.eu/en/documents/product-information/vidaza-epar-product-information_en.pdf [Accessed 2019 Dec 13]
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