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NantKwest Announces Achievement of End Point in Merkel Cell Carcinoma Phase II Trial With Evidence of Efficacy of Activated Natural Killer (aNK) Cells in Solid Tumors

On November 14, 2016 NantKwest Inc. (Nasdaq:NK), a pioneering, next generation, clinical-stage immunotherapy company focused on harnessing the unique power of the immune system using natural killer (NK) cells to treat cancer, infectious diseases and inflammatory diseases, reported a presentation of early analysis of the Company’s ongoing Phase II Merkel cell carcinoma study at the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) held November 9-13, 2016, in National Harbor, Maryland (Press release, NantKwest, NOV 14, 2016, http://ir.nantkwest.com/phoenix.zhtml?c=254059&p=RssLanding&cat=news&id=2222275 [SID1234516596]).

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NantKwest’s presentation on Friday, November 11th, Adoptive Cellular Therapy (ACT) With Allogeneic Activated Natural Killer (aNK) Cells in Patients With Advanced Merkel Cell Carcinoma (MCC): Preliminary Results of a Phase 2 Trial, highlighted interim results from the Company’s ongoing Phase II clinical study of the Company’s investigational aNK natural killer cell therapy in Merkel cell carcinoma. Dr Shailender Bhatia from Fred Hutchinson Cancer Research Center presented the first evidence of a radiological complete response following single agent aNK infusion in a patient with recurrent disease after multiple lines of therapy including relapse after checkpoint inhibitor therapy.

Merkel cell carcinoma is a rare and aggressive skin cancer that is increasing in incidence. Patients with metastatic or locally advanced Merkel cell carcinoma have an extremely poor prognosis with less than 20% of patients surviving longer than five years.

Commenting on the results, Patrick Soon-Shiong, MD, Chairman and CEO of NantKwest, said the following: "We are encouraged to see, even in a heavily pretreated patient population, including patients who have failed checkpoint inhibitor therapy, that our aNK natural killer cell therapy exhibited clinically meaningful antitumor activity, including a promising radiological complete response in one patient, and we look forward to the rapid development of our aNK program in Merkel cell carcinoma. In addition, through our clinical development program, we strive to bring the potential for long-term survival to a broad range of cancer patients in a number of additional cancer indications."

Dr. Soon-Shiong continued, "We believe this data, while a small data set, provides the foundation to submit to the FDA our plans to transition this trial to a pivotal study. Subject to FDA authorization, this transitional study will include our aNK cell therapy in combination with ALT-803, an investigational IL-15 superagonist complex shown to synergistically activate NK and T cells in human clinical trials and currently in development by Altor Biosciences. We believe this novel combination offers the potential to further improve response rates and bring NantKwest’s natural killer cell therapy one step closer to routine clinical cancer care in a patient population in urgent need of better treatment options."

About NantKwest

Pfizer to Collaborate with National Cancer Institute to Study Three Immunotherapy Agents Targeting Multiple Cancers

On November 14, 2016 Pfizer Inc. (NYSE:PFE) reported that it has entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) (Press release, Pfizer, NOV 14, 2016, View Source [SID1234516593]). As part of the CRADA, Pfizer will collaborate with NCI’s Center for Cancer Research (link is external) (CCR) to arrange and conduct preclinical and clinical trials to evaluate three investigational immunotherapy agents. These include Pfizer’s proprietary immunotherapy agonistic monoclonal antibodies targeting OX40 (CD134), (also known as PF-04518600); and utomilumab, targeting 4-1BB (CD137), (also known as PF-05082566); as well as avelumab, a fully human anti-PD-L1 IgG1 monoclonal antibody (also known as PF-06834635 and MSB0010718C), which is being developed through an alliance between Merck KGaA, Darmstadt, Germany, and Pfizer.

