On October 6, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that the U.S. Patent and Trademark Office has issued U.S. Patent No. 9,150,517, entitled "Bendamustine Derivatives and Methods of Using Same (Press release, Ignyta, OCT 6, 2015, View Source [SID:1234507655])." This patent contains claims that cover the composition of matter of Ignyta’s product candidate RXDX-107, and pharmaceutical compositions comprising RXDX-107. RXDX-107 is the company’s new chemical entity, next generation chemotherapeutic comprising an alkyl ester of bendamustine encapsulated in human serum albumin (HSA) to form nanoparticles. The patent has an expiration date of 2033, which does not include any potential patent term extension.

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"The issuance of this patent is an important development relating to maintaining exclusivity for our RXDX-107 product candidate"

"The issuance of this patent is an important development relating to maintaining exclusivity for our RXDX-107 product candidate," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "We believe this patent will be eligible for listing in the FDA’s Orange Book, should RXDX-107 receive FDA approval, and the timing of the issuance is favorable because it allows us to begin accruing a period of patent term extension during the time this product candidate is undergoing clinical development."

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.

In July 2015, the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug application (IND) for RXDX-107. Ignyta has initiated a new Phase 1/1b, multicenter, open-label clinical trial of RXDX-107 in adult patients. This dose-escalation study is designed to determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), tolerability, pharmacokinetics and preliminary clinical activity of RXDX-107 in patients with locally advanced or metastatic solid tumors.

On October 06, 2015 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported that last Thursday the company received verbal notice from the U.S. Food and Drug Administration (FDA) that its Investigational New Drug (IND) application for axalimogene filolisbac (formerly ADXS-HPV) has been placed on clinical hold, affecting four clinical trials (Press release, Advaxis, OCT 6, 2015, View Source [SID:1234507654]).

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The clinical hold, which pertains only to axalimogene filolisbac, was issued in response to Advaxis’s recent submission of a safety report to the FDA. The report involved a single event of one patient with end-stage cervical cancer who last received axalimogene filolisbac in early 2013 in an investigator-initiated trial. In late July 2015, the patient was hospitalized for end-stage cervical cancer symptoms. During hospitalization, routine blood cultures were positive for Listeria monocytogenes (Lm). Subsequent analysis determined that it was the highly attenuated strain of Lm used in axalimogene filolisbac which was incapable of causing infection and was highly sensitive to antibiotics. The patient received a course of intravenous antibiotics and was discharged. The patient returned to the hospital in mid-August, approximately two weeks later, with respiratory distress caused by her metastatic disease. The patient passed away later that day. The investigator ruled that the cause of death was due to progression of her cervical cancer.

The company has evaluated this case and agrees with the investigator’s conclusion that the cause of death was due to cervical cancer progression. The company believes that axalimogene filolisbac played no role in the patient’s death. In investigating this event, Advaxis learned that the patient underwent multiple surgical procedures during the time she was receiving axalimogene filolisbac, including extensive orthopedic reconstruction and receipt of a bone graft and other medical implants. Due to these circumstances, the company believes these implants could have provided a location for axalimogene filolisbac to exist within the body without causing any infection.

Advaxis is working closely with the FDA to facilitate the review and evaluation of this isolated event. The Agency has requested additional information to support a determination that axalimogene filolisbac did not contribute to the patient’s death. This additional information has now been provided to the FDA. Advaxis expects that this clinical hold will be resolved expeditiously and without significant interruption to our HPV clinical development program.

Ongoing clinical trials with Advaxis’s other product candidates, ADXS-PSA and ADXS-HER2, are not affected by this hold and continue to actively enroll and dose patients.

On October 6, 2015 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported the opening of the Phase I/II trial of IPH2201, a first-in-class NKG2A checkpoint inhibitor, tested in combination with ibrutinib in patients with relapsed or refractory Chronic Lymphocytic Leukemia ("CLL") (Press release, Innate Pharma, OCT 6, 2015, View Source [SID:1234507648]). This trial, which will include up to 45 patients, is multicentric and will be performed in the United States.

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Pierre Dodion, Chief Medical Officer of Innate Pharma, said: "HLA-E is expressed by CLL cells of virtually all patients. IPH2201 is a new checkpoint inhibitor targeting both T and NK cells and preventing their inhibition by HLA-E on tumor cells. In addition, ibrutinib has been demonstrated to create a favorable pro-inflammatory environment; this could result in a synergistic effect with the immunomodulating action of IPH2201". He added: "The Ohio State University Comprehensive Cancer Center is a leading center in developing new therapies to cure Chronic Lymphocytic Leukemia. It is a great opportunity for the development of IPH2201 to work with them".

