On June 2, 2016 Kite Pharma, Inc. (NASDAQ: KITE) ("Kite") and Cell Design Labs, Inc. reported a research collaboration and license agreement to develop next generation, precision-controlled chimeric antigen receptor (CAR) product candidates that incorporate Cell Design Labs’ molecular "on/off switch" technology (Press release, Kite Pharma, JUN 2, 2016, View Source [SID:1234512956]).

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The use of CARs to redirect T-cells against B-cell malignancies has shown promise as a powerful tool to eradicate cancers. The switch technology employs small molecule-mediated protein dimerization domains to functionally activate the CAR and, similarly, to turn "off" the CAR in the absence of the small molecule. By incorporating "on/off switches" into next generation CAR products, physicians will have the potential to rapidly control and reversibly titrate the activity of CAR T-cells.

Under the agreement, Cell Design Labs will develop "on/off switches" for Kite’s CAR T-cell pipeline. Kite will receive exclusive worldwide rights to develop and commercialize CAR T-cell therapies containing Cell Design Labs’ "on/off switches" directed to certain targets for the treatment of acute myeloid leukemia (AML). Kite also has the exclusive option to develop and commercialize CAR T-cell products containing "on/off switches" directed to certain targets for the treatment of B-cell malignancies.

"Cell Design Labs was established to deploy exciting advances in synthetic biology to build and control cell signaling networks through our "on/off switch" technology," said Brian Atwood, Co-founder, President, and Chief Executive Officer of Cell Design Labs. "Our platform takes advantage of the modular design of CARs that we believe will create a next generation of CARs whose activation can be titrated or switched on and off by using small molecules that are clinically available. We look forward to working with Kite, a company whose deep understanding of CAR T-cell biology and manufacturing has already generated advanced clinical programs for cancer patients."

"Kite remains highly focused on accessing important technologies that could augment the activity and/or improve the safety of our engineered T-cell therapy candidates," said Arie Belldegrun, M.D., FACS, Chairman, President, and Chief Executive Officer of Kite. "Cell Design Labs has developed an elegant approach to designing CARs. Our collaboration with Cell Design Labs exemplifies Kite’s commitment to bringing the next generation CAR T-cell immunotherapies to patients."

Under the terms of the agreement, Kite will pay Cell Design Labs an upfront payment and additional payments to support Cell Design Labs’ research. Cell Design Labs will be eligible to receive milestone payments based upon the successful achievement of pre-specified research, clinical, regulatory and commercial milestones, as well as tiered royalties on product sales. Kite has increased its equity investment in Cell Design Labs as part of Cell Design Labs’ recent private financings. Arie Belldegrun will join the Board of Directors of Cell Design Labs and David Chang, M.D., Ph.D., Executive Vice President, Research & Development, and Chief Medical Officer of Kite, will join as a Board Observer.

On June 2, 2016 Novartis reported that the European Commission has approved Afinitor (everolimus) tablets for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin in adults with progressive disease (Press release, Novartis, JUN 2, 2016, View Source [SID:1234512955]). Afinitor is the first approved therapy in all 28 member states of the European Union (EU), plus Iceland and Norway, for this type of lung NET, and one of very few treatment options available for this type of GI NET.

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"With this decision, Afinitor is now approved in the EU to treat the three most common types of advanced NET," said Bruno Strigini, President, Novartis Oncology. "As a company that has long been dedicated to advancing care for NET patients, we are pleased that this latest milestone makes Afinitor available to patients in the EU who previously had few or no approved treatment options."

Neuroendocrine tumors are a type of cancer that originate in neuroendocrine cells throughout the body, and most commonly arise in the GI tract, lungs or pancreas[1],[4]. NET can be defined as functional or nonfunctional[5]. The majority of patients with NET (72%) have nonfunctional NET, which are characterized by symptoms caused by tumor growth, such as intestinal obstruction, pain and bleeding for GI NET, and asthma, chronic obstructive pulmonary disease and pneumonia for lung NET[5],[6],[7],[8],[9]. In contrast, functional NET are characterized by symptoms caused by the oversecretion of hormones and other substances[5]. Five to 44% (depending on site of tumor origin) of those with GI NET and 28% of those with lung NET have advanced disease at time of diagnosis, meaning the cancer has spread to other areas of the body, and patients face limited treatment options[1],[4]. Progression, or the continued growth or spread of the tumor, is typically associated with poor prognoses[10].

The EU approval of Afinitor was based on efficacy and safety data from a pivotal Phase III study (RADIANT-4) evaluating Afinitor versus placebo in patients with advanced, progressive, well-differentiated nonfunctional NET of GI or lung origin. Results showed that Afinitor reduced the risk of disease progression by 52% (hazard ratio = 0.48; 95% confidence interval [CI], 0.35-0.67; p<0.00001) compared to placebo. The data also showed Afinitor increased median progression-free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95% CI, 9.2-13.3) in the Afinitor arm and 3.9 months (95% CI, 3.6-7.4) in the placebo arm[3].

