Astex, Genentech to Study Guadecitabine Plus Atezolizumab Treatment for AML

Genentech and Astex Pharmaceuticals will collaborate in a clinical trial of a combination hypomethylating and immune checkpoint blockade therapy for patients with acute myeloid leukemia (AML), the companies have announced.

The initial phase Ib trial will assess safety, tolerability, and preliminary efficacy data of different dosing levels of Astex’s subcutaneously administered, small molecule DNA hypomethylating agent guadecitabine (SGI-110) and Genentech’s atezolizumab (MPDL3280A), an investigational monoclonal antibody that targets programmed death ligand 1 (PD-L1), facilitating T-cell attacks on tumor cells.

“The collaboration will test the hypothesis that upfront ‘priming’ of patients’ immune systems with guadecitabine, an epigenetic investigational drug, may result in enhanced responses to immunotherapy,” Astex announced in a press release. “The hypothesis is based on the observation that guadecitabine demethylates and induces re-expression of tumor-associated antigens, as well as inducing or upregulating the expression of immune checkpoints such as programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) and 2 (PD-L2), rendering the tumor more immunogenic, and more susceptible to treatment with a checkpoint inhibitor antibody such as atezolizumab.”

The trial is anticipated to begin in the second half of 2016, and will enroll an estimated 40 patients, said Astex spokesman Martin Buckland. The study is expected to last 2.5 years, he said.

“The idea of combining epigenetic therapies such as guadecitabine with immune checkpoint inhibitors such as atezolizumab, has the potential to open up new therapeutic options with enhanced outcomes for patients with a range of cancer types,” commented Astex President and Chief Medical Officer Mohammad Azab in the company’s press release.

Phase I clinical trial results for subcutaneous guadecitabine monotherapy (60 mg/m² daily for 5 consecutive days) administered to 93 patients with myelodysplastic syndrome (MDS) or AML were reported in September 2015, in The Lancet Oncology. At that dose, guadecitabine was “well tolerated” and “clinically and biologically active” among both treatment-naïve patients and those with relapsed/refractory MDS or AML.