Phase 1 Dose-Escalation Study of PF-04449913, An Oral Hedgehog (Hh) Inhibitor, in Patients with Select Hematologic Malignancies

Hh signaling is activated in a variety of human cancers and is required for maintenance of leukemic stem cell (LSC) populations in several hematologic malignancies. PF-04449913 selectively inhibits Hh signaling by binding Smoothened, a membrane protein that regulates the Hh pathway. PF-04449913 significantly reduced LSC burden following xenotransplantation of patient-derived CD34+ imatinib-resistant chronic myeloid leukemia (CML) cells in preclinical models.

This first-in-patient Phase 1a dose-escalation study is assessing first-cycle dose-limiting toxicities (DLTs) and the recommended Phase 2 dose (RP2D) of PF-04449913 in patients with select hematologic malignancies (primary endpoint). Secondary endpoints include safety, pharmacokinetics (PK), pharmacodynamics, and preliminary signs of efficacy as defined by disease-specific guidelines. Patients had refractory, resistant, or intolerant select hematologic malignancies and could be previously untreated but not candidates for standard therapies: CML including T315I mutations (any phase), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelofibrosis (MF), or chronic myelomonocytic leukemia (CMML). Cohorts of ≥3 patients received PF-04449913 alone, administered continuously in 28-day cycles, starting at a dose of 5 mg orally once daily.

Thirty-two patients have been enrolled at doses up to 270 mg: 18 males/14 females; AML, 18; MF, 6; CML, 5; MDS, 3; with a median age of 68.5 (35–79) years. ECOG PS was 0/1/2: n=11/16/5. Treatment duration ranged from 1 to 387 days (AML: 1–266; CML: 1–281; MDS: 2–335; MF: 44–387 days). One patient discontinued the study due to a treatment-related adverse event (AE) after 137 days of therapy at the 10 mg dose level (grade [G] 3 hemorrhagic gastritis in the setting of chronic proton pump inhibitor administration prior to and during the study). One AML patient evolved from CMML on 80 mg had a DLT comprising G3 hypoxia and G3 pleural effusion. The majority of AEs were of G1/2 severity; the most frequent treatment-related AEs included dysguesia (16%), alopecia (6%), arthralgia (6%), decreased appetite (6%), nausea (6%), and vomiting (6%). Preliminary indications of efficacy were observed across all hematologic diseases studied. One patient with AML (evolved from CMML and with a concurrent diagnosis of systemic mastocytosis) achieved a complete remission with incomplete blood count recovery; bone marrow blast count decreased from 92% to 1%. Five AML patients had a ≥50% reduction in bone marrow blast counts (20% to 10%, 70% to 20%, 44% to 8%, 14% to 7%, 40% to 10%). One patient with low-risk MDS, currently remaining on study after 335 days, achieved significant reduction in spleen size and a hematologic improvement in platelets (from 98.5 to 369 ×10⁹/L) and neutrophils (ANC from 410 to 5490), and is no longer granulocyte colony-stimulating factor (G-CSF) dependent. Five patients with MF attained stable disease; an additional MF patient, currently remaining on study after 385 days, achieved clinical improvement with a >50% reduction in extramedullary disease (spleen size decreased from 10 cm to 3.5 cm sustained over 8 weeks). One patient with T3151 lymphoid blast crisis CML on study for 115 days achieved a major cytogenetic response with loss of their T3151 mutation. PF-04449913 PK data (5–180 mg) indicated a dose-proportional profile, with a median time to maximum concentration (T_max) of 1–2 hours, a mean half-life ranging from 17 to 35 hours, and a large volume of distribution (mean range 250–480 L). Following daily dosing, steady state was achieved by Day 8 and the median accumulation ratio ranged from 1.3 to 2.9.

PF-04449913 was safe and well tolerated, with early signs of efficacy observed in all hematologic diseases studied. Several patients with aggressive malignancies remained on trial for prolonged durations with improved quality of life; some exhibited cellular differentiation as determined by flow cytometry. On-target AEs (e.g. dysgeusia and alopecia) were observed at multiple dose levels. Pharmacokinetics were linear, predictable, and compatible with once-daily dosing. On the basis of these encouraging results, a Phase 1b study of PF-04449913 in combination with bosutinib and dasatinib is planned in patients with CML.

Jamieson:Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Wintherix: Equity Ownership. Cortes:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer Oncology: Research Funding; Novartis: Research Funding; BMS: Research Funding; Infinity: Research Funding. Oehler:Pfizer Oncology: Research Funding. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Zhang:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Shaik:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Courtney:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Levin:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Martinelli:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.