On September 17, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported the initiation of the company’s Phase 1/1b clinical trial of RXDX-107, its next generation alkyl ester of bendamustine encapsulated in human serum albumin (HSA) to form nanoparticles (Press release, Ignyta, SEP 17, 2015, View Source [SID:1234507491]). This multicenter, open-label, dose-escalation clinical trial is designed to determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), tolerability, pharmacokinetics and preliminary clinical activity of RXDX-107 in adult patients with locally advanced or metastatic solid tumors.

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"We are excited to be able to begin dosing patients with this product candidate at leading cancer centers in this clinical trial," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "RXDX-107 represents our third product candidate in the clinic, furthering our goal of attacking cancer on multiple fronts for the benefit of cancer patients. The speed with which we have been able to file an IND and bring this molecule into clinical development six months after acquisition from Teva is a testament to the Ignyta team’s strong execution."

About RXDX-107

RXDX-107 is a new chemical entity comprising an alkyl ester of bendamustine encapsulated in HSA to form nanoparticles. RXDX-107 is designed to have increased half-life and improved tissue biodistribution by leveraging the affinity characteristics of albumin for tumor cells, while retaining the unique cytotoxic properties of bendamustine. These improvements may provide meaningful benefit to patients with solid tumors. In preclinical pharmacology studies, RXDX-107 has demonstrated anti-tumor activity in multiple in vitro and in vivo studies, including cell line-based and patient-derived xenograft models of solid tumors.

On September 17, 2015 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, and the Gynecologic Oncology Group (GOG, now part of NRG Oncology), reported clinical data from Stage 1 of an ongoing two-stage Phase 2 study (GOG-0265) of Advaxis’s lead Lm Technology immunotherapy, axalimogene filolisbac (ADXS-HPV), in patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) who have progressed on at least one prior line of systemic therapy (Filing, 8-K, Advaxis, SEP 17, 2015, View Source [SID:1234507490]). The Stage 1 data showed that treatment with axalimogene filolisbac resulted in a 38.5 percent 12-month overall survival rate in 26 patients.

Evaluation of safety data showed that Grade 1 or 2 adverse events occurred in 19 out of 26 patients (73 percent), with fatigue, chills and fever being the most common. Four patients (15 percent) experienced a Grade 3 adverse event (hypotension and cytokine release syndrome) and one patient (4 percent) experienced a Grade 4 adverse event (lung infection and sepsis). The results were presented at the American Gynecological & Obstetrical Society (AGOS) annual meeting in Half Moon Bay, Calif. by Tom Herzog, M.D., Clinical Director at the University of Cincinnati Cancer Institute.

"Patients with PRmCC who have failed at least one line of therapy face a life threatening condition with an estimated survival of 4 to 7 months and no available treatment options," said Dr. Herzog. "The Stage 1 results for axalimogene filolisbac, which show 12-month survival, are a meaningful step forward in meeting the needs of women who require second-line treatment for PRmCC."

The GOG has conducted over 17 studies of a diverse set of investigational agents and regimens, but never has the 12-month overall survival rate exceeded 30 percent in people with PRmCC. Stage 2 of the GOG-0265 study is currently enrolling and the protocol has been amended by GOG to allow for continuous cycles of treatment until disease recurrence (the Stage 1 protocol provided for 3 doses of axalimogene filolisbac over 3 months).

"The axalimogene filolisbac data presented at AGOS by the GOG and Dr. Herzog represent some of the most encouraging Phase 2 data to date in metastatic cervical cancer and supports the results previously observed in Advaxis’s own Phase 2 study," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. "Advaxis is grateful to NRG Oncology and the GOG for having the foresight several years ago to design, sponsor and conduct this study."

Advaxis has submitted a Special Protocol Assessment (SPA) request to the U.S. Food and Drug Administration (FDA) for a Phase 3 study evaluating the safety and efficacy of axalimogene filolisbac in high-risk, locally advanced cervical cancer (HRLACC). The SPA review process remains ongoing. The planned Phase 3 trial will be conducted in collaboration with the GOG Foundation, Inc. and is intended to begin enrollment by the end of 2015, depending on the length of the FDA’s SPA review process.

