Abstract B279: A phase I study determining the safety and tolerability of combination therapy with Pazopanib (P), a VEGFR/PDGFR/Raf inhibitor, and GSK1120212 (Trametinib: T), a MEK inhibitor, in advanced solid tumors with expansion cohorts in advanced differentiated thyroid cancer (DTC), cholangiocarcinoma (ChCA), and soft tissue sarcoma (STS).
Authors: Azad Nilofer , Ball Douglas , Sherman Steven , Rudek Michelle , Falchook Gerald , Nelkin Barry , Janku Filip , Papadopoulos Nicholas , O'Conner Ashley , Ahmed Shabina , Wilky Breelyn , Markus Susan , Gong Jing , Cosgrove David , Zahurak Marianna , Zinner Ralph , Kurzrock Razelle 
Published: August 2014

Background: P is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-β, c-kit, and FGFR 1-3 and is approved for renal cancer and STS. T is a potent, highly selective, allosteric inhibitor of MEK1/2 approved for BRAF-mutated advanced melanoma. Increased signaling of growth factor receptor tyrosine kinases have been shown to be important to cell survival in multiple tumor types, and their inhibition has been effective therapeutically in STS, DTC, and ChCa. In addition, increased RAS/RAF/MEK/ERK signaling plays a critical role in the development of many different types of cancers, including ChCA and DTC. We hypothesized that combination therapy with P and T would be tolerable and effective for this range of tumor types.

Methods: We designed a phase I, open label, dose escalation trial with P+T open to patients with advanced solid tumors. The study was a standard 3+3 design with an expansion cohort of 25 pts each for advanced DTC, STS, and ChCA for correlative endpoints and PK studies. Pts were treated with T held constant at 1 mg QD and P at 400 mg QD (DL1), 600 mg QD (DL2)and 800 mg QD (DL3); T was then escalated to 1.5 mg QD (DL4) and 2 mg QD (DL5). Eligibility included adequate end organ function, PS 0-1, and PD within 6 months in the expansion cohort of DTC. The primary objective was to determine the safety and tolerability of P+T and to find the MTD. Secondary objectives include assessing preliminary efficacy and exploration of PK/PD endpoints with tumor biopsies.

Results: We report the results of the dose escalation component of the study. 26 pts were accrued to 5 dose levels and treated for a median of 3 cycles (range &lt;1-9.5). MTD was defined as DL5. There was one DLT on DL1 with gr3 fatigue and muscle weakness. There were no gr4 AEs at least possibly attributable to study therapy. Grade 3 AES attributable to study therapy were diarrhea and elevated transaminases (15%), HTN (12%), fatigue (8%), and proteinuria, muscle weakness, rash, or abdominal cramping (4%). Common gr1-2 AES included diarrhea (73%), nausea and rash (54%), fatigue (46%), HTN (38%), anorexia or vomiting (27%). 7 pts discontinued study tx due to AEs. 9 pts had dose reductions at a median of cycle 2 (range 1-9) due to HTN (3), diarrhea (3), fatigue (2), elevated transaminases or glaucoma exacerbation (1). Out of 25 evaluable pts, 3 had a partial response (ChCA, ovarian, DTC) and were treated 4-9.5 cycles and 16 had stable disease at least through first reassessment.

Conclusions: P+T is a tolerable combination with some preliminary signs of efficacy. Accrual to expansion cohorts in DTC, STS, and ChCA for further exploration of efficacy and correlative endpoints is ongoing. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by GlaxoSmithKline.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B279.

Citation Format: Nilofer Azad, Douglas Ball, Steven Sherman, Michelle Rudek, Gerald Falchook, Barry Nelkin, Filip Janku, Nicholas Papadopoulos, Ashley O'Conner, Shabina Ahmed, Breelyn Wilky, Susan Markus, Jing Gong, David Cosgrove, Marianna Zahurak, Ralph Zinner, Razelle Kurzrock. A phase I study determining the safety and tolerability of combination therapy with Pazopanib (P), a VEGFR/PDGFR/Raf inhibitor, and GSK1120212 (Trametinib: T), a MEK inhibitor, in advanced solid tumors with expansion cohorts in advanced differentiated thyroid cancer (DTC), cholangiocarcinoma (ChCA), and soft tissue sarcoma (STS). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B279.