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Kite Pharma Announces That the First Patient in Its Phase 1/2 Clinical Trial Has Been Treated With KTE-C19, Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, for Refractory Aggressive Non-Hodgkin’s Lymphoma (NHL)

On May 21, 2015 Kite Pharma reported that the first patient in its Phase 1/2 clinical trial of KTE-C19 in patients with refractory aggressive NHL has been treated (Press release, Kite Pharma, MAY 21, 2015, View Source [SID:1234504619]). KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

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"This is a very exciting time for Kite, and we’re grateful to the patients and clinical researchers who greatly contribute to the progress of our KTE-C19 program," said Arie Belldegrun, M.D., FACS, Chairman, President and Chief Executive Officer. "We are at a pivotal moment for our Company and for the industry as a whole as we initiate the first company-sponsored clinical trial of CAR T-cell therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL)."

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Dr. Belldegrun continued, "Kite has met its goal of initiating the first company-sponsored clinical trial of KTE-C19 in the first half of this year and plans to commence an additional three trials of KTE-C19 before year-end. Our first study is expected to provide pivotal results in 2016, leading to the potential launch and commercialization of KTE-C19 in 2017."

Kite’s Phase 1/2 clinical trial of KTE-C19 is a single arm, open-label, multi-center study, designed to determine the safety and efficacy of KTE-C19 in patients with refractory DLBCL, primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL). Upon completion of the Phase 1 portion of the study, Kite expects to proceed with the Phase 2 portion that will include a total of approximately 112 patients. Additional information about Kite’s Phase 1/2 study may be found at ClinicalTrials.gov, using Identifier NCT: 02348216.

CytRx Reports Positive Updated Phase 2 Aldoxorubicin Clinical Trial Results in Glioblastoma Multiforme (Brain Cancer)

On May 21, 2015 CytRx reported positive updated results from its ongoing Phase 2 clinical trial with aldoxorubicin for the treatment of unresectable glioblastoma multiforme (GBM), a deadly form of brain cancer (Press release, CytRx, MAY 21, 2015, View Source [SID:1234504616]). The open-label, multisite trial is designed to investigate the preliminary efficacy and safety of aldoxorubicin in patients whose tumors have progressed following prior treatment with surgery, radiation and temozolomide.

Study subjects (n=18) have received between 1 and 14 cycles of aldoxorubicin, with 4 subjects continuing to receive aldoxorubicin treatment. Subjects received either 350 mg/m2 (260 mg/m2 doxorubicin equivalent) (n=6) or 250 mg/m2 (185 mg/m2 doxorubicin equivalent) (n=12) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until discontinuation. Notably, 2 subjects (11%) diagnosed with tumor progression following aldoxorubicin treatment (1 and 5 cycles, respectively) demonstrated no microscopic evidence of tumor tissue, a pathological complete response, when tissue was examined after resection. Fourteen of 18 subjects discontinued aldoxorubicin treatment, although there is a significant possibility that some of the patients experienced pseudo-progression. Pseudo-progression refers to post-treatment imaging changes in the tumor where the tumor appears larger compared to the pre-treatment baseline images. These changes can be misleading in that the tumor appears to get worse (true progression), when in fact the changes may be the result of tumor destruction and related swelling around the tumor bed. Following discontinuation of aldoxorubicin treatment, 10 of 14 subjects received treatment with bevacizumab (Avastin) for 1 to 14 cycles. Deaths have occurred in only 4 of 18 subjects (22%) to date, with survival duration so far of up to 10 plus months.

Aldoxorubicin was well tolerated at both dose levels with all adverse events consistent with known doxorubicin toxicities, but not cardiotoxity. Grade 3 or 4 adverse events were comprised primarily of neutropenia, anemia and fatigue and occurred mainly in the 350 mg/m2 dose group and were resolved before the next dose. Only two aldoxorubicin-related serious adverse events have occurred in the trial, and both resolved successfully.