The collaborative preclinical and clinical studies will be co-led by Dr. Jeffrey Schlom, chief of the Laboratory of Tumor Immunology and Biology at CCR, Dr. James Gulley, chief of the Genitourinary Malignancies Branch (link is external) at CCR, and Dr. Chris Boshoff, Senior Vice President and Head of Immuno-oncology, Translational Oncology and Early Development, Pfizer Global Product Development. Under the CRADA, the three investigational immunotherapies will be studied alone, in various combinations with each other, and in combination with standard therapies, such as chemotherapy, radiation and targeted therapies across a range of cancers.

"We are looking forward to combining our expertise with those at the NCI to explore agents targeting the immune system in doublet and triplet combinations. Clinical studies focused on translational endpoints will allow us to optimally develop potential rational combinations," said Chris Boshoff. "The CRADA is an important collaboration for us as we seek to realize the full potential of immunotherapy and hope to ultimately transform the cancer treatment paradigm."

Beyond this collaboration, Pfizer is advancing these and other assets from its growing immuno-oncology portfolio with single agent and novel combination studies, both internally and through other collaborations.

Ignyta Announces Six Upcoming Presentations at the 2016 EORTC-NCI-AACR Annual Meeting

On November 14, 2016 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported six data presentations at the 2016 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Molecular Targets and Cancer Therapeutics Symposium in Munich, Germany (Press release, Ignyta, NOV 14, 2016, View Source [SID1234516588]).

One poster presentation will include updated clinical safety and efficacy data from the Phase 1b basket study of RXDX-105, the company’s VEGFR-sparing, potent RET inhibitor.

The company’s data that examine a novel combination of entrectinib — the company’s orally available, CNS-penetrant tyrosine kinase inhibitor targeting tumors that harbor TRK, ROS1 or ALK fusions — with trametinib, designed to overcome drug resistance to TRK inhibition, will be presented as a late-breaking oral plenary presentation.

The company also announced four additional poster presentations related to its robust pipeline of molecularly targeted oncology therapies — entrectinib, RXDX-105, and RXDX-106. These will be the first data Ignyta has disclosed for RXDX-106, and the data presented in the posters highlight both immuno-therapeutic and targeted activity of this novel agent.

"We are excited to provide updated clinical and preclinical data across multiple compounds from our cancer precision medicine pipeline," said Pratik Multani, M.D., Ignyta’s Chief Medical Officer. "In particular, the team is excited to present new clinical data on RXDX-105, and is honored that the ENA Scientific Program Committee has chosen entrectinib for an oral plenary presentation."

Details of the presentations are as follows:

Late-Breaking Oral Plenary Presentation:

Title:
Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside (Abstract number 8LBA)
Presenter: Alexander Drilon, M.D., Memorial Sloan Kettering Cancer Center
Date/Time: Plenary Session 8: Exceptional Response and Expected Resistance

Friday, December 2, 2016, 10:30 am CET

Poster Presentations:

Entrectinib
Title:
Entrectinib, a highly potent pan-Trk, ROS1, and ALK inhibitor, has broad-spectrum, histology-agnostic anti-tumor activity in molecularly defined cancers (Abstract number 78, Poster number P049)
Date/Time: Tuesday, November 29, 2016, 11:45 am – 18:30 pm CET

RXDX-105
Title:
A phase 1/1b study of RXDX-105, an oral RET and BRAF inhibitor, in patients with advanced solid tumors (Abstract number 437, Poster number P116)
Date/Time: Thursday, December 1, 2016, 10:15 am – 17:00 pm CET

Title:
RXDX-105 demonstrates anti-tumor efficacy in multiple preclinical cancer models driven by molecular alterations in RET or BRAF oncogenes (Abstract number 85, Poster number P056)
Date/Time: Tuesday, November 29, 2016, 11:45 am – 18:30 pm CET

RXDX-106
Title:
Immuno-oncologic efficacy of RXDX-106, a selective, TAM family small molecule kinase inhibitor (Abstract number 65, Poster number P036)
Date/Time: Tuesday, November 29, 2016, 11:45 am – 18:30 pm CET

Title:
RXDX-106 is an orally-available, potent and selective TAM/MET inhibitor demonstrating preclinical efficacy in MET-dependent human malignancies (Abstract number 73, Poster number P044)
Date/Time: Tuesday, November 29, 2016, 11:45 am – 18:30 pm CET

A copy of the presentation and posters will be made available during the sessions in the Scientific Presentations section of the company’s website at View Source, and will be archived and available at that site.

