On July 30, 2018 Astex Pharmaceuticals, a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co. Ltd., reported that 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 (Press release, Astex Pharmaceuticals, JUL 30, 2018, View Source [SID1234527955]). 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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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