"GBM is the most common and aggressive malignant primary brain cancer in humans and carries an extremely poor prognosis for the vast majority of diagnosed patients. Prognosis at recurrence is especially poor," said Morris D. Groves, M.D., Neuro-Oncologist, Texas Oncology-Austin Brain Tumor Center and co-principal investigator of the trial. "Pseudo-progression is commonly seen in CNS malignancies undergoing radiation therapy, and it mimics tumor progression, but it is thought to be a treatment-related reaction that could represent an active, inflammatory response against the tumor. The findings from this trial are early but exciting; the finding of no tumor cells in the resected GBM tumor samples after treatment with aldoxorubicin is worth further investigation. This suggests, somewhat paradoxically, that by binding to albumin, aldoxorubicin may allow doxorubicin to cross the blood:brain barrier and into the malignancy."

"These results suggest the possibility that the administration of Avastin after treatment with aldoxorubicin could prolong survival in patients with relapsed GBM, and patient follow up is currently ongoing," said Daniel Levitt, M.D., Ph.D., CytRx Executive Vice President and Chief Medical Officer. "At the upcoming 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, we will be convening with the study investigators to discuss the potential for a pivotal trial evaluating aldoxorubicin in combination with Avastin for the treatment of relapsed GBM, with survival as the primary endpoint. We also look forward to submitting the results from this ongoing Phase 2 clinical trial for presentation at a neuro-oncology-focused medical meeting in 2015."

The primary objective of this Phase 2 trial is to determine progression-free survival (PFS) at 6 months and overall survival (OS) in patients with recurrent glioblastoma multiforme. The principal secondary objective is to evaluate the safety of aldoxorubicin in study patients as assessed by the frequency and severity of adverse events. Only patients who have not received prior treatment with bevacizumab (Avastin) are eligible to participate in the trial. The clinical trial is expected to enroll up to 28 patients randomly assigned equally to receive either 350 mg/m2 (260 mg/m2 doxorubicin equivalent) or 250 mg/m2 (185 mg/m2 doxorubicin equivalent) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until evidence of tumor progression, unacceptable toxicity or withdrawal of consent. Tumor response is monitored every 6 weeks by MRI until disease progression occurs. The trial is being conducted at the John Wayne Cancer Center/Sarcoma Oncology Center in Santa Monica, CA, City of Hope in Duarte, CA, the Louisiana State University Health Sciences Center in New Orleans, LA, and Texas Oncology in Austin, TX.

This Phase 2 study follows positive confirmatory results reported in 2013 from a preclinical study in which aldoxorubicin demonstrated statistically significant efficacy (p<.0001) in the treatment of rapidly growing human brain (glioblastoma) cancer in the brains of animals. In that study, animals treated with aldoxorubicin had median survival of more than 63 days, compared with approximately 25 days for animals treated with doxorubicin or saline. In addition, because aldoxorubicin uptake was confined to the tumor in the brain rather than normal brain tissue, the principal investigator concluded that aldoxorubicin has the potential to safely shrink glioblastoma tumors, which could dramatically prolong patient survival.

About Glioblastoma Multiforme

Glioblastoma is the most common and most malignant primary brain tumor in adults and afflicts more than 12,000 new patients in the U.S. annually. The median survival after diagnosis is approximately 14 months, despite patients subsequently receiving surgical resection, radiotherapy and chemotherapy. Limited efficacy of chemotherapeutic agents has been attributed to several contributing factors including insufficient drug delivery to the tumor site through the blood:brain barrier.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

Celsion Announces Potent, Durable Preclinical Lung Expression Data for Its Novel TheraSilence™ RNA Program

On May 21, 2015 Celsion reported data from a preclinical study confirming that the Company’s TheraSilence technology platform can safely and effectively deliver RNA to the lungs in non-human primates (Press release, Celsion, MAY 21, 2015, View Source [SID:1234504615]). TheraSilence is designed to enable the delivery of synthetically-generated mRNA, inhibitory RNA (RNAi) such as small inhibitory RNAs (siRNAs), microRNAs, microRNA mimics, and related molecules that can regulate protein expression at the transcript level by exploiting endogenous cell mechanisms.

