On January 6, 2018 Context Therapeutics, a biopharma company dedicated to developing new medicines for patients with hormone responsive cancers, reported that it has acquired worldwide rights to Apristor (Onapristone XR) (Press release, Context Therapeutics, JAN 16, 2018, View Source [SID1234523265]). Onapristone has been extensively studied and has established efficacy in two Phase 2 metastatic breast cancer clinical trials. In these trials, meaningful clinical benefit and response rates were seen in 120 metastatic breast cancer patients, 101 of whom were actively progressing on Tamoxifen before Onapristone treatment initiation. Onapristone has been studied in over 200 patients, and it was well tolerated with no drug-related serious adverse events.

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Martin Lehr, CEO of Context stated: "We are excited to advance the development of Apristor and to potentially provide a mechanistically novel option for patients diagnosed with metastatic breast cancer. Unfortunately, the median life expectancy of a woman diagnosed with metastatic breast cancer is approximately three years. In the United States alone 40,000 women die each year as a result. These women deserve better, and we are committed to improving their treatment and removing the fear that comes along with this diagnosis."

Apristor blocks the binding of progesterone, a carcinogen, to the progesterone receptor (PR). Up to 70% of metastatic breast cancers express PR and are said to be PR+. If approved, Apristor would provide physicians with a novel product that could be used in combination with standard of care agents targeting the estrogen receptor or as a monotherapy.

Context made a one-time payment to Arno Therapeutics in exchange for the worldwide rights to Apristor. Apristor is a new chemical entity and is protected by a robust patent estate that should provide exclusivity through at least 2034.

Scott Applebaum, President of Context stated: "Context has taken a big leap forward and is now a clinical-stage company. This transformation is consistent with our mission of discovering, developing, and commercializing treatments for hormone-responsive cancers. We are building a world-class global clinical trial organization to bring Apristor to market as fast as possible. In addition, we have an Apristor fast-follower program for progesterone receptor-mediated diseases and continue to advance our preclinical Sigma1 program."

On January 16, 2018 Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company developing tumor-targeted and immuno-oncology therapies based on its pioneering research and development in cancer epigenetics, reported it has initiated a Phase 1b/2 clinical trial to evaluate CPI-1205, a small-molecule inhibitor of Enhancer of Zeste Homolog 2 (EZH2), combined with checkpoint inhibitor ipilimumab (marketed as YERVOY by Bristol-Myers Squibb) and potentially other cancer immunotherapies (Press release, Constellation Pharmaceuticals, JAN 16, 2018, View Source [SID1234523138]). The study, named ORIOn-E, is based on translational insights which identified combination approaches using epigenetics-mediated mechanisms aimed at Overcoming Resistance to Immune Oncology therapies by inhibiting EZH2.

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"This is the second combination study we’ve initiated evaluating the potential for CPI-1205 to overcome resistance mechanisms to existing cancer therapies," said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. "Our preclinical results with CPI-1205 demonstrate that epigenetic targets can be utilized by cancers to suppress the immune system and render immunotherapy treatment options less effective. We aim to build on this insight with CPI-1205 in clinical trials and with other epigenetic therapies that we discover and develop in this important area of research."

CPI-1205 is a potent, highly selective, first-generation small-molecule inhibitor of an enzyme called EZH2. In pre-clinical studies, CPI-1205 has shown potential to re-wire T regulatory and T effector cells within tumors to enhance tumor rejection alone and synergistically in combination with immune checkpoint inhibition.

"Since they were first made available in the U.S., checkpoint inhibitor therapies like ipilimumab have provided considerable benefit for patients with many different cancers. However, many patients do not respond to therapy or relapse after initial response," said Adrian Senderowicz, M.D., senior vice president and chief medical officer of Constellation Pharmaceuticals. "CPI-1205 plays a critical role in inhibiting the suppressive function of regulatory T cells and consequently may address resistance mechanisms that limit the benefit of immune checkpoint inhibitors in patients."

