Hedgehog blockade promising in myeloid malignancies

Aug 5 2015

By Shreeya Nanda, Senior medwireNews Reporter

Phase I trial results published in The Lancet Haematology show that the hedgehog signalling pathway antagonist PF-04449913 is tolerable and has activity in patients with haematological cancers.

In a linked commentary, Paolo Ghia (IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy) writes that “[t]hese findings provide the rationale to move beyond the promising results obtained in monotherapy in the phase 1 study by testing [smoothened] inhibition in combination with tyrosine kinase inhibitors or chemotherapeutic drugs to prevent or overcome therapeutic resistance and increase long-term efficacy.”

And indeed PF-04449913 is being tested in phase II trials as monotherapy and in combination with cytotoxic treatments in patients with acute myeloid leukaemia, myelodysplastic syndrome and myelofibrosis, say the study authors.

Aberrant activation of the hedgehog signalling pathway is known to be associated with cancer, they explain, adding that PF-04449913 blocks the activation of smoothened, a key step for the initiation of signalling, and has shown “significant antitumour activity in vivo”.

In this first-in-patient trial, 47 patients with a haematological malignancy refractory, resistant or intolerant to previous therapy were given open-label oral PF-04449913 at doses ranging from 5 mg/day to 600 mg/day for up to 12 cycles of 28 days.

Two participants, one each in the 80 mg and 600 mg group, experienced dose-limiting toxicities. And 25 patients experienced treatment-related adverse events of grade 1 to 3, of which the most common were dysgeusia (28%), reduced appetite (19%) and alopecia (15%). One participant developed grade 4 neutropenia and two had grade 4 thrombocytopenia.

A total of 15 patients died, either during treatment or follow-up, but none of the deaths were attributed to the study drug.

“Some suggestion” of clinical efficacy was observed in 23 of the study participants, note Catriona Jamieson (Moores UC San Diego Cancer Center, La Jolla, California, USA) and study co-authors, which Ghia says is “good news for patients and haematologists”.

Among 28 participants with acute myeloid leukaemia, 16 achieved a response, including one patient with complete remission and four with partial remission, in both cases with incomplete haematological recovery.

Three of six myelodysplastic syndrome patients and the single chronic myelomonocytic leukaemia patient achieved stable disease. And two of seven participants with myelofibrosis demonstrated clinical improvement, defined as at least a 50% reduction in splenomegaly, while one of five patients with chronic myeloid leukaemia attained a blast-phase partial cytogenetic response.

Based on their results, the researchers recommend 200 mg or less per day as the dose for phase II studies.

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