"The findings from this study are consistent with the data observed in earlier preclinical studies and underscore the differentiating and widespread potential of our TheraSilence RNA delivery platform," stated Dr. Khursheed Anwer, Celsion’s Executive Vice President and Chief Scientific Officer. "Development for RNA therapeutics has been significantly limited due to the delivery challenges associated with nucleic acid-based therapies, with development efforts in the space focused primarily on diseases of the liver. Our chemically-flexible approach offers the opportunity to significantly expand the development of RNA therapies to include major unmet medical needs affecting the lung, such as lung cancer, asthma and pulmonary hypertension."

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The study was designed to evaluate the expression profile and safety of RNA formulated with Celsion’s TheraSilence delivery system in non-human primates. Three primates were dosed in the study, receiving either TheraSilence-formulated RNA intravenously at one of two doses, or intravenous RNA formulated with a liver-directed formulation used as a positive control. Following the treatment, an analysis for safety and RNA expression was performed.

In the study, TheraSilence-formulated signaling RNA resulted in preferential expression in the lungs, with expression in the liver at less than 15% of expression levels observed in the lungs. Expression levels in tissues other than the lung, spleen and liver were very low or at background levels. The TheraSilence-formulated RNA was well-tolerated at both dose levels as determined by safety analysis including complete blood cell count, blood chemistry, histopathology, interferon response and compliment activation. A liver-directed delivery system, used as a positive control for the study, yielded preferential expression in liver and spleen, with only background expression levels observed in the lung.

These data build on previous preclinical studies indicating the preferential delivery of RNA to the lung using the TheraSilence RNA delivery system. A murine study evidenced that the delivery of TheraSilence-formulated siRNA molecules targeting anti-vascular endothelial receptor 2 (VEGF2), a protein that is critical for the growth of new blood vessels in tumors, significantly inhibit lung tumor growth. Additionally, delivery of a TheraSilence-formulated anti-micro RNA molecule into rats with experimentally induced pulmonary arterial hypertension appeared to normalize vascular remodeling that occurs in the lung and help restore cardiac function that is compromised as a result of the disease.

"The data highlights the great potential of our TheraSilence technology platform to provide unique treatment options for lung diseases that are not addressable by conventional drugs," said Michael H. Tardugno, the Company’s Chairman, President and Chief Executive Officer. "TheraSilence has significant potential in a wide variety of indications, including those that fall outside our core focus of oncology. Our strategy is to seek to maximize the value of this platform in the near-term by pursuing collaborations and licensing agreements, while focusing internal development efforts on our two clinical stage candidates, ThermoDox and GEN-1, our DNA-based immunotherapy for the localized treatment of ovarian and brain cancers."

Eureka Therapeutics Inc. and Boehringer Ingelheim Announce a Collaboration to Identify Next Generation Antibodies for Cancer Treatment

On May 21, 2015 Eureka Therapeutics and Boehringer Ingelheim reported that they have entered into a research agreement for the discovery of novel therapeutic antibodies in oncology (Press release, Boehringer Ingelheim, MAY 21, 2015, View Source [SID:1234504614]).

Eureka Therapeutics will apply its proprietary human sequence antibody libraries and its unique technology platform to identify antibodies recognizing intracellular proteins, which represent approximately 90% of cancer-specific targets. Cancer-specific peptides that can be displayed via the MHC-complex (major histocompatibility complex) on the cell surface will be selected by Boehringer Ingelheim to develop better therapies for cancer patients, for whom treatment options are inadequate or non-existent. Boehringer Ingelheim will have the option to conduct further development and commercialization of the antibodies. Under the terms of the agreement, Eureka Therapeutics will receive an undisclosed upfront technology access fee and research funding for each program, and may receive technical success fees, option exercise fees, and other downstream payments.