The Phase 1b portion is a dose escalation study designed to evaluate the safety, pharmacokinetics, pharmacodynamics and the assessment of potential predictive biomarkers in patients across solid tumors when treated with CPI-1205 in combination with ipilimumab. The Phase 2 portion will be conducted in melanoma patients, among other cancers.

About CPI-1205
CPI-1205 is a therapeutic candidate from Constellation Pharmaceuticals’ EZH2 portfolio and is an inhibitor of Enhancer of Zeste Homolog 2 (EZH2). The function of EZH2 is to selectively suppress gene expression of several pro-cancer pathways that contribute to drug resistance.

On January 16, 2018 Foundation Medicine, Inc. (NASDAQ:FMI) reported that the company has entered into a broad partnership with Pfizer Inc. (NYSE: PFE)(Press release, Foundation Medicine, JAN 16, 2018, View Source [SID1234523141]) . The partnership focuses on development, regulatory support and commercialization of companion diagnostics (CDx) that will be included in updates to FoundationOne CDx. FoundationOne CDx is Foundation Medicine’s FDA-approved comprehensive genomic profiling (CGP) assay for all solid tumors that incorporates multiple companion diagnostics. Pfizer will also benefit from access to FoundationInsights, Foundation Medicine’s data analytics platform, to facilitate novel biomarker discovery and to optimize clinical trial design. The unique combination of FoundationInsights and FoundationOne CDx will potentially enable Pfizer to leverage Foundation Medicine’s platform technology to accelerate discovery and development of precision oncology therapeutics.

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Pfizer currently has 10 FDA-approved oncology medicines that treat a diverse array of solid tumors and hematologic malignancies. In addition, its oncology pipeline includes 17 assets in clinical development and 19 phase 3 studies.

"Our mission to transform cancer care includes partnering with biopharma companies to expedite development of personalized treatment options for patients. We are proud to partner with Pfizer who shares our commitment to precision oncology and biomarker-driven drug development," said Melanie Nallicheri, chief business officer and head of biopharma at Foundation Medicine. "The combination of our FDA-approved comprehensive genomic profiling platform and molecular information solutions, coupled with Pfizer’s robust oncology portfolio, enables us to enhance the impact of precision oncology to advance patient care."

FoundationOne CDx assesses all classes of genomic alterations in 324 genes known to drive cancer growth, providing potentially actionable information to help guide treatment decisions. It also reports genomic biomarkers, such as microsatellite instability (MSI) and tumor mutational burden (TMB), that can help inform the use of immunotherapies; genomic alterations in other genes relevant to patient management; and relevant clinical trial information. As such, it is designed to help streamline companion diagnostic development, mitigate risk and advance targeted therapy development. Currently FoundationOne CDx is FDA-approved as a CGP assay for all solid tumors and a broad companion diagnostic for patients with certain types of non-small cell lung cancer, melanoma, colorectal cancer, ovarian cancer or breast cancer to identify those patients who may benefit from treatment with one of 17 on-label targeted therapies.

Concurrent with FDA approval, the Centers for Medicare & Medicaid Services (CMS) issued a preliminary National Coverage Determination (NCD) for FoundationOne CDx. The draft NCD would provide coverage for FDA-approved companion diagnostic claims, as well as a pathway for additional coverage with evidence development in other solid tumor types. The final policy is expected to issue during the first quarter of 2018 following public comment on the preliminary NCD and an administrative period.

On January 16, 2018 Linnaeus Therapeutics, Inc. ("Linnaeus"), a privately held biopharmaceutical company focused on the development and commercialization of novel, small molecule oncology therapeutics, reported that preclinical data from studies conducted at the University of Pennsylvania by its scientific founders was published in the journal eLife (Press release, Linnaeus Therapeutics, JAN 16, 2018, View Source [SID1234539506]).

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The paper, entitled "Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade" was authored by Natale, et al.

