Astex Pharmaceuticals has entered into a clinical collaboration with Genentech. The collaboration will evaluate the potential for combining Astex’s next generation hypomethylating agent, guadecitabine (SGI-110), with Genentech’s investigational anti-PD-L1 monoclonal antibody, atezolizumab, in the treatment of acute myeloid leukemia (AML). An initial Phase 1b study will investigate the safety and pharmacology of the combination.
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. 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 (Maio et al, Clin. Cancer Research, 2015; 21:4040-47).
Guadecitabine has been evaluated in multiple Phase 1 and Phase 2 trials to investigate its potential in the treatment of a range of cancers. Astex has recently completed a large (over 400 patients) randomized Phase 1/2 study in patients with myelodysplastic syndromes (MDS) or AML. The trial included a Phase I dose escalation stage (93 patients) and a randomized Phase 2 stage (308 patients) that investigated four different patient populations: treatment naïve and relapsed/refractory AML and MDS. The trial demonstrated that guadecitabine was clinically active and well tolerated in all four patient groups. The results from the Phase 1 portion of the trial were recently published in Lancet Oncology (http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2900038-8/abstract). Additional information about the study can be found online at http://clinicaltrials.gov/ct2/show/NCT01261312.
Guadecitabine is now being evaluated in the ASTRAL-1 trial, a large, global, randomized 800-patient study in treatment naïve AML patients who are unfit to receive, or unsuitable for, intensive induction chemotherapy. The trial compares guadecitabine with physician’s choice of low-dose cytarabine, decitabine or azacitidine. Additional information about the study can be found online at: https://www.clinicaltrials.gov/ct2/show/NCT02348489.
Mohammad Azab, Astex’s President and Chief Medical Officer said: “We are delighted that Genentech has chosen to partner with Astex on this exciting study. 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. Astex is committed to exploring the broad potential of guadecitabine as a “backbone” therapy for use in immunotherapy combinations.