A completed randomized Phase 2 trial of axalimogene filolisbac with or without cisplatin chemotherapy in Indian patients with PRmCC (0-2 prior lines of therapy) also demonstrated promising activity (12-month overall survival rate of 32 percent) and acceptable tolerability with chills and flu-like symptoms the most common treatment-related adverse events. Results from this trial were featured in a poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in 2014.

Business Update & Webcast

Advaxis will hold a business update conference call today, September 17, at 4:30 p.m. ET / 1:30 p.m. PT to provide Advaxis investors and stakeholders with a review of the Stage 1 clinical data from the GOG-0265 study presented at AGOS 2015. Dr. Herzog will be the featured presenter on the call.

A live broadcast of the conference call will be available by direct dial at 1-888-364-3109 in the U.S. or 1-719-325-2455 outside of the U.S.; Conference Passcode 2197270, or by live webcast available online at this URL: View Source

The call will be recorded and available for playback through October 1 by dialing 1-877-870-5176 in the U.S. and 1-858-384-5517 outside of the U.S.; Replay Passcode 2197270. In addition, the webcast will be available for replay at the URL above.

About the GOG-0265 Study

GOG-0265 is an open-label, single-arm, two-stage Phase 2 study designed to evaluate the safety, tolerability and efficacy of axalimogene filolisbac in approximately 67 patients with PRmCC who have received at least one prior line of systemic therapy. The primary efficacy endpoint is 12-month overall survival rate, with secondary efficacy endpoints of progression-free survival, overall survival and objective tumor response. The primary safety endpoints are the number of patients with dose-limiting toxicities and the frequency and severity of adverse effects.

The trial is being conducted in the United States by GOG, now part of NRG Oncology, under the sponsorship of the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI). Further information about the study can be found on ClinicalTrials.gov, using Identifier NCT01266460.

About Cervical Cancer

Cervical cancer is the fourth most common cancer and the most common cause of mortality in women worldwide. In the United States, nearly 13,000 new cases are diagnosed and approximately 4,100 deaths are reported because of cervical cancer. According to the WHO/ICO Information Centre on HPV and Cervical Cancer, about 3.9 percent of women in the U.S. are estimated to harbor high-risk cervical HPV infection at a given time, and 71.7 percent of invasive cervical cancers are attributed to high-risk HPV strains.

About Axalimogene Filolisbac

Axalimogene filolisbac (ADXS-HPV) is Advaxis’s lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology.

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On September 17, 2015 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, reported poster presentations at the 40th European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper)/18th European Cancer Congress being held September 25-29, 2015 at the Messe Wien Exhibition & Congress Centre in Vienna, Austria (Press release, Verastem, SEP 17, 2015, View Source;p=RssLanding&cat=news&id=2088485 [SID:1234507488]).

The details for the poster presentations at ESMO (Free ESMO Whitepaper) are as follows:

Title: FAK Inhibitor Defactinib (VS-6063) Targets Mesothelioma Cancer Stem Cells: Rationale for Maintenance Therapy after Conventional Chemotherapy
Date and time: Monday, September 28, 2015, 4:45 pm – 6:45 pm CEST
Location: Hall C; Poster #P287
Session info: Translational Research-Tumor Stem Cells

Title: VS-5584, a dual PI3K/mTOR inhibitor, demonstrates robust activity in pre-clinical models of SCLC with the inhibition of both cancer stem cells and bulk tumor cells
Date and time: Monday, September 28, 2015, 4:45 pm – 6:45 pm CEST
Location: Hall C; Poster #P288
Session info: Translational Research-Tumor Stem Cells

About VS-6063
VS-6063 (defactinib) is an orally available compound designed to target cancer stem cells through the potent inhibition of focal adhesion kinase (FAK). Cancer stem cells are an underlying cause of tumor resistance to chemotherapy, recurrence and ultimate disease progression. Research has demonstrated that FAK activity is critical for the growth and survival of cancer stem cells. VS-6063 is currently being studied in the registration-directed COMMAND trial in mesothelioma (www.COMMANDmeso.com), a "Window of Opportunity" study in patients with mesothelioma prior to surgery, a Phase 1/1b study in combination with paclitaxel in patients with ovarian cancer, a trial in patients with KRAS-mutated non-small cell lung cancer and a trial evaluating the combination of VS-6063 and VS-5584 in patients with relapsed mesothelioma. VS-6063 has been granted orphan drug designation for use in mesothelioma in the U.S. and EU.

