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Astex Pharmaceuticals and Otsuka Announce Results of the Phase 3 ASTRAL-1 Study of Guadecitabine (SGI-110) in Treatment-Naïve AML Patients Ineligible to Receive Intense Induction Chemotherapy

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  • Guadecitabine did not meet the co-primary endpoints of complete
    response (CR) rate or overall survival (OS) in the ASTRAL-1 study
  • Astex continues to focus on completing the phase 3 ASTRAL-2 and
    ASTRAL-3 studies evaluating the efficacy and safety of guadecitabine
    in relapsed and refractory acute myeloid leukemia (R/R AML) and
    relapsed and refractory myelodysplastic syndromes (R/R MDS) and
    chronic myelomonocytic leukemia (CMML)

Astex Pharmaceuticals, a member of the Otsuka group of companies, and
Otsuka Pharmaceutical Co. Ltd., announce top-line results from the
ASTRAL-1 study evaluating the efficacy and safety of guadecitabine
(SGI-110) in adults with previously untreated AML who are not eligible
for intensive induction chemotherapy. The study did not meet its
co-primary endpoints: complete response (CR) rate (p>0.04), and overall
survival (OS) (p>0.01) as per the protocol analysis plan, compared with
the control arm of physician's choice of azacitidine, decitabine, or low
dose cytarabine. Evaluation of the study's secondary endpoints and
safety data is ongoing. The full data will be presented at an upcoming
scientific meeting.

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https://www.businesswire.com/news/home/20180730005782/en/

The company continues to focus on completing the ongoing global phase 3
ASTRAL-2 and ASTRAL-3 studies evaluating guadecitabine in the treatment
of relapsed and refractory AML and relapsed and refractory MDS and CMML.

"We are disappointed in the outcome of the ASTRAL-1 study," said
Mohammad Azab, Astex's president and chief medical officer. "The study
used very strict criteria of ineligibility to receive intensive
chemotherapy based on age (over 75 years) or poor performance status
(ECOG PS of 2 or 3) or comorbidities, which made it a difficult
population to show superior benefit of guadecitabine." Dr. Azab also
added, "ASTRAL-1 is the largest global prospective study ever conducted
in this specific patient population with low intensity therapy, with 815
patients randomized, of whom about 90% were treated with hypomethylating
agents or HMAs (guadecitabine, azacitidine, or decitabine). The large
body of clinical and genetic data will still provide the medical
community with very valuable insights into the role of several
prognostic clinical and genetic markers that may influence outcome with
HMA treatment. We are extremely grateful to all the patients, physicians
and other healthcare professionals, and partner research and
manufacturing organizations who contributed to this global effort. We
are now looking forward to the completion of the ASTRAL-2 and ASTRAL-3
studies currently actively recruiting in two different indications."

About Guadecitabine (formerly SGI-110)

Guadecitabine is a next-generation DNA hypomethylating agent.1,2
Guadecitabine was rationally designed to be resistant to degradation by
cytidine deaminase, prolonging the exposure of tumor cells to the active
metabolite, decitabine, thus ensuring greater uptake of decitabine into
the DNA of rapidly dividing cancer cells.3 Guadecitabine,
through the action of decitabine, inhibits DNA methyl transferase
(DNMT), with the potential to reverse aberrant DNA methylation, an
epigenetic change characteristic of many cancer cells that results in
silencing of critical genes. This action may restore the expression of
silenced tumor suppressor genes and tumor-associated antigens.4
Through this re-expression of silenced genes, guadecitabine may have the
potential to sensitize tumor cells to other anticancer agents,5,6,7
including immunotherapeutics,8 as well as re-sensitizing
cancer cells previously resistant to chemotherapeutics.7

Guadecitabine is currently being studied in two additional phase 3
studies:

  • ASTRAL-2: A randomized, open-label study in leukemia patients with
    relapsed or refractory acute myeloid leukemia (AML) following
    intensive chemotherapy. See www.clinicaltrials.gov
    NCT02920008.
  • ASTRAL-3: A randomized, open-label study in myelodysplastic syndromes
    (MDS) or chronic myelomonocytic leukemia (CMML) after failure of
    treatment with azacitidine, decitabine, or both. See www.clinicaltrials.gov
    NCT02907359.

In addition, guadecitabine is being evaluated in over twenty
investigator and company-sponsored trials in other hematological
malignancies and in solid tumors, both as a single agent, and in
combination with chemotherapy or immunotherapy.

Guadecitabine was designed to be administered subcutaneously as a
low-volume, stable formulation.

