On July 6, 2015 Ignyta reported a clinical collaboration with the University of California, San Francisco (UCSF), under which UCSF will study entrectinib in a proof-of-concept clinical trial in cancer patients with metastatic melanoma that is positive for activating alterations to NTRK1/2/3 (encoding TrkA/TrkB/TrkC) or ROS1 (Press release, Ignyta, JUL 6, 2015, View Source [SID:1234506174]).

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"We are excited to collaborate with UCSF, a world-renowned academic research institution," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "The focus on melanoma in this study will complement the broader range of indications on which we are focused in our own clinical trials, and we expect the findings to accelerate our understanding of the potential role of entrectinib in treating patients with NTRK-positive and ROS1-positive cancers."

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Under the terms of the collaboration agreement, Ignyta will contribute $1 million toward the funding of the clinical trial, as well as per-patient fees based on enrollment of NTRK-positive or ROS1-positive patients and their participation in the trial. Ignyta will also provide UCSF with sufficient supply of entrectinib for use in the clinical trial. In addition to the safety and efficacy data from the trial, UCSF will provide Ignyta with tumor samples and genetic sequencing data for patients screened for inclusion in the trial for further genomic analysis.

The study is a multicenter, open label umbrella trial designed by UCSF to obtain proof-of-concept data in patients with metastatic melanoma that is positive for molecular alterations in specific tyrosine kinase receptors. UCSF will exclusively use entrectinib for patients enrolled in the clinical trial having activating molecular alterations to NTRK1/2/3 or ROS1.

About Entrectinib

Entrectinib is a novel, orally available, selective tyrosine kinase inhibitor targeting tumors that harbor activating alterations to NTRK1/2/3 (encoding TrkA/ TrkB/TrkC), ROS1 or ALK.

In June 2015, Ignyta announced interim results from two Phase 1 clinical trials of entrectinib: the ALKA-372-001 study and the STARTRK-1 study, which is the first of the "Studies of Tumor Alterations Responsive to Targeted Receptor Kinase" inhibition. Both trials were designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose, as well as preliminary anti-cancer activity, of single agent entrectinib in patients with solid tumors with the relevant molecular alterations: NTRK1 (encoding TrkA), ROS1 or ALK for ALKA-372-001 and NTRK1/2/3 (encoding TrkA/TrkB/TrkC), ROS1 or ALK for STARTRK-1.

As of the May 1, 2015 data cut-off for the presentation, the findings showed:

A total of 67 patients with a range of solid tumors had been dosed across both clinical trials;

Entrectinib was well tolerated, with no treatment-related serious adverse events. Other safety findings included:
In the ALKA-372-001 study, two Grade 3 treatment-related adverse events were observed: fatigue and muscle weakness, each of which subsided with dose reduction. The most frequent adverse events were paresthesia, nausea, myalgia, asthenia, dysgeusia, and vomiting;

In the STARTRK-1 study, three Grade 3 treatment-related adverse events were observed: neutropenia, which resolved with dose reduction, and two dose-limiting toxicities of reversible cognitive impairment and fatigue, both of which resolved upon study drug interruption. The most frequent adverse events were fatigue, dysgeusia, constipation, nausea, and paresthesia;

Pharmacokinetic measurements showed dose-proportional increases across the daily dosing regimens evaluated, with a half-life compatible with once-daily dosing;

The body surface area (BSA)-based recommended Phase 2 dose was determined to be 400 mg/m2 once per day (QD); both studies are continuing in order to determine a fixed daily dose regimen;

11 patients across both clinical trials met the company’s expected Phase 2 eligibility criteria, which include:
Presence of NTRK1/2/3, ROS1 or ALK fusions, as opposed to other types of molecular alterations (e.g., SNPs, amplifications, deletions);
ALK inhibitor and/or ROS1 inhibitor naïve; and
Treatment at or above the recommended Phase 2 dose of 400 mg/m2;

The response rate in the 11 patients that met these criteria across both studies was 91% (10 of 11 responses as assessed by the clinical sites), with 9 patients remaining on study treatment with durable responses of up to 16 treatment cycles. The responses included:
3 of 3 responses in patients with NTRK1/2/3 fusions, including patients with non-small cell lung cancer (NSCLC), colorectal cancer and acinic cell cancer;
5 of 6 responses, including one complete response, in patients with ROS1 fusions, all of which were in NSCLC; and
2 of 2 responses in patients with ALK fusions, including one NSCLC patient and one patient with another solid tumor.