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About VS-5584
VS-5584 is an orally available compound that has demonstrated potent and highly selective activity against class 1 PI3K enzymes and dual inhibitory actions against mTORC1 and mTORC2. In preclinical studies, VS-5584 has been shown to reduce the percentage of cancer stem cells and induce tumor regression in chemotherapy-resistant models. Verastem is currently conducting a dose escalation trial of VS-5584 in patients with advanced solid tumors as a single agent and a combination trial of VS-5584 and VS-6063 in patients with relapsed mesothelioma. VS-5584 has been granted orphan drug designation for use in mesothelioma in the U.S. and EU.

On September 17, 2015 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported that The Lancet, one of the world’s leading medical journals, published a peer-reviewed article detailing the successful results of its phase 2b trial with VGX-3100 in treating women with high grade cervical neoplasia (Press release, Inovio, SEP 17, 2015, View Source [SID:1234507487]). Previously, medical researchers have tried to stimulate therapeutic immune responses against the human papillomavirus (HPV) and cervical lesions with little success. This publication details that VGX-3100, a first-in-class product for treating high grade cervical neoplasia associated with HPV, is the first therapy to demonstrate that activated killer T cells induced in the body have the power to clear neoplastic lesions as well as the virus which caused the disease.

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Dr. J. Joseph Kim, Inovio’s President and CEO, said, "Inovio’s SynCon products have overcome the elusive and difficult challenge of generating activated killer T cells in the body which clear established disease as well as eradicate cancer-causing HPV virus."

"Building on this proof-of-concept phase 2b study, Inovio is mobilizing to initiate our phase 3 trial for VGX-3100 next year. We are also advancing our two major immunotherapy partnerships, one with MedImmune and another with Roche, as well as driving forward multiple clinical and preclinical cancer products based on our core SynCon platform."

Commenting on Inovio’s HPV results, two senior investigators at the U.S. National Cancer Institute Division of Cancer Epidemiology & Genetics (Dr. Mark Schiffman and Dr. Nicolas Wentzensen) wrote in The Lancet: "The current trial represents a major breakthrough and proof-of-principle that therapeutic HPV vaccination is feasible. More broadly, the trial shows that it is possible to boost immune clearance of HPV among women who initially failed to control infection."

Dr. Mark L. Bagarazzi, Inovio’s Chief Medical Officer and the senior author of The Lancet article, said, "For women with cervical dysplasia there is no alternative treatment except for surgery – a procedure that can bring side effects such as bleeding and fertility complications. Our study of VGX-3100 provides hope for women that a safe, non-surgical option will be available to them."

Results of the trial were reported in the article entitled, "Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomized, double-blind, placebo-controlled phase 2b trial," by C. Trimble, et al. Dr. Cornelia Trimble, Professor of Gynecology and Obstetrics, Oncology, and Pathology at Johns Hopkins School of Medicine, was the principal investigator for the study.

Specifically, the phase 2b trial showed that histopathological regression of high grade cervical neoplasia (CIN2/3) to low grade neoplasia (CIN 1) or no disease occurred in a significantly higher percentage of VGX-3100 recipients compared with placebo recipients. Furthermore, concomitant histopathological regression and clearance of HPV occurred in a significantly higher percentage of VGX-3100 recipients compared with placebo recipients. HPV-specific CD8+ "killer T cells" were also generated in the blood as well as a substantial infiltration of CD8+ cells in the cervical tissue of VGX-3100 recipients, underscoring the role played by Inovio’s best-in-class T-cell responses. VGX-3100 was safe and generally well-tolerated.

In VGX-3100-treated women who regressed their lesion, most (43 out of 53) completely cleared their lesions to normal (complete response). Moreover, eighty percent of VGX-3100-treated women who regressed their lesion also eradicated the infecting HPV genotype (i.e. 16 or 18) in the cervix. This is an important outcome as persistence of the virus is associated with recurrence of the disease. All data analyzed per protocol or modified intent to treat were similar with equal statistical significance.

Analyses of patient immune responses showed that overall antigen-specific T cell levels in women treated with VGX-3100 were greater than those treated by placebo at all observation periods. At week 14, T cell levels in women treated with VGX-3100 were ten times greater than those in the placebo group.