About the ASTRAL-1 Study

The ASTRAL-1 study evaluated the efficacy and safety of guadecitabine
(formerly SGI-110) in adults with previously untreated AML who are not
eligible for intensive induction chemotherapy (see www.clinicaltrials.gov
NCT02348489). The study is the largest global prospective study ever
conducted in this specific patient population, with 815 patients
randomized from 163 investigator sites in 24 countries worldwide. The
study compared guadecitabine, delivered subcutaneously (SC) 60mg/m2/day
for 5 days, with physicians' choice of azacitidine IV or SC 75 mg/m2/day
for 7 days, decitabine IV 20 mg/m2/day for 5 days, or low
dose cytarabine SC 20 mg bid for 10 days, all administered in 28-day
cycles. In addition to the co-primary endpoints of OS and CR, the study
evaluated multiple secondary endpoints including progression-free
survival; composite CR or CRc (CR + CRi + CRp); overnight stays in
hospital; red cell / platelet transfusions; QOL (EQ-5D-5L); duration of
response and safety.

About Acute Myeloid Leukemia

AML is the most common form of acute leukemia in adults.9
There were an estimated 21,380 new cases of AML diagnosed in the US in
2017,10 and an estimate of 10,590 patients were projected to
have died from AML in the US in 2017.11 Although 60 to 80
percent of AML patients less than 60 years of age may achieve a complete
response (CR) with standard intensive induction chemotherapy,12
the outlook for patients 60 years of age or more is significantly worse,
with response rates less than 50 percent, cure rates following
transplant remaining at less than 10 percent and a median survival of
less than one year.12,13,14 These figures have not
significantly improved during the last three decades. These patients
have few therapeutic options available.15,16 Effective, less
toxic therapies are needed for the treatment of AML, particularly for
elderly patients where comorbidities and other consequences of aging may
often render them ineligible to receive intensive induction
chemotherapy, thus denying them a potentially curative transplant.14

About Astex Pharmaceuticals and Otsuka Pharmaceutical

Astex is a leader in innovative drug discovery and development,
committed to the fight against cancer and diseases of the central
nervous system. Astex is developing a proprietary pipeline of novel
therapies and has multiple partnered products being developed under
collaborations with leading pharmaceutical companies. In October 2013
Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co.
Ltd., based in Tokyo, Japan.

Otsuka Pharmaceutical is a global healthcare company with the corporate
philosophy: "Otsuka – people creating new products for better health
worldwide." Otsuka researches, develops, manufactures and markets
innovative and original products, with a focus on pharmaceutical
products for the treatment of diseases and nutraceutical products for
the maintenance of everyday health.

For more information about Astex Pharmaceuticals, please visit http://www.astx.com

For more information about Otsuka Pharmaceutical, please visit http://www.otsuka.com/en/

References

  1. Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in
    treatment-naive patients with acute myeloid leukaemia: phase 2 results
    from a multicentre, randomised, phase 1/2 trial. Lancet Oncol
    2017; 18(10): 1317-26.
  2. Roboz GJ, Kantarjian HM, Yee KWL, et al. Dose, schedule, safety, and
    efficacy of guadecitabine in relapsed or refractory acute myeloid
    leukemia. Cancer 2018; 124(2): 325-34.
  3. Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of
    guadecitabine (SGI-110) in patients with myelodysplastic syndrome and
    acute myeloid leukaemia: a multicentre, randomised, dose-escalation
    phase 1 study. Lancet Oncol 2015; 16(9): 1099-110.
  4. Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. SGI-110:
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  5. Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N.
    Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma
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  6. Srivastava P, Paluch BE, Matsuzaki J, et al. Immunomodulatory action
    of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells
    and xenografts. Leuk Res 2014; 38(11): 1332-41.
  7. Fang F, Munck J, Tang J, et al. The novel, small-molecule DNA
    methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin
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    2014; 20(24): 6504-16.
  8. Lindblad KE, Goswami M, Hourigan CS, Oetjen KA. Immunological effects
    of hypomethylating agents. Expert Review of Hematology 2017;
    10(8): 745-52.
  9. De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a
    comprehensive review and 2016 update'. Blood Cancer J. 2016;
    6(7):e441.
  10. Society AC. Key Statistics for Acute Myeloid Leukemia 2018 [Available
    from: https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html.
  11. SEER. Cancer Stat Facts: Leukemia - Acute Myeloid Leukemia (AML) 2018
    [Available from: https://seer.cancer.gov/statfacts/html/amyl.html.
  12. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et
    al. Diagnosis and management of AML in adults: 2017 ELN
    recommendations from an international expert panel. Blood.
    2017; 129(4):424-47.
  13. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute
    myeloid leukemia. J Clin Oncol. 2011; 29(5):487-94.
  14. Dombret H, Gardin C. An update of current treatments for adult acute
    myeloid leukemia. Blood. 2016; 127(1):53-61.
  15. Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big
    data analysis of treatment patterns and outcomes among elderly acute
    myeloid leukemia patients in the United States. Ann Hematol.
    2015; 94(7):1127-38.
  16. Wang R, Zeidan AM, Halene S, Xu X, Davidoff AJ, Huntington SF, et al.
    Health Care Use by Older Adults With Acute Myeloid Leukemia at the End
    of Life. J Clin Oncol. 2017; 35(30):3417-24.

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