Pr. John Byrd, Director, and Dr Farrukh Awan, Principal Coordinating Investigator, both expert leaders in the field of CLL at the Division of Hematology, Department of Internal Medicine, Ohio State University, said: "Ibrutinib represents a breakthrough medicine that was approved for the treatment of relapsed and del(17(p13.1) CLL in 2014. However, although ibrutinib induces a high response rate in patients with CLL, responses are rarely complete. Ultimately the disease progresses in a number of patients. Achieving complete responses would be of great interest to potentially prolong remission, and maybe eventually improve survival rate. Targeting the immune system in several novel ways is the rationale to combine IPH2201 and ibrutinib in this trial".

This trial is part of a global co-development and commercialization agreement with AstraZeneca for IPH2201. Within this frame, Innate Pharma expects to have four trials opened by the end of 2015. In addition to the CLL trial, two Phase I/II studies are currently ongoing, testing IPH2201 as a single agent respectively in squamous cell carcinoma of the Head and Neck and in Ovarian cancer . The fourth trial, testing IPH2201 in combination cetuximab in patients with Head and Neck cancer, will start in the coming months.

The co-development plan also includes Phase II combination clinical trials with IPH2201 and durvalumab (MEDI4736), a PD-L1 immune checkpoint inhibitor, in solid tumors, which will be performed by AstraZeneca/MedImmune.

About study IPH2201-202:

This Phase Ib/IIa study is a multicenter open label trial of the combination of IPH2201 and ibrutinib in patients with relapsed or refractory Chronic Lymphocytic Leukemia. Its primary objective is to evaluate the anti-leukemic activity of the combination and the primary endpoint for efficacy is complete response rate. The secondary objectives are to assess the safety of the combination of IPH2201 and ibrutinib. The trial will be performed in the United States under the coordination of leading investigators at the Ohio State University.

36 to 45 patients are planned to be enrolled. The trial is conducted in two parts:

In the first part of the study, 12 to 24 patients will receive a combination of ibrutinib at the approved dosage and IPH2201; 4 dose levels of IPH2201 up to 10 mg/kg will be explored. Based on previous experience with IPH2201, these dosages are expected to induce saturation of the NKG2A receptor.

In the second part of the study, IPH2201 at the dose selected in the dose-escalating part will be assessed in combination with ibrutinib during 26 cycles in up to 24 patients.

The rationale of this trial is based on the observation that HLA-E is expressed in virtually all patients with CLL, at higher levels compared to normal B cells (Veuillen, Aurran-Schleinitz et al. 2012). IPH2201 is a NGK2A checkpoint inhibitor that blocks the HLA-E driven inhibition of NK and CD8+ cells. By binding to NGK2A, IPH2201 restores the capability of those cells to destroy tumor cells. Furthermore, ibrutinib has been demonstrated to create a favorable pro-inflammatory environment; this could result in a synergistic effect with the immunotherapeutic action of IPH2201. Thus, treatment with IPH2201 in combination with ibrutinib may improve the quality of response above and beyond that achieved with ibrutinib alone and achieve complete responses; a higher rate of complete response should lead to improved overall survival.

In a Phase I dose-escalation safety trial, IPH2201 was found to be safe and well-tolerated.

About Chronic Lymphocytic Leukemia (CLL):

CLL results from progressive accumulation of morphologically mature B lymphocytes in the blood, bone marrow and lymphatic tissues. In Western countries, CLL is the most common form of leukemia, accounting for about 25% of all leukemias. Incidence increases with age and the median age of diagnosis is 70 for males and 74 for females. It is estimated that 15,720 new cases will occur in 2014 in the US, causing 4,600 deaths (Siegel, Ma et al., 2014).

Ibrutinib, a first in class kinase inhibitor of BCR signaling, has been approved in 2014 for the treatment of patients with CLL who have received at least one prior therapy. Its approval was based on the safety and efficacy results of several trials which have shown mainly partial responses. The indication for ibrutinib was subsequently extended to include CLL with 17p deletion, irrespectively of the line of therapy.

About IPH2201:
IPH2201 is a first-in-class immune checkpoint inhibitor targeting NKG2A receptors expressed on tumor infiltrating cytotoxic CD8 T lymphocytes and NK cells.

NKG2A is an inhibitory receptor binding HLA-E. By expressing HLA-E, cancer cells can protect themselves from killing by NKG2A+ immune cells. HLA-E is frequently up-regulated on cancer cells of many solid tumors or hematological malignancies. IPH2201, a humanized IgG4, blocks the binding of NKG2A to HLA-E allowing activation of NK and cytotoxic T cell responses.

