Epigenetic Modifying Therapies Explored in Advanced Solid Tumours, AML, MDS

The safety and tolerability of the epigenetic drugs RRx-001 and guadecitabine is investigated in solid tumours and acute myeloid leukaemia or myelodysplastic syndrome, respectively

  • Date: 24 Aug 2015
  • Author: Shreeya Nanda, Senior medwireNews Reporter
  • Topic: Drug Development

medwireNews: Two phase I trials published in The Lancet Oncology suggest that the epigenetic modifying agents RRx-001 and guadecitabine are well tolerated in patients with advanced solid tumours and those with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), respectively.

Researcher Tony Reid, from the University of California and San Diego in La Jolla, USA, and co-authors recruited 25 patients with advanced, malignant solid tumours who were free of residual side effects of prior treatments into a phase I trial of RRx-001, a drug belonging to the dinitroazetidine class of compounds.

By binding to haemoglobin and inducing tumour hypoxia that leads to the generation of reactive oxygen and nitrogen species, RRx-001 can “epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation”, they explain.

In this dose-escalation study, six patients received open-label intravenous RRx-001 at the starting dose of 10 mg/m2, and between three and six patients received the drug at doses ranging from 16.7 mg/m2 to 83.0 mg/m2, respectively, either as a once or twice-weekly regimen for at least 4 weeks.

One patient each in the 33 mg/m2 and 55 mg/m2 groups experienced a grade 3 adverse event – infusion-site pain and anxiety, respectively – but generally the drug was well tolerated, say Tony Reid et al. The majority of treatment-related adverse events were grade 1 or 2; injection-site pain, observed in 84% of participants, was the most common of these, followed by arm swelling or oedema (32%) and vein hardening (28%).

No dose-limiting adverse events were observed in the study cohort, the team reports.

Among 21 evaluable patients, a partial response was achieved by one patient at 8 weeks while 14 had stable disease and six progressed.

Four RRx-001–treated patients were rechallenged with a previously effective therapy they had become refractory to (FOLFIRI in three and gemcitabine in one patient). All patients responded to the rechallenge – thus RRx-001 was able to resensitise drug-resistant tumours to established chemotherapeutical agents, say the researchers.

They conclude that such resensitisation “could alter the therapeutic landscape in favour of reuse and reintroduction of multiple different lines of formerly effective treatments”.

In a second phase I trial published in the journal, a team led by Jean-Pierre Issa, from Temple University in Philadelphia, Pennsylvania, USA, investigated the second-generation hypomethylating agent guadecitabine in relapsed, refractory or unresponsive patients with AML or MDS.

A total of 54 AML and 12 MDS patients were randomly assigned to receive open-label subcutaneous guadecitabine either once a day for 5 consecutive days or once a week for 3 weeks, at doses ranging from 3 mg/m2 to 90 mg/m2 in the daily cohort and up to 125 mg/m2 in the weekly cohort. A further nine AML and three MDS patients were given the study drug at 125 mg/m2 daily for 5 days. And an additional 11 patients with AML and four with MDS were enrolled to evaluate a twice-weekly schedule after a protocol modification.

During a median follow-up of 27 months, the most frequent treatment-related adverse events of grade 3 or above were thrombocytopenia (14%), anaemia (11%), neutropenia (10%) and leukopenia (8%). And serious adverse events related to the study drug occurred in 9% of the total study cohort of 93 participants.

In patients with MDS, dose-limiting toxicities were observed in the 125 mg/m2 daily for 5 days group, while AML patients did not display any dose-limiting adverse events.

Six of 74 patients with AML and six of 19 with MDS had a clinical response to treatment, with a correlation between response and level of demethylation, as assessed by the long interspersed nuclear element assay. “[R]esponding patients have better DNA demethylation than non-responders”, note Jean-Pierre Issa and colleagues.

Both drugs are being evaluated further in phase II trials at a recommended dose of 16.7 mg/m2 for RRx-001, and 60 mg/m2 once a day for 5 days for guadecitabine.

References

Reid T, Oronsky B, Scicinski J, et al. Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study. Lancet Oncol; Advance online publication 18 August 2015: DOI: dx.doi.org/10.1016/S1470-2045(15)00089-3

Issa J-PJ, 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; Advance online publication 18 August 2015. DOI: dx.doi.org/10.1016/S1470-2045(15)00038-8

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