Patients who regressed their lesions had higher frequencies of HPV-specific CD8+T cells which co-expressed key molecules important in T cell killing cascade and directly correlated with clinical efficacy. Specifically, we determined that higher levels of CD8+ killer T cells which co-expressed checkpoint molecule CD137 on their surface as well as the cytolytic protein perforin could be a predictive tool for efficacy. As a strong activation marker for CD8+ T cells, stimulation through CD137 has been shown in some systems to confer resistance of CD8+ T cells to the suppressive activity of regulatory T cells and its presence can identify tumor reactive T cells. Perforin is a pore-forming protein deployed by killer T cells to bore holes into the target cell’s plasma membrane and destroy the cell. In fact, the difference in frequencies of CD8+ cells expressing CD137 and perforin was greatest in patients who had both regressed their lesions and cleared HPV compared to patients who did not.

This is the first publication to our knowledge that demonstrates the correlation of antigen-specific CD8 T cells directly to clinical efficacy. Inovio has successfully identified several key biomarkers of killer T cells which can be used to predict the clinical efficacy of VGX-3100 as well as other immunotherapies in future clinical studies.

About VGX-3100

Inovio’s VGX-3100 is an immunotherapy containing two DNA plasmids targeting the E6 and E7 oncogenes of HPV types 16 and 18. These oncogenes are responsible for transforming HPV-infected cells into pre-cancerous and cancerous cells. The treatment is administered to patients by injection into muscle (typically in the arm), followed by electroporation using Inovio’s CELLECTRA device. VGX-3100 has been shown to induce a robust immune response against the E6 and E7 oncogenes associated with HPV types 16 and 18.

About HPV and Cervical Dysplasia

Human papillomavirus (HPV) is the most common sexually transmitted disease. At any given time, approximately 11% percent of the world population is infected with HPV. Roughly 75% or less of HPV 16/18 infections are cleared by naturally occurring immune responses in women of all ages.

Persistent HPV infection can lead to dysplasia, or premalignant changes, in cervical cells. HPV types 16 and 18 cause 70% of cervical dysplasia and cervical cancer cases. Each year in the United States, 1.4 million women are diagnosed with CIN1 and 300,000-400,000 women are diagnosed with CIN 2/3. All cervical cancers arise from untreated CIN2/3.

On September 17, 2015 Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory and cancer diseases, reported the U.S. Food and Drug Administration (FDA) has granted the Company’s drug candidate CF102 Fast Track designation as a second line treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer (Filing, 6-K, Can-Fite BioPharma, SEP 17, 2015, View Source [SID:1234507485]). CF102 had already received the FDA’s Orphan Drug designation.

Can-Fite is currently conducting a Phase II study for this indication in the U.S., Europe and Israel. The randomized, double blind, placebo controlled study is expected to complete enrollment by the end of the first half of 2016 in 78 patients with Child-Pugh Class B cirrhosis who failed the only FDA approved drug on the market, Nexavar (sorafenib). Patients are treated twice daily with 25 mg of oral CF102, which has been found to be the most efficacious dose in Can-Fite’s earlier Phase I/II study resulting in the longest overall survival time, with excellent safety results.

Fast Track, aimed at getting important new drugs that meet an unmet need to patients earlier, is expected to expedite the development of CF102. Drugs that receive Fast Track designation benefit from more frequent meetings and communications with the FDA to review the drug’s development plan to support approval. It also allows the Company to submit parts of the New Drug Application (NDA) on a rolling basis for review as data becomes available. Since the Fast Track Program started, from March 1998 through June 30, 2015 a total of 318 Fast Track applications have been received by the FDA. The FDA has granted 202 of them, and denied 110, with 6 more pending.

"We are very pleased that the FDA recognizes the potential for CF102 to treat HCC patients who have tried, and not been responsive to Nexavar, the only FDA approved drug currently on the market for this indication," stated Can-Fite CEO Dr. Pnina Fishman. "We consider Fast Track designation to be a major catalyst for our CF102 development program and we believe it could shorten our time to market for CF102, thereby making a considerable difference for patients."

According to Global Industry Analysts, the global market for liver cancer drugs is projected to exceed $2 billion in 2015. Nexavar annual sales, as reported by Bayer, were €773 million in 2014.

About CF102

CF102 is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). A3AR is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. In Can-Fite’s pre-clinical and clinical studies, CF102 has demonstrated a robust anti-tumor effect via deregulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells.

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