Hence, IPH2201 may re-establish a broad anti-tumor response mediated by NK and T cells. IPH2201 may also enhance the cytotoxic potential of other therapeutic antibodies. IPH2201 is partnered with AstraZeneca and MedImmune, the Company’s global biologics research and development arm, through a co-development and commercialization agreement. The initial
development plan includes: Phase II combination clinical trials with durvalumab (MEDI4736) in solid tumors; multiple Phase II trials planned by Innate Pharma to study IPH2201 both as monotherapy and in combination with currently approved treatments across a range of cancers; and the development of associated biomarkers. As previously announced, under the terms of this agreement, Innate Pharma is eligible to cash payments of up to $1.275 billion as well as double digit royalties on sales. In addition to the initial payment of $250 million to Innate Pharma, AstraZeneca will pay a further $100 million prior to initiation of Phase III development, as well as additional regulatory and sales-related milestones of up to $925 million. AstraZeneca will book all sales and will pay Innate Pharma double-digit royalties on net sales. The arrangement includes the right for Innate Pharma to co-promote in Europe for a 50% profit share in the territory.

On October 6, 2015 GTx, Inc. (Nasdaq: GTXI) reported the enrollment of the first patient into its Phase 2 clinical trial of enobosarm (GTx-024) to treat women with advanced, androgen receptor positive (AR+), triple negative breast cancer (TNBC) (Press release, GTx, OCT 6, 2015, View Source [SID:1234507646]). Enobosarm is the Company’s lead product candidate and is also being evaluated in a separate Phase 2 clinical trial to treat estrogen receptor positive (ER+), AR+ breast cancer, which the Company recently announced had also enrolled its first patient.

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"Most women with triple negative breast cancer have extremely limited treatment options and poor prognoses," said Robert J. Wills, Ph.D., Executive Chairman of GTx. "Based on our preclinical research and positive data from patient-derived and cell line-derived xenografts of TNBC, we are hopeful that enobosarm, by targeting the androgen receptor, may offer another treatment option to women with this disease."

The open-label, multi-center, multinational Phase 2 clinical trial (NCT02368691) will evaluate the efficacy and safety of orally administered enobosarm in up to 55 women with advanced, AR+ TNBC. Patients will receive 18 mg of enobosarm once daily for up to 12 months. The initial stage will be assessed among the first 21 evaluable patients. If at least 2 of 21 patients achieve clinical benefit at week 16, then the trial will proceed to the second stage of enrollment of up to a total of 41 evaluable patients. Clinical benefit is defined as a complete response, partial response, or stable disease, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) at 16 weeks. The trial, which is being conducted under the leadership of Dr. Hope Rugo from the University of California at San Francisco, will include investigators from more than 40 clinical trial sites in the U.S. and abroad.

About enobosarm

Enobosarm, a selective androgen receptor modulator (SARM), has been evaluated in multiple completed or ongoing clinical trials enrolling over 1,500 subjects at doses ranging from 0.1 mg to 100 mg. At all evaluated dose levels, enobosarm was observed to be generally safe and well tolerated.

Most recently, enobosarm 9 mg has been tested in a Phase 2, proof of concept clinical trial of 22 postmenopausal women with ER+ metastatic breast cancer who have previously responded to endocrine therapy. Seventeen of the 22 patients were confirmed to be AR+. Six of these 17 patients demonstrated clinical benefit at six months. Seven patients in total (one patient with indeterminate AR status) achieved clinical benefit at six months. The results also demonstrated that, after a median duration on study of 81 days, 41 percent of all patients (9/22) achieved clinical benefit as best response and also had increased serum PSA levels which may be an indicator of AR activity. Enobosarm was well tolerated. The most common adverse events reported were pain, fatigue, nausea, hot flash/night sweats, and arthralgia.

About Triple Negative Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women and one in eight women will develop invasive breast cancer in their lifetime. In 2012, 1.7 million women were diagnosed with breast cancer, and there were 6.3 million women alive who had been diagnosed with breast cancer in the previous five years. Clinical assessment of breast cancer includes routine characterization of receptor status including the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in the tumor tissue. Receptor status is used to assess metastatic potential as well as to guide treatment decisions. Although the majority of breast cancers are considered hormone receptor positive, expressing ER and/or PR, 15–20 percent of women diagnosed with breast cancer will have triple negative breast cancer (TNBC), which is characterized by a lack of expression of ER, PR, and HER2. TNBC occurs more frequently in younger patients (< 50 years of age) and generally shows a more aggressive behavior. For those patients with advanced TNBC, standard palliative treatment options are limited to cytotoxic chemotherapy. However, even after initial response to chemotherapy, the duration of the response may be short, and there is a higher likelihood of visceral metastases, rapidly progressing disease, and inferior survival compared to hormone positive breast cancer. Therefore, research is focused on identifying therapeutic targets in TNBC.

Studies have demonstrated that up to 50 percent of TNBC will express the androgen receptor. Both preclinical and patient-derived and cell line-derived AR+ TNBC xenografts support the clinical approach of targeting the androgen receptor with enobosarm.