Clinical Pipeline

Phase 1Phase 2Phase 3

Guadecitabine (SGI-110)

DNMT inhibitor (Hematological Malignancies and Solid Tumors)

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Ownership: Astex

Mechanism of Action: DNA methyltransferase (DNMT) inhibition

Indications: Relapsed/Refractory Acute Myeloid Leukemia (AML), Relapsed/Refractory Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukaemia (CMML)

How this therapy can help

Guadecitabine was rationally designed to be resistant to degradation by cytidine deaminase and prolong the exposure of tumor cells to the active metabolite, decitabine, ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.

As a next-generation DNA hypomethylating agent, guadecitabine inhibits DNMT to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells, restoring the expression of silenced tumor suppressor genes and tumor-associated antigens. Guadecitabine-mediated inhibition of DNA methylation upregulates tumor-associated antigens and may sensitize tumor cells to other anticancer agents, including immunotherapeutics, as well as resensitize resistant cancer cells to chemotherapeutics.

Clinical studies

Astex is conducting the ASTRAL-2 and ASTRAL-3 Global Phase 3 clinical studies with guadecitabine.

ASTRAL-2 (Relapsed/Refractory AML):  404-patient multicenter, randomized, open-label study of Acute Myeloid Leukemia (AML) patients who failed or relapsed following prior intensive chemotherapy.

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HiDAC- high-dose cytarabine; MEC – mitoxantrone, etoposide, cytarabine; FLAG±Ida – fludarabine, cytarabine, G-CSF, ± idarubicin; LDAC – low-dose cytarabine; DAC – decitabine; AZA – azacitidine; BSC – best supportive care

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ASTRAL-3 (Relapsed/Refractory MDS or CMML): 408-patient multicenter, randomized, open-label study in Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) after failure of prior azacitidine, decitabine, or both.

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LDAC – low-dose cytarabine; IC (7+3) – intensive chemotherapy (cytarabine/anthracycline); BSC – best supportive care

For more information on clinical studies and status visit: www.clinicaltrials.gov or email: ASTRAL-2@astx.com or ASTRAL-3@astx.com.

Previous clinical studies

The ASTRAL-2 and ASTRAL-3 clinical studies are based on data from a completed 400-patient Phase 1/2 study of guadecitabine in patients with AML or MDS (www.clinicaltrials.gov).

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Astex has also completed the ASTRAL-1 Phase 3 clinical study:

ASTRAL-1 (Treatment Naïve AML):  800-patient multicenter, randomized, open-label study of SGI-110 versus treatment choice (TC) in adults with previously untreated Acute Myeloid Leukemia (AML) who are not considered candidates for intensive remission induction chemotherapy.

The results from this study were presented at the Annual Meeting of the European Hematology Association in June 2019.

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LDAC – low-dose cytarabine; DAC – decitabine; AZA – azacitidine

Other active clinical programs

Astex also has an active program evaluating the combination of guadecitabine with checkpoint inhibitors in the treatment of both hematological malignancies and solid tumors, and as a single agent and in combination with chemotherapy for the treatment of solid tumors. Astex has also completed studies investigating combination with carboplatin in the treatment of platinum-resistant ovarian cancer and in hepatocellular (liver) cancer following failure of Nexavar® (sorafenib).

View all clinical trials with guadecitabine

View Presentations and Publications

Exploring the mechanism of action: Guadecitabine