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.

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"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."

"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.

On September 30, 2015 Celsion Corporation (Celsion) (NASDAQ:CLSN), a fully-integrated oncology company focused on the development of a portfolio of innovative cancer treatments, including directed chemotherapies, immunotherapies and RNA- or DNA-based therapies for the treatment of cancer and other difficult-to-treat diseases, reported the enrollment of the first patient in its Phase Ib dose escalating clinical trial (the OVATION Study) combining GEN-1, the Company’s DNA-based immunotherapy, with the standard of care for the treatment of newly-diagnosed ovarian cancer patients who will undergo neoadjuvant chemotherapy (Press release, Celsion, SEP 30, 2015, View Source [SID:1234507612]).

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The first patient in the OVATION Study was enrolled at the University of Alabama at Birmingham (UAB). In addition to UAB, Oklahoma University Medical Center is now also recruiting patients in the OVATION Study. Celsion plans to initiate two additional sites in the coming months. Interim findings from this open label study are expected in the fourth quarter of 2015. The study will continue into the first half of next year at higher doses of GEN-1.

The OVATION Study will seek to identify a safe, tolerable and therapeutically active dose of GEN-1 by recruiting and maximizing an immune response. The trial is designed to enroll three to six patients per dose level and will evaluate safety and efficacy and attempt to define an optimal dose for a follow-on Phase I/II study combining GEN-1 with Avastin and Doxil. In addition, the OVATION Study establishes a unique opportunity to assess how cytokine-based compounds such as GEN-1, directly affects ovarian cancer cells and the tumor microenvironment in newly diagnosed patients. The study is designed to characterize the nature of the immune response triggered by GEN-1 at various levels of the patients’ immune system, including:

infiltration of cancer fighting T-cell lymphocytes into primary tumor and tumor microenvironment including peritoneal cavity, which is the primary site of metastasis of ovarian cancer;
changes in local and systemic levels of immuno-stimulatory and immunosuppressive cytokines associated with tumor suppression and growth, respectively; and
expression profile of a comprehensive panel of immune related genes in pre-treatment and GEN-1-treated tumor tissue.
These extensive mechanistic studies will assist in the design of novel combination approaches with immunotherapies and other anti-cancer agents driven by potential synergistic action mechanisms, and define an enhanced patient population based on molecular characteristics inherent to tumor tissue or the immune system.

GEN-1 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. GEN-1 has demonstrated encouraging safety and efficacy data in a Phase Ib trial in combination with PEGylated doxorubicin in patients with platinum-resistant ovarian cancer. The findings from this trial demonstrated an overall clinical benefit of 57% for all treatment arms, with a partial response (PR) rate of 21% and a stable disease (SD) rate of 36%. The overall clinical benefit observed at the highest dose cohort in this difficult-to-treat patient population was 100% (PR=33% and SD=67%) in all six evaluable patients. GEN-1 was well tolerated, with no dose limiting toxicities and no overlapping toxicities between GEN-1 and pegylated doxorubicin.

"Developing more effective immunotherapy approaches for ovarian cancer is a high priority for those of us who care for the thousands of patients affected by advanced ovarian cancer. GEN-1 is a novel IL-12 expressing lipopolymer that has demonstrated promising activity in preclinical and early phase clinical trials in ovarian cancer," stated Premal H. Thaker, M.D., associate professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine. "In preclinical and clinical studies performed to date, GEN-1 has demonstrated good safety and impressive immune system stimulation and activity, and this trial will evaluate its value as an adjuvant to chemotherapy in patients with a relatively healthy immune system."

"GEN-1 is designed to locally activate IL-12 production, which can stimulate the patient’s immune system to attack and destroy cancer," stated Dr. Nicolas Borys, Celsion’s senior vice president and chief medical officer. "Increases in IL-12 concentrations at the tumor site could create a potent immune environment against tumor activity resulting in a more robust and durable antitumor response compared to chemotherapy alone. We are conducting this trial in newly diagnosed patients with good immune systems in order to maximize the success of GEN-1’s novel mechanism."

"GEN-1 holds tremendous promise as a potential treatment in the rapidly emerging area of immuno-oncology. Unlike the toxicities, poor tolerability, and poor pharmacokinetics of systemically administered recombinant IL-12, the beauty of GEN-1 is that it inspires secretion of highly-tolerable endogenous IL-12," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "Designed in consultation with clinicians, this Phase I trial is expected to define an optimal dose and potentially an enhanced population. It will also provide insights on powering for a registration program as the candidate progresses through development."

About GEN-1 Immunotherapy

GEN-1, designed using the TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer and in combination with PEGylated doxorubicin in patients with platinum resistant ovarian cancer. GEN-1 has also demonstrated preclinical activity in glioblastoma multiforme (brain cancer) and the Company plans to initiate a Phase I study in this indication.