In the pivotal trial, the most common treatment-related, all-grade adverse events (AEs) (incidence >=20%) for Afinitor and placebo, respectively, were stomatitis (63% vs 19%), diarrhea (31% vs 16%), fatigue (31% vs 24%), infections (29% vs 4%), rash (27% vs 8%) and peripheral edema (26% vs 4%). The most common treatment-related grade 3/4 AEs (incidence >=5%) for Afinitor versus placebo were stomatitis (9.0% vs 0.0%), diarrhea (7.0% vs 2.0%) and infections (7.0% vs 0.0%)[3].

In February 2016, the US Food and Drug Administration approved Afinitor for the treatment of adult patients with progressive, well-differentiated nonfunctional NET of GI or lung origin that are unresectable, locally advanced or metastatic. In April 2016, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Afinitor tablets for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) nonfunctional NET of GI or lung origin in adults with progressive disease. Afinitor received approval for this indication in Canada in May 2016, and additional worldwide regulatory filings are underway.

About RADIANT-4 Study: Part of the largest clinical trial program in advanced NET
RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. It examined the efficacy and safety of Afinitor plus best supportive care (BSC) vs placebo plus BSC in 302 patients with unresectable, progressive, well-differentiated nonfunctional, locally advanced or metastatic NET of GI (excluding pancreatic) or lung origin. The primary endpoint of RADIANT-4 was PFS based on independent radiological assessment evaluated by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival and best overall response rate (defined as complete response plus partial response)[3].

Patients were randomized 2:1 to receive a daily dose of Afinitor 10 mg or placebo (supplied as tablets). During treatment, all patients received BSC, which excluded somatostatin analogues (SSAs). Patients had low or intermediate grade histology, no history or active symptoms of carcinoid syndrome, and documented disease progression within the previous 6 months, and were required to have stopped treatment with SSAs for 4 weeks before study entry[3],[11].

The safety profile of Afinitor was consistent with what has been observed in previous studies of this drug[3].

About Afinitor (everolimus) tablets
Afinitor (everolimus) tablets is approved in in more than 110 countries, including the US and in the European Union, for locally advanced, metastatic or unresectable progressive NET of pancreatic origin. Afinitor is not indicated for the treatment of patients with functional carcinoid tumors in the US. Afinitor is now also approved in the US and EU for the treatment of adult patients with progressive, well-differentiated (Grade 1 or Grade 2), nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable, locally advanced or metastatic.

It is also approved in more than 120 countries including the US and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy (in the US, specifically following sunitinib and sorafenib).

Additionally, Afinitor is approved in more than 110 countries including the United States and European Union for advanced HR+/HER2- breast cancer in combination with
exemestane, after prior endocrine therapy.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor or Votubia, Certican and Zortress and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

On June 2, 2016 Medivation, Inc. (NASDAQ: MDVN) and Astellas Pharma Inc. (TSE: 4503) reported plans to commence a Phase III clinical trial to investigate the use of enzalutamide for the treatment of triple-negative breast cancer (TNBC) (Press release, Medivation, JUN 2, 2016, View Source [SID:1234512954]).

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The ENDEAR (A Phase III, Randomized, International Study Comparing the Efficacy and Safety of ENzalutamiDe in Combination With PaclitaxEl Chemotherapy or as Monotherapy Versus Placebo With Paclitaxel in Patients With Advanced, Diagnostic-Positive, Triple-Negative BReast Cancer) trial will evaluate the efficacy and safety of enzalutamide in combination with paclitaxel chemotherapy or as monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC whose tumors test positive for a novel gene expression profile, which is referred to as diagnostic-positive TNBC. The trial, which will be led by Medivation, is expected to begin patient enrollment in the fourth quarter of 2016.

In the United States, breast cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer deaths in women. According to the American Cancer Society, approximately 246,000 new cases of breast cancer will be diagnosed in women and 40,000 women will die of breast cancer in 2016.1 Approximately 15-20 percent of breast cancers are triple negative or basal-like, the subtype that the ENDEAR trial will study.2 Patients with TNBC have a poor prognosis3 and there are currently no therapies specifically approved to treat this patient population.

"Our initiation of this trial represents our commitment to explore the potential of enzalutamide in patients with advanced TNBC," said Mohammad Hirmand, M.D., interim chief medical officer, Medivation.

"The initiation of the ENDEAR trial reflects our ongoing commitment to investigate the full clinical utility of enzalutamide," said Claire Thom, Pharm D., senior vice president and oncology therapeutic area head, Astellas.

Enzalutamide, which is known by the brand name XTANDI, is not approved for use in patients with TNBC.

About ENDEAR
ENDEAR will be a Phase III, randomized, international trial, enrolling approximately 780 patients with advanced diagnostic-positive TNBC who have received either no or one prior line of systemic therapy for advanced disease. The primary efficacy endpoint is progression-free survival (PFS), defined as the time from randomization to the first evidence of disease progression or death, whichever occurs first. The trial will evaluate enzalutamide at a dose of 160 mg per day taken orally, either with paclitaxel (90 mg/m2) administered intravenously once weekly for 16 weeks (or longer at investigator discretion), or as monotherapy compared to placebo with paclitaxel.

