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OncoMed’s Phase 2 Trial of Tarextumab in Small Cell Lung Cancer Does Not Meet Endpoints

On April 17, 2017 OncoMed Pharmaceuticals, Inc. (Nasdaq:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported top-line results from the company’s randomized 145-patient Phase 2 PINNACLE clinical trial of tarextumab (anti-Notch2/3, OMP-59R5) in combination with etoposide plus either cisplatin or carboplatin chemotherapy ("chemotherapy") in previously untreated patients with extensive-stage small cell lung cancer (Press release, OncoMed, APR 17, 2017, View Source [SID1234518580]). Results for the combination of tarextumab plus chemotherapy were undifferentiated from those of chemotherapy plus placebo, and therefore the trial did not meet its primary endpoint of progression-free survival or secondary endpoints of overall survival and biomarkers reflective of Notch pathway gene activation.

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"Small cell lung cancer is a very difficult-to-treat disease and unfortunately, tarextumab did not show benefit over placebo in this Phase 2 trial," said Paul J. Hastings, OncoMed’s Chairman and CEO. "We deeply appreciate the participation by the investigators and staff, patients and caregivers who all contributed to the conduct and completion of this Phase 2 clinical trial."

OncoMed also announced today that it will discontinue enrollment in the Phase 1b clinical trial of brontictuzumab (anti-Notch1, OMP-52M51) in combination with trifluridine/tipiracil (Lonsurf) in third-line colorectal cancer patients. The combination of brontictuzumab plus chemotherapy was not tolerable in this patient population.

"Based on the events of today and last week, we will be undertaking a comprehensive portfolio prioritization review immediately," continued Mr. Hastings. "The immediate task ahead is to thoroughly examine the available data, our resources and the opportunities to re-focus our efforts. We ended the first quarter of 2017 with $156.9 million in cash and short-term investments."

The median progression-free survival (mPFS) for tarextumab plus chemotherapy was 5.6 months versus 5.5 months for chemotherapy plus placebo (HR=0.969). The median overall survival (mOS) analysis did not show a benefit for tarextumab in combination with chemotherapy (mOS=9.3 months) compared to the chemotherapy plus placebo arm (10.3 months; HR=1.01). Five individual Notch biomarkers (Hes1, Hes6, Hey1, Hey2 and Notch3) failed to identify a definitive subset of patients with a treatment effect on either mPFS or mOS. Overall response rates were 68.5% and 70.8% in the tarextumab and placebo arms respectively. The combination of tarextumab plus chemotherapy was well tolerated. The safety profile appeared to be similar between the two groups except for diarrhea and thrombocytopenia, which were more prevalent in the tarextumab treatment arm, and constipation, which was more prevalent in the placebo arm.

OncoMed management will host a conference call today at 8:30 a.m. ET/5:30 a.m. PT to discuss the PINNACLE clinical trial data. OncoMed plans to present full study findings, including results from the biomarker analyses, at a future scientific conference.

About the Phase 2 PINNACLE Trial
Patients enrolled in the randomized, double-blinded, multi-center PINNACLE clinical trial were randomized into two study arms and received either 15mg/kg of tarextumab every three weeks in combination with six cycles of etoposide and either cisplatin or carboplatin chemotherapy followed by tarextumab maintenance to progression or six cycles of chemotherapy and a placebo. The primary endpoint of the trial was progression-free survival. Secondary endpoints included overall survival and overall response rate, pharmacokinetics, safety and biomarker analyses. Overall survival, progression-free survival and overall response rates are also being assessed against elevated tumor expression of the Notch pathway genes Hes1, Hes6, Hey1, Hey2 and Notch3 as a secondary endpoint. The PINNACLE trial was conducted at 36 sites in the United States.

About Tarextumab (anti-Notch2/3, OMP-59R5)
Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Preclinical studies suggested that tarextumab exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, tarextumab appears to have anti-cancer stem cell effects, and (2) tarextumab affects pericytes, impacting stromal and tumor microenvironment. Tarextumab is part of OncoMed’s collaboration with GlaxoSmithKline (GSK).

About Small Cell Lung Cancer
According to the American Cancer Society, lung cancer (both small cell and non-small cell) is the second most common cancer in men and women and is by far the leading cause of cancer death. Small cell lung cancer is expected to make up about 10%-15% of the 224,390 newly diagnosed lung cancer cases and the 158,080 deaths estimated to occur in the U.S. in 2016. Small cell lung cancer tends to grow and spread quickly, and is typically not discovered until it has metastasized to other parts of the body (extensive stage). The current standard of care in treating small cell lung cancer is the chemotherapeutic etoposide in combination with either cisplatin or carboplatin. In spite of a high sensitivity to chemotherapy and remission rates of up to 80% following initial treatment, the median overall survival is less than one year for patients with extensive stage disease1.

argenx receives first preclinical milestone payment in AbbVie collaboration

On April 13, 2017 argenx (Euronext Brussels: ARGX), a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported the achievement of the first of two preclinical milestones on its way to the investigational new drug (IND) filing of ARGX-115, triggering a $ 10 million payment from AbbVie (Press release, arGEN-X, APR 13, 2017, View Source [SID1234518538]).

