Abstract B225: A phase I dose-escalation study of selumetinib in combination with docetaxel in patients with advanced solid tumors.
Authors: Kim Kevin , Infante Jeffery , Cohen Roger , Burris Howard , Emeribe Ugochi , Curt Gregory , Clemett Delyth , LoRusso Patricia 
Published: June 2012

Abstract
Background: Selumetinib (AZD6244, ARRY-142866), an orally available potent, selective, non-ATP-competitive MEK1/2 inhibitor, has shown clinical activity as monotherapy in various solid tumors (recommended dose 75mg capsule BID). Preclinical models have shown enhanced antitumor activity for selumetinib combined with a number of agents, including docetaxel (DOC). This study aimed to assess the safety, tolerability and pharmacokinetics (PK) of escalating doses of selumetinib in combination with different agents, including DOC, in patients (pts) with advanced solid tumors and define the maximum tolerated dose (MTD) of selumetinib in these combinations.
Methods: In this Phase I open-label multicenter study (NCT00600496), pts received selumetinib combined with DOC, dacarbazine, temsirolimus or erlotinib. Selumetinib/DOC results are reported here. Pts ≥18 years, WHO performance status 0–1, who were candidates for DOC or may have benefited from combination therapy were eligible. DOC 75mg/m2 iv infusion was administered over 60 mins on D1 of each 21-day cycle. Selumetinib (capsule) was initiated on D3 of the first cycle and continuously BID thereafter. Part A of the study explored three selumetinib combinations to determine MTD: 50mg BID + DOC, 75mg BID + DOC, 75mg BID + DOC + prophylactic GCSF. Part B further explored dosing without prophylactic GCSF. Supportive GCSF was given as required in Parts A+B. Selumetinib and DOC PK parameters were determined after administration of each agent alone and combined.
Results: The study enrolled 140 pts, 35 in the selumetinib + DOC arm. In part A, 18/22 pts were evaluable for dose-limiting toxicity (DLT): selumetinib 50mg BID + DOC (n=6), 75mg BID + DOC (n=6), 75mg BID + DOC + GCSF (n=6) (mean prior chemotherapy treatments in each cohort: 3, 6, 5 respectively). 75mg selumetinib (no GCSF) exceeded the MTD with DLTs of grade 4 neutropenia (n=2) and febrile neutropenia (n=1). No DLTs occurred in the other Part A cohorts. In part B, 13 pts (mean prior chemotherapy treatments: 3) received selumetinib 75mg BID + DOC without prophylactic GCSF; 2 pts had grade 4 AEs (neutropenia n=1, febrile neutropenia n=1, first cycle). The most common AEs (≥40%, Parts A+B) were peripheral edema (71%), diarrhea (69%), fatigue (63%), nausea (49%), vomiting (46%), neutropenia (43%), and dermatitis acneiform (40%). The most common grade ≥3 AEs were hematological events (51%), infections (26%), fatigue/asthenia (23%), peripheral edema (10%), and gastrointestinal events (10%). AEs led to 1 death (pneumonia and febrile neutropenia in pt with esophageal tumor, not considered study drug related) and 2 permanent study drug discontinuations (multiple AEs). Median total selumetinib exposure was 130 days (range 1–714). In part B, 77% (10/13) and 46% (6/13) of pts completed ≥4 and ≥6 cycles of DOC, respectively. Combination therapy did not appear to affect selumetinib or DOC PK. Responses were observed in 5/28 pts (18%) receiving selumetinib 75 mg BID + DOC +/− GCSF in this non-comparative study.
Conclusions: The combination treatment AE profile was largely consistent with selumetinib or DOC monotherapy. In combination with DOC 75mg/m2 q21d + GCSF, selumetinib MTD is 75mg BID in heavily pre-treated pts. The recommended phase 2 dose of selumetinib + DOC without GCSF in less heavily pre-treated pts is 75mg BID.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B225.