About XTANDI (enzalutamide) capsules
XTANDI (enzalutamide) capsules are an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors as well as inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this MOA is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

Important Safety Information

Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions

Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from two combined clinical studies that occurred more commonly (≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.

On June 2, 2016 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported it has entered into a research agreement with Leiden University Medical Center (LUMC), Netherlands, to discover and validate natural high-affinity TCR (T cell receptor) product candidates targeting several cancers (Press release, Bellicum Pharmaceuticals, JUN 2, 2016, View Source [SID:1234512952]). The new collaboration builds on an earlier agreement with LUMC that gave Bellicum worldwide rights to TCR product candidates targeting solid tumors that express PRAME (preferentially-expressed antigen in melanoma) and other antigens.

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"We are enthusiastic about the potential of TCRs that incorporate our switch technology to produce a targeted, potent and controlled attack on certain cancers," said Tom Farrell, President and Chief Executive Officer of Bellicum Pharmaceuticals. "Dr. Mirjam Heemskerk and her group from the Department of Hematology of the LUMC, have made significant breakthroughs in the development of natural high-affinity TCRs, and we look forward to their continued discoveries as we prepare to launch clinical studies this year of our first TCR, BPX-701, under our current license from Leiden."

Under terms of the new collaboration, Bellicum will provide financial support to LUMC over a three-year term in exchange for the right to exclusively license any high-affinity TCRs discovered under the agreement.

TCRs are engineered T cells that become activated in the presence of cancer cells containing a target antigen. Bellicum’s first TCR product candidate, BPX-701 targeting PRAME, is expected to enter Phase 1/2 clinical trials in mid-2016 to treat refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). BPX-701 was licensed from Leiden in 2015 and incorporates Bellicum’s proprietary safety mechanism, CaspaCIDe, for improved control over the cells.

On June 1, 2016 Oncternal Therapeutics, Inc. and Tokalas, Inc., reported that the two companies have completed a merger to create a new world-class clinical-stage oncology company with two promising, first-in-class pipeline products (Press release, Oncternal Therapeutics, JUN 2, 2016, View Source [SID:1234512921]). The transaction was approved by both companies’ shareholders, and results in the combination of all assets, research and developments programs and operations under the name Oncternal Therapeutics, Inc.

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"We are merging two San Diego companies developing clinical-stage therapeutic candidates against novel and important cancer targets, creating an exciting new oncology company with a clinical-stage pipeline spanning multiple technologies and cancer indications," said Dr. James Breitmeyer, President and CEO. "Common regulatory and development strategies result in significant synergies for the combined company. Our highly experienced management team will lead Oncternal forward and rapidly advance our two products, cirmtuzumab and TK216, into additional clinical trials for some of the most devastating and underserved forms of cancer."

The Oncternal board of directors and management team has extensive experience in the formation and successful development of biotechnology companies and innovative pharmaceutical products. The company announced key leadership appointments including:

President and CEO will be James B. Breitmeyer, M.D. and Ph.D., an oncologist with over 25 years in the industry who has led efforts resulting in approval of eight US or international product approvals.
The board of directors will be chaired by Dave Johnson, who most recently led Acerta to a strategic transaction with AstraZeneca valued at up to $7 billion. The other initial board members will be David Hale, Cam Garner, Scott Glenn, and James Breitmeyer, who have been involved in founding and/or developing over thirty successful life sciences companies.

As a combined company, Oncternal Therapeutics will hold exclusive worldwide development and commercialization rights to two clinical-stage oncology products with potential across a range of cancer indications:

Cirmtuzumab, a first-in-class anti-ROR1 monoclonal antibody, currently in a phase 1 clinical trial for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Cirmtuzumab was developed by Thomas Kipps, M.D. at the Moores Cancer Center of UC San Diego, who conducted extensive research to characterize the function and expression of ROR1, which may identify cancer stem cells in a number of hematologic malignancies and solid tumors. Oncternal and UC San Diego are planning studies in CLL, breast cancer and mantle cell lymphoma this year. Oncternal also has rights to develop antibody-drug conjugates (ADCs), genetically modified effector immune cells, such as chimeric antigen receptor T-cells (CAR-T), and bispecific antibodies related to ROR1.

TK216, a first-in-class small molecule ets-family transcription factor inhibitor, about to enter phase 1 testing for patients with Ewing sarcoma. TK216 is based upon the discoveries of Jeffrey A. Toretsky, M.D. at Georgetown University, who conducted extensive research on the ets-family oncogenic translocations that cause or drive tumor growth in a number of solid and hematologic malignancies. Oncternal and Georgetown are planning clinical studies in Ewing sarcoma, glioblastoma and prostate cancer in the next year.