In April 2016, argenx entered into a collaboration agreement with AbbVie to develop and commercialize ARGX-115. Under the terms of the collaboration agreement, argenx is responsible for conducting and funding all ARGX-115 research and development activities up to completion of IND-enabling studies.

argenx has granted AbbVie an exclusive option, for a period following completion of IND-enabling studies, to obtain a worldwide, exclusive license to the ARGX-115 program to develop and commercialize products. argenx is eligible to receive two near-term preclinical milestones of $ 10 million each. The first milestone was achieved today.

About ARGX-115

ARGX-115 employs argenx’s SIMPLE Antibody technology and works by stimulating a patient’s immune system after a tumor has suppressed the immune system by co-opting immunosuppressive cells such as activated regulatory T-cells (Tregs). While the normal function of Tregs is to suppress portions of the immune system to prevent a self-directed immune response through the release of active transforming growth factor beta (TGF-β), Tregs can also prevent the immune system from recognizing and suppressing pathogenic cells including cancer cells. By binding to glycoprotein A repetitions predominant (GARP), which plays a key role in the regulation of production and release of active TGF-β, ARGX-115 works to limit the immunosuppressive activity of Tregs and thereby stimulate the immune system to attack cancer cells. We believe this specific inhibition of TGF-β release by Tregs is potentially superior as a therapy to systemic inhibition of TGF-β activity or the depletion of Tregs with a potentially improved safety profile.

ARGX-115 was discovered under argenx’s Innovative Access Program with the de Duve Institute / Université Catholique de Louvain / WELBIO.

G1 Therapeutics files for IPO

The initial offering amount is for $115M and will be used to advance the development of trilaciclib, G1T38, G1T48 for treatment of breast cancer and small cell lung cancer (Filing, S-1, G1 Therapeutics, APR 13, 2017, View Source [SID1234518582]).

The stock will trade on the Nasdaq with symbol "GTHX."

Celsion Corporation Reports Preclinical Results of ThermoDox® for the Treatment of Bladder Cancer Published in the International Journal of Hyperthermia

On April 13, 2017 Celsion Corporation (NASDAQ:CLSN) reported publication of the article, "Lyso-Thermosensitive Liposomal Doxorubicin for Treatment of Bladder Cancer," in the International Journal of Hyperthermia (Press release, Celsion, APR 13, 2017, View Source [SID1234518537]). The article describes the results of porcine in vivo studies to evaluate ThermoDox in combination with loco-regional mild hyperthermia for targeted drug delivery to the bladder wall as a potential treatment for bladder cancer. Swine bladder walls are similar in proportion and composition to human bladders. Doxorubicin accumulation and distribution within the bladder wall with ThermoDox plus mild bladder hyperthermia was achieved at concentrations nearly ten times higher than with free intravenous doxorubicin combined with mild bladder hyperthermia. The study was conducted under a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health (NIH) to evaluate whether ThermoDox combined with mild heating of the bladder can target drug delivery in the bladder.

It is estimated that over 79,000 new cases of urinary bladder cancer will be diagnosed in the United States in 2017 and over 16,800 people will die of the disease during this same period. Approximately 70 percent of new cases of bladder cancer present with non-muscle invasive disease and are typically treated by a technique called transurethral resection of the bladder which removes as much of the tumor as possible. However, 40 percent of patients with high risk non-muscle invasive disease experience a recurrence and another 33 percent experience disease progression. To reduce this high rate of recurrence, intravesical (in the bladder) therapy is used. Intravenous administration of free doxorubicin is commonly used as part of an effective standard perioperative chemotherapy regimen for muscle invasive disease; however results with intravesical doxorubicin have been less effective presumably from inability to deliver doxorubicin across the bladder urothelium (epithelial surface of the bladder).
The NIH studies were conducted under the direction of Dr. Bradford Wood, MD, Director, NIH Center for Interventional Oncology and Chief, NIH Clinical Center Interventional Radiology. The results of the studies are summarized below:
• Range of doxorubicin concentrations from the urothelium to the serosa (outer surface of the bladder):
20.32 – 3.52 ug/g for ThermoDox + hyperthermia (HT)
2.34 – 0.61 ug/g for free doxorubicin + hyperthermia
2.18 – 0.51 ug/g for ThermoDox with no hyperthermia
• Average doxorubicin concentrations in the urothelium/lamina:
9.7 +/- 0.67 ug/g for ThermoDox + hyperthermia (HT)
1.2 +/- 0.39 ug/g for free doxorubicin + hyperthermia
1.15 +/- 0.38 ug/g for ThermoDox with no hyperthermia
• Average doxorubicin concentrations in the muscularis:
4.09 +/- 0.81 ug/g for ThermoDox + hyperthermia (HT)
0.86 +/- 0.24 ug/g for free doxorubicin + hyperthermia
0.62 +/- 0.15 ug/g for ThermoDox with no hyperthermia
Computational model results were similar to the measured doxorubicin levels and suggest that adequate temperatures were reached within the bladder for drug release from the lyso-thermosensitive liposomal doxorubicin,
ThermoDox.

