Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1α.

Abstract

3076 Background: Hypoxia inducible factor-1 (HIF-1) transcription factor is an important regulator of cellular response to hypoxia. Increased HIF-1α is correlated with increased angiogenesis and aggressive tumor growth. PX-478 is a novel agent derived from melphalan by oxidation of the nitrogen mustard moiety. In preclinical models, PX-478 demonstrated antitumor activity and, in contrast to melphalan, inhibited HIF-1α expression. PX-478 was tested in a phase I, dose escalation study in patients (pts) with advanced solid tumors. Methods: Initial accelerated dose escalation cohorts consisted of 1 pt each, with expansion to 3-4 pts following first occurrence of Gr 2 toxicity. Cohorts were expanded to 6 pts if one experienced DLT. A dose was considered not tolerated if 2 or more pts experienced DLT. Study assessments included safety, response, pharmacokinetics (PK), and pharmacodynamics (PD) consisting of measurement of HIF-1α levels in peripheral blood mononuclear cells (PBMCs). Results: Forty pts (age 33-82; median ECOG PS 1) received doses between 1.0 and 88.2 mg/m2 orally on days 1-5 of a 21 day cycle. Treatment was well tolerated with no DLTs between 1 and 58.8 mg/m2. Most AEs were Gr 1/2, including fatigue, nausea, vomiting, anorexia, and anemia. One heavily pretreated pt at 88.2 mg/m2 experienced DLT of prolonged Gr 3 thrombocytopenia without bleeding. Other related Gr 3 AEs were anemia (n=1), acute renal failure (n=1), hypotension, (n=1), and elevated ALT/AST (n=1). Best response was SD in 14/36 evaluable pts (received ≥1 cycle or had documented PD). Pts with SD received a median of 4 cycles (range 2-16); 4 pts received ≥6 cycles (adenoid cystic, pheochromocytoma, prostate and vaginal cancers). PK analyses demonstrate low parent drug levels with evidence for conversion to melphalan and other metabolites. PD studies show HIF-1α inhibition proportional to drug dose. Conclusions: PX-478 has been well tolerated and associated with prolonged SD in pts with advanced cancers. Inhibition of HIF-1α despite low PX-478 levels is consistent with the idea that active metabolites other than melphalan may be responsible for the PD observations. These data support the continued evaluation of HIF-1α inhibition as a therapeutic target. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncothyreon Oncothyreon