Celldex Presents Data on New Product Candidate, CDX-1140, a Novel CD40 Agonist Antibody

On November 14, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported data on new product candidate CDX-1140, a fully human antibody targeted to CD40 that has demonstrated potent agonist activity (Press release, Celldex Therapeutics, NOV 14, 2016, View Source [SID1234516583]). Found on antigen presenting cells, such as dendritic cells, macrophages and B cells, CD40 is a key activator of the immune response. The data were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (SITC) (Free SITC Whitepaper) on Saturday, November 12 in a poster titled "Functional characterization of CDX-1140, a novel CD40 antibody agonist for cancer immunotherapy." CDX-1140 is expected to be ready to enter clinical studies in 2017.

"The CD40 pathway plays a critical role in the activation of innate and adaptive immune responses," said Tibor Keler, Ph. D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "We believe an ideal CD40 immunotherapy candidate should have the right balance of agonist activity and safety profile to allow systemic dosing at levels that provide good tissue and tumor penetration. The data presented at SITC (Free SITC Whitepaper) show that CDX-1140 has a unique profile to meet this goal relative to other CD40 agonist antibodies and will be an important addition to our growing immunotherapy pipeline."

The poster features detailed analyses of the preclinical data and is available on the "Publications" page of the "Science" section of the Celldex website. Key findings include:

CDX-1140 binds CD40 with high affinity and specificity and does not block CD40 ligand binding
CDX-1140 has an unmodified IgG2 backbone and demonstrates potent agonist activity independent of Fc receptor interactions
CDX-1140 demonstrates direct anti-tumor activity in immune-deficient mice challenged with human lymphomas
Pharmacological activity was observed in vivo with minimal evidence of toxicity
Celldex is currently performing manufacturing and IND-enabling studies to support Phase 1 dose-escalation studies. The Company believes that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies or conventional cancer treatments.

Novartis drug PKC412 (midostaurin) granted FDA Priority Review for newly-diagnosed FLT3-mutated AML and advanced systemic mastocytosis

On November 14, 2016 Novartis reported that the US Food and Drug Administration (FDA) granted Priority Review to the PKC412 (midostaurin) new drug application (NDA) for the treatment of acute myeloid leukemia (AML) in newly-diagnosed adults with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of advanced systemic mastocytosis (SM) (Press release, Novartis, NOV 14, 2016, View Source [SID1234516572]). The premarket approval application (PMA) for the PKC412 (midostaurin) FLT3 companion diagnostic, developed in collaboration with Invivoscribe Technologies, Inc. (IVS)* has also been accepted for review by the FDA. Outside the US, the marketing authorization application for PKC412 (midostaurin) in these indications has already been accepted by the European Medicines Agency (EMA).

"FLT3-mutated AML and advanced SM are devastating and rare diseases, with significant unmet needs due to limited existing treatment options," said Bruno Strigini, CEO, Novartis Oncology. "This regulatory designation signifies the importance of midostaurin as a potential therapy for these patients who haven’t had the benefit of targeted medicines."

The NDA submission for PKC412 (midostaurin) includes data from the largest clinical trials conducted to date in each indication. In the Phase III RATIFY trial (CALGB 10603), which investigated PKC412 (midostaurin) plus standard chemotherapy versus placebo plus standard chemotherapy in adult patients less than 60 years of age with FLT3-mutated AML, those in the PKC412 (midostaurin) arm experienced a statistically significant improvement in overall survival (OS) with a 23% reduction in risk of death compared to the placebo arm (hazard ratio [HR] = 0.77, P = 0.0074)[1]. Based on these data, PKC412 (midostaurin) was also granted Breakthrough Therapy designation by the FDA earlier this year for newly-diagnosed FLT3-mutated AML.

