Novel TKI Leads to Responses in Heavily Pretreated Patients with Chronic Myeloid Leukemia
Atlanta, GA—A novel, third-generation, oral tyrosine kinase inhibitor (TKI), PF-114 mesylate, has antileukemic activity in heavily pretreated patients with chronic myeloid leukemia (CML), including those with T315I mutation, said Jorge E. Cortes, MD, Deputy Chair, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at ASH 2017.
In an ongoing, phase 1, dose-escalation clinical trial of patients with CML, 50% of whom had received ≥3 previous TKIs, major cytogenetic responses were achieved in 40% of patients with chronic-phase (CP) CML. Based on these results, a phase 2, multicenter, international study is planned for 2018, said Dr Cortes.
PF-114 mesylate is an ATP competitive inhibitor of BCR-ABL kinases, including the gatekeeper mutation T315I. It is designed to avoid interaction with off-target kinases, such as VEGF receptor-2 and BRAF, which could potentially lead to life-threatening toxicities.
“That leads to a kinase inhibition profile that is much more selective…and very few are inhibited at potent concentrations, suggesting the possibility of a better toxicity profile,” Dr Cortes told attendees.
Preclinical work supported the phase 1 clinical trial of PF-114 mesylate in patients with CP or accelerated-phase (AP) Philadelphia chromosome–positive CML who are resistant to ≥1 second-generation TKIs, intolerant to treatment with TKIs, or have T315I mutation in the BCR-ABL gene. The trial was a 3+3 design of dose escalation until the maximum tolerated dose, followed by expanded cohorts planned for doses below the maximum tolerated dose.
At data cut-off, 24 patients with a median time of 11.4 years since CML diagnosis had been enrolled. Of these patients, 21 had CP-CML, 2 had AP-CML, and 1 had blast-phase CML. Eleven patients had T315I mutation, 13 patients had received ≥3 previous TKIs, and 16 patients had no cytogenetic response at the time of enrollment.
To date, 5 cohorts have been fully enrolled, at oral doses of 50 mg, 100 mg, 200 mg, 400 mg, and 500 mg once daily. A sixth cohort of 600 mg daily has started enrollment. Intra-patient dose escalation is permitted, allowing patients to move to the next dose level. The doses most thoroughly explored have been 200 mg and 400 mg, with a median number of cycles of 9 and 5, respectively. The maximum tolerated dose has not yet been reached.
In a preliminary analysis for efficacy (maximum 9 cycles of therapy), major cytogenetic responses have been achieved in 4 patients, all with CP-CML and T315I mutation. Four patients in chronic phase, 1 in accelerated phase, and 1 in blast phase have had hematologic responses. Hematologic toxicity was modest.
“There have been only 5 patients in total that have had at least 1 hematologic toxicity, and this represents 1 patient in the blast phase that had anemia and thrombocytopenia, and 4 patients with chronic-phase CML; all of them had a history of cytopenias grades 1 to 4, and all of them had received at least 2 prior TKIs,” said Dr Cortes.
The most common nonhematologic adverse event has been skin toxicity, mostly dry skin and psoriasiform skin lesions. Overall, 13 patients had grade 2, and 4 had grade 3 skin toxicity, 1 of which was a dose-limiting toxicity.