On September 30, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported the initiation of its Phase 2 clinical trial of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK (Press release, Ignyta, SEP 30, 2015, View Source [SID:1234507614]). This clinical trial is called STARTRK-2, the second of the "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases." The trial is a global, multicenter, open label, potentially registration-enabling Phase 2 clinical trial of entrectinib that utilizes a basket design with screening of patient tumor samples for the relevant targets. Such a basket design takes full advantage of entrectinib’s demonstrated preliminary clinical activity across a range of different tumor types and molecular targets. Schedule your 30 min Free 1stOncology Demo! "The initiation of this potentially registration-enabling trial builds upon the promising data from our Phase 1 clinical trials of this product candidate, including responses in patients with activating alterations to each of NTRK1, NTRK3, ROS1 and ALK, across multiple different tumor types."
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"We are excited to be able to expand the clinical development program for entrectinib with this clinical study, which we expect will include patients at over 100 leading cancer centers in the U.S., Europe, and Asia," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "The initiation of this potentially registration-enabling trial builds upon the promising data from our Phase 1 clinical trials of this product candidate, including responses in patients with activating alterations to each of NTRK1, NTRK3, ROS1 and ALK, across multiple different tumor types."
The initiation of the STARTRK-2 clinical trial enabled the company to draw down an additional $10 million on September 30, 2015, under its term loan facility with Silicon Valley Bank. The company now has total indebtedness of approximately $31 million under the loan facility.
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 September 2015, Ignyta announced updated 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 (RP2D), 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 August 15, 2015, data cut-off for the presentation, the findings showed:
A total of 92 patients with a range of solid tumors had been dosed across both clinical trials, with nine patients treated at or above the RP2D beyond six months and one patient beyond one year.
Entrectinib was well tolerated to date:
Across both studies, the most frequent (>10% incidence) treatment-related adverse events were fatigue, dysgeusia, paresthesia, nausea, and myalgia. Seven of these were Grade 3 in severity, consisting of fatigue (4 patients), cognitive impairment (2 patients), and diarrhea (1 patient). No Grade 4 treatment-related adverse events were observed;
Across both studies, there were only three treatment-related serious adverse events: Grade 3 cognitive impairment and Grade 3 myocarditis, both of which occurred above the RP2D, and Grade 2 fatigue. All events were reversible and resolved upon dose modification;
The fixed daily dose RP2D was determined to be 600 mg, taken orally once per day (QD);
18 patients across both clinical trials met the company’s expected Phase 2 eligibility criteria, which include:
Presence of NTRK1/2/3, ROS1 or ALK gene rearrangements, 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 RP2D;
The response rate in the 18 patients who met these criteria across both studies was 72% (13 responses out of 18 treated patients, as assessed by the clinical sites). Nine of these responders remain on study treatment with durable responses of up to 21 treatment cycles. An additional 3 patients remain on study with stable disease. The responses included:
3 responses out of 4 patients with NTRK1/2/3 gene rearrangements, including patients with non-small cell lung cancer (NSCLC), colorectal cancer and salivary gland cancer, with one of the responding patients remaining on treatment at 6 months. A fourth patient with an astrocytoma remains on treatment after two months with stable disease;
6 responses, including one complete response, out of 8 patients with ROS1 gene rearrangements, all of which were in NSCLC. All of the patients who responded remain on treatment, the longest at 21 months; and
4 responses out of 6 patients with ALK gene rearrangements, including two NSCLC patients and two patients with other solid tumors. Two of the 4 responders subsequently progressed.
Entrectinib has demonstrated objective tumor response in the central nervous system (CNS), a frequent site of metastases and progression of advanced solid tumors.