In the RATIFY trial, no statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events (AEs) in the PKC412 (midostaurin) treatment group versus the placebo group[5]. The most frequent all grade AEs were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae (small red skin spots) and pyrexia[5]. A total of 36 deaths occurring within 30 days of the last dose of study drug were reported, with no difference in treatment-related deaths observed between groups[5].

Data from the Phase II single-arm study (CPKC412D2201) evaluating the efficacy of PKC412 (midostaurin) in patients with advanced SM were also published in the New England Journal of Medicine in June 2016. The study showed that treatment with PKC412 (midostaurin) resulted in an overall response rate of 60% (defined as complete or partial resolution of organ damage) with a median duration of response of 24.1 months (95% CI, 10.8-not estimated [NE]) and a median OS of 28.7 months (95% CI, 18.1-NE)[2]. The most frequent AEs were low-grade nausea, vomiting and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred mostly in patients with pre-existing cytopenias[2].

A Priority Review designation is granted by the FDA to therapies that may provide significant improvements in the treatment, diagnosis or prevention of serious conditions[3]. According to the FDA, the goal is to take action on a Priority Review application within six months, compared to 10 months under the standard review process[3]. Novartis has been granted a growing number of Priority Review designations by the FDA, underscoring the company’s ongoing commitment to developing innovative therapies for rare diseases or underserved cancer patients.

Since PKC412 (midostaurin) remains investigational at this time, both within the US and globally, Novartis opened a Global Individual Patient Program (compassionate use program) and in the US, an Expanded Treatment Protocol, to enable access to eligible patients with newly-diagnosed AML and advanced SM. Physicians who wish to request PKC412 (midostaurin) for eligible patients should contact a Novartis medical representative in their respective countries. In the US, physicians can call 1-888-NOW-NOVA (1-888-669-6682) for more information.

About AML and the FLT3 mutation
AML is a rare and aggressive cancer of the blood and bone marrow[6]. It is the most common acute leukemia in adults[7]. Of the approximately 350,000 people with leukemias worldwide[8], about 25% have AML[7]. AML has a low survival rate, with around 25% of patients surviving at 5 years[9].

AML is associated with the accumulation of blood cells that are unable to mature properly, causing a buildup of immature "blast" cells that do not allow room for normal blood cell development[6]. Mutations in specific genes are found in many cases of AML, and molecular testing is recommended for newly-diagnosed patients to help determine prognosis and best possible treatment[4].

FLT3 is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells. The FLT3 gene mutation is one of the most common in AML, occurring in about one-third of patients, and commonly results in faster disease progression, a higher relapse rate and shorter survival[10]-[12].

About the FLT3 companion diagnostic
In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412 (midostaurin), Novartis is collaborating with IVS for the development and FDA approval of the FLT3 companion diagnostic. The same test is being CE marked in Europe. Regulatory submissions for the companion diagnostic are being led by IVS.

About advanced SM
Systemic mastocytosis (SM) comprises a group of rare diseases, affecting between 1 in 20,000 to 40,000 people worldwide[13]. The disease is characterized by uncontrolled growth and accumulation of mast cells – or mediators of allergic responses – in one or more organs[14]. In advanced SM, mast cells accumulate in such high quantities that they begin to cause organ damage[15]. Patients also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin), among other symptoms, caused by mast cells releasing inflammatory mediators such as histamine into the blood[15]. Median OS is currently between 3.5 years to less than six months depending on subtype[14].

The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients[16]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[15].

About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor in development for the treatment of patients with AML with a FLT3 mutation and for patients with advanced SM. The safety and efficacy profile has not been fully established, and it is not approved for any indication in any market at this time. There is no guarantee that PKC412 (midostaurin) will become commercially available.