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"We are excited to partner with Boehringer Ingelheim, a leader in oncology research and development to develop next generation cancer immunotherapies targeting intracellular oncogenes", said Dr. Cheng Liu, President and Chief Executive Officer of Eureka Therapeutics. "Intracellular oncogenes represent 90% of cancer-specific antigens, many of which were considered "undruggable targets" until recently. This collaboration builds upon Eureka’s success in discovery and development of fully human antibodies against intracellular oncogenes. We look forward to working with Boehringer Ingelheim to advance the immuno-oncology frontier and address some of the most challenging unmet medical needs".

This collaboration underlines our long-term commitment to oncology and our interest in exploring new target spaces with antibodies that recognize intracellular proteins. It will open up entirely new opportunities for the development of tumor cell- as well as immune cell-targeted therapies. We are looking forward to working closely with Eureka´s scientists to develop novel, effective therapies targeting cancers that have proved particularly difficult to treat in the past", said Dr. Michel Pairet, Senior Corporate Vice President of Research and Non-clinical Development at Boehringer Ingelheim.

Novartis drug Afinitor® extended progression-free survival in Phase III trial in advanced gastrointestinal or lung neuroendocrine tumors

On May 21, 2015 Novartis reported that the Phase III study of Afinitor (everolimus) tablets plus best supportive care in patients with advanced nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin met its primary endpoint: significant extension of progression-free survival (PFS) compared to placebo plus best supportive care[1] (Press release, Novartis, MAY 21, 2015, View Source [SID:1234504609]). The RADIANT-4 study is part of one of the largest clinical trial programs in NET[1].

NET are a rare type of cancer that originate in neuroendocrine cells found throughout the body, and are most often found in the GI tract, lungs or pancreas[4]. NET can be functional or nonfunctional: functional NET produce symptoms caused by the secretion of hormones and other substances; nonfunctional NET do not secrete hormones, and may only produce symptoms caused by the tumor’s growth, such as intestinal blockage, pain and bleeding[5],[6],[7]. At time of diagnosis, up to 44% of patients with GI NET and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other parts of the body and is more difficult to treat[2],[3],[4]. There are limited treatment options for patients with advanced GI or lung NET[4].

"We look forward to presenting the findings from the RADIANT-4 trial of everolimus, which has the potential to become an important treatment option for patients with advanced nonfunctional GI or lung NET," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The results will serve as the basis of planned worldwide regulatory filings for everolimus in these two types of NET, bringing us closer to our goal of offering Afinitor for these patients."

Full results from the RADIANT-4 study will be submitted to a major medical meeting. Worldwide regulatory filings are planned for 2015.

About RADIANT-4

RADIANT-4 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care versus placebo plus best supportive care in 302 patients with well differentiated advanced NET of GI or lung origin, and no history or active symptoms of carcinoid syndrome, who had documented disease progression within the previous 6 months. Patients were randomized 2:1 to receive either daily everolimus 10 mg or daily placebo orally.

The primary endpoint of RADIANT-4 was PFS. Secondary endpoints included safety, objective response rate and overall survival.

About Afinitor (everolimus) tablets

Afinitor (everolimus) is approved in more than 95 countries, including the United States and throughout the European Union, for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin. It is also approved in 119 countries including the United States and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy.

Afinitor is approved in the European Union for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

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.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, absence of menstrual periods, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, and pneumonia), nausea, decreased appetite, low level of red blood cells, high levels of cholesterol, abnormal taste, acne, irregular menstrual periods, inflammation of lung tissue, high level of blood sugar, weight loss, itching, swelling of extremities or other parts of the body, nose bleeds, and headache. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, absence of menstrual periods, low level of red blood cells, infections (including pneumonia), high level of blood sugar, feeling tired or weak, low white blood cells, inflammation of lung tissue, diarrhea, and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.