A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.
In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).
Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.
Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.
Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.
“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.
“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”
For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.
Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.
Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.
Dosing and AEs
Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).
The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.
Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).
In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.
There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.
Clinical activity
The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).
Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.
Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.
Two of the 7 patients with MF had clinical improvement.
Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.
Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.
“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”
