Citation: European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 5

P. Chapman¹, I. Puzanov², J. Sosman³, K. Kim⁴, A. Ribas⁵, G. McArthur⁶, R. Lee⁷, J. Grippo⁸, K. Nolop⁹, K. Flaherty<sup>10

1</sup>Memorial Sloan-Kettering Cancer Center, Department of Medicine, New York, USA
²Vanderbilt Ingram Cancer Center, Department of Medical Oncology, Nashville, USA
³Vanderbilt University Medical Center, Department of Medical Oncology, Nashville, USA
⁴MD Anderson Cancer Center, Department of Melanoma Medical Oncology, Houston, USA
⁵UCLA, Division of Hematology and Oncology, Los Angeles, USA
⁶Peter MacCallum Cancer Center, Division of Hematology and Oncology, East Melbourne, Australia
⁷Hoffmann-La Roche Inc., Department of Oncology, Nutley, USA
⁸Hoffmann-La Roche Inc., Clinical Research and Exploratory Development – Pharmacology, Nutley, USA
⁹Plexxikon Inc., Development, Berkeley, USA
¹⁰University of Pennsylvania, Department of Hematology/Oncology, Philadelphia, USA

Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant BRAF kinase, observed in a variety of cancers, including approx. 60% of melanomas (MEL) and 10% of colorectal carcinomas. We conducted a phase I trial with PLX4032 (RO5185426) to determine maximum tolerated dose (MTD), safety, and pharmacokinetics (PK). We also evaluated anti-tumor responses and, in select patients (pts), tumor biopsies for pharmacodynamics.
Materials and Methods: Pts took PLX4032 by mouth twice daily. Doses were escalated in cohorts of 3 to 6 pts. PK was measured on days 1 and 15. Once the MTD was determined, an extension cohort of MEL patients with BRAF mutations was treated at the MTD. Anti-tumor effects were evaluated by RECIST criteria every 8 weeks.
Results: 55 pts were enrolled in the dose escalation phase. Of these, 30 pts were treated at doses from 160 mg to 1120 mg bid using an optimized formulation with much greater bioavailability. With the optimized formulation, minimum target exposure (≥400 μM·h) was achieved at 240 mg bid, and systemic exposure increased in a dose-proportional manner up to 960 mg bid (1700 μM·h). At 1120 mg bid, 4/6 pts developed dose-limiting toxicity (DLT; Grade 3 rash with pruritus, fatigue, or arthralgia), which resolved with temporary drug interruption. In all cases, pts resumed treatment at lower doses. The MTD was determined to be 960 mg bid. Of the 26 pts treated at doses ≥240 mg bid, 16 had MEL with an activating BRAF mutation. Of these 16 MEL pts, 11 had a partial response (PR) that has been confirmed in 9 pts to date. 30 additional MEL pts with activating BRAF mutations have been treated at the MTD of 960 mg bid. Most patients had been previously treated for systemic disease (median # prior therapies = 2, range 0–7). Of the 22 pts evaluable for response to date, there have been 14 PRs (64%); 6 other pts have had regression but do not fulfill criteria for PR. Responses have been seen in subcutaneous sites, liver, lung, GI, and bone, and have been associated with resolution of symptoms. DLTs (all grade 3) at the MTD reported to date were: fatigue, arthralgias, photosensitivity, rash, and elevated alkaline phosphatase. Squamous cell cancer of the skin as been seen in 4 pts.
Conclusions: Dose escalation of PLX4032 reached DLT at 1120 mg bid; 960 mg bid is the MTD. In heavily pre-treated MEL patients with tumors that harbor an activating mutation in BRAF, we have observed anti-melanoma activity in the majority of patients treated at doses >240 mg bid and in almost all patients treated at the MTD. Phase II and phase III trials are planned.