"The incomplete response of bladder tumors to intravesical drugs, like doxorubicin and mitomycin C, has been attributed in part to inadequate drug delivery and poor penetration across the urothelium resulting in sub-therapeutic drug concentrations in the bladder wall," said Dr. Bradford Wood, MD, Director, NIH Center for Interventional Oncology and Chief, NIH Clinical Center Interventional Radiology. "To address this limitation, one promising strategy to enhance the permeability of the bladder wall to improve the efficacy of intravesical chemotherapy is the use of hyperthermia to stimulate the release of chemotherapeutic agents from thermosensitive nanocarriers for patients who have failed standard first line therapy for bladder cancer."

"The NIH’s continued research interest in ThermoDox and its application in the treatment of many difficult to treat cancers underscores the significance of ThermoDox’s potential and its unique means of locally concentrating doxorubicin in a highly effective way," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "This study not only reinforces ThermoDox’s mechanism, it provides further assurance that the conclusions from the NIH’s independent analysis of ThermoDox plus radio frequency ablation for the treatment of primary liver cancer are based on a broad set of clinical and preclinical evidence. The data presented by the NIH at the 2016 RSNA Annual Meeting in November 2016 showed that the longer the target tissue is heated, the greater is the clinical benefit. Multiple experiments conducted by Celsion suggest that this is the result of increased doxorubicin tissue concentration, and we believe provides strong validation for our ongoing global Phase III OPTIMA Study in primary liver cancer. A successful OPTIMA Study will provide the means to expand ThermoDox’s utility for patients with bladder cancer."

About ThermoDox
Celsion’s most advanced program is a heat-mediated, tumor-targeting drug delivery technology that employs a novel heat-sensitive liposome engineered to address a broad range of difficult-to-treat cancers. The first application of this platform is ThermoDox, a lyso-thermosensitive liposomal doxorubicin (LTLD), whose novel mechanism of action delivers high concentrations of doxorubicin to a region targeted with the application of localized heat at 40°C, just above body temperature. ThermoDox has the potential to address a broad range of cancers.

Celsion’s LTLD technology leverages two mechanisms of tumor biology to deliver higher concentrations of drug directly to the tumor site. In the first mechanism, rapidly growing tumors have leaky vasculature, which is permeable to liposomes and enables their accumulation within tumors. Leaky vasculature influences a number of factors within the tumor, including the access of therapeutic agents to tumor cells. Administered intravenously, ThermoDox is engineered with a half-life to allow significant accumulation of liposomes at the tumor site as these liposomes recirculate in the blood stream. In the second mechanism, when an external heating device heats tumor tissue to a temperature of 40°C or greater, the heat-sensitive liposome rapidly changes structure and the liposomal membrane selectively dissolves, creating openings that can release a chemotherapeutic agent directly into the tumor and into the surrounding vasculature. Drug concentration increases as a function of the accumulation of liposomes at the tumor site, but only where the heat is present. This method damages only the tumor and the area related to tumor invasion, supporting more precise drug targeting.

AVEO Announces Submission of Response to Tivozanib Marketing Authorization Application Day 180 List of Outstanding Issues

On April 13, 2017 AVEO Oncology (NASDAQ: AVEO) reported that its European licensee for tivozanib, EUSA Pharma, has submitted responses to the European Medicines Agency (EMA) Day 180 List of Outstanding Issues (LOI) related to the Marketing Authorization Application (MAA) for tivozanib as a first-line treatment for renal cell carcinoma (Press release, AVEO, APR 13, 2017, View Source [SID1234518533]). With submission of the response complete, EUSA remains tentatively scheduled to provide an oral explanation to the EMA’s Committee for Medicinal Products for Human Use (CHMP) at its May 2017 meeting.

"Responding to the Day 180 List of Outstanding Issues is another important step in the tivozanib MAA, and we continue to work with EUSA Pharma in their effort to seek regulatory approval for tivozanib in Europe," said Michael Bailey, president and chief executive officer of AVEO. "This includes supporting EUSA as they proceed toward a planned oral explanation to the CHMP in May, while at the same time we continue to advance our registration strategy for tivozanib in the United States. We look forward to providing updates on these dual paths as we complete the final phase of the European approval process and work toward our goal of full enrollment in our U.S. registration-directed TIVO-3 study."

As previously announced, the Day 180 LOI signified that the MAA is not approvable at that time, and outlines outstanding deficiencies, which are then required to be satisfactorily addressed in an oral explanation and/or in writing prior to a final application decision.

About Tivozanib

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.