For decades, research has associated female sex and a history of previous pregnancy with better outcomes after a melanoma diagnosis, but the mechanism for this protective effect has remained a mystery. This publication provides a potential explanation for this melanoma-protective effect. The mechanism is related to a cellular protein called the G protein-coupled estrogen receptor (GPER). When GPER was activated and combined with anti–PD-1 inhibitor drugs in mouse cancer models, the therapy dramatically extended survival in all animals and completely eliminated the tumor in up to 50 percent of the mice.

"The validation of our science by the acceptance of this paper in eLife underscores the importance of the G protein estrogen receptor ("GPER") as a therapeutic target," said Patrick Mooney, M.D., Chief Executive Officer of Linnaeus. "This data clearly demonstrates that using LNS8801 to target GPER should have therapeutic effects in various cancers, and we are excited to move this toward human studies in the future."

On January 16, 2018 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company developing targeted and immuno-oncology therapeutics, reported that the first patient has been dosed in a Phase 1 clinical trial evaluating Leap’s GITR agonist, TRX518, in combination with gemcitabine chemotherapy or in combination with KEYTRUDA (pembrolizumab) or Opdivo (nivolumab), anti-PD-1 therapies marketed by Merck (known as MSD outside the United States and Canada) or Bristol-Myers Squibb, respectively (Press release, Leap Therapeutics, JAN 16, 2018, View Source;p=RssLanding&cat=news&id=2326652 [SID1234523143]).

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"TRX518 has demonstrated the ability to reduce immunosuppressive regulatory T cells and to activate tumor-killing T effector cells in clinical and preclinical studies. The combination of TRX518 with anti-PD-1 immunotherapy has strong scientific rationale and could act synergistically, enabling improved responses without significant additional toxicity. We look forward to evaluating the safety and efficacy of TRX518 in combination with pembrolizumab or nivolumab," commented Diwakar Davar, M.D., Assistant Professor of Medicine of the University of Pittsburgh and an investigator on the study.

"There is strong preclinical evidence for synergistic efficacy when combining immune activators targeting GITR with chemotherapy," commented Cynthia Sirard, M.D., Vice President, Clinical Development of Leap Therapeutics. "This trial represents an important step in our strategy to evaluate the combination activity of TRX518 as a backbone immunotherapy."

The TRX518-003 study is a multipart study evaluating TRX518 as a monotherapy and in combination with gemcitabine, KEYTRUDA (pembrolizumab), or Opdivo (nivolumab) in patients with advanced solid tumor malignancies.

The combination arms evaluating TRX518 with gemcitabine includes both dose escalation and dose confirmation cohorts and are designed to evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of the combination. The study will enroll patients who have metastatic or locally advanced, incurable solid malignancies for which gemcitabine is clinically appropriate (e.g., non-small cell lung, breast, ovarian, pancreatic, and renal cancer). The TRX518 + gemcitabine study will enroll approximately 32 patients.

The combination arms evaluating TRX518 with pembrolizumab or nivolumab includes both dose escalation and dose confirmation cohorts and are designed to evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of the combinations. The study will enroll patients who have received treatment with pembrolizumab or nivolumab for ≥4 months with a best response of stable disease and plans to continue treatment in accordance with package insert; or are not currently taking, but eligible for treatment with, pembrolizumab or nivolumab in accordance with the approved indications for each as referenced in the package insert. The TRX518 + PD-1 antagonist study will enroll approximately 64 patients.

About TRX518
TRX518 is a humanized monoclonal antibody with agonist activity targeting glucocorticord-inducible TNF-superfamily receptor (GITR). TRX518 is engineered to enhance immune responses to cancer. TRX518 is being studied in two ongoing repeat-dose clinical trials in patients with advanced solid tumor malignancies. Data from the trials have shown that patients receiving TRX518 monotherapy achieved durable stable disease with signs of pharmacodynamic activity including CD8+ T cell activation and modulation of immunosuppressive regulatory T cells.