TG Therapeutics Announces Special Protocol Assessment (SPA) Agreement With the FDA for Its First Phase 3 Clinical Trial of TG-1101 (ublituximab) in Combination With Imbruvica(R) (ibrutinib) for Patients With Previously Treated Chronic Lymphocytic Leukemia

On September 15, 2014 TG Therapeutics reported that it has reached an agreement with the U.S. Food and Drug Administration (FDA) regarding a Special Protocol Assessment (SPA) on the design, endpoints and statistical analysis approach of a Phase 3 clinical trial for TG-1101 (ublituximab), its glycoengineered anti-CD20 monoclonal antibody, in combination with Imbruvica (ibrutinib) for the treatment of Chronic Lymphocytic Leukemia (CLL) in patients with high risk cytogenetics (Press release TG Therapeutics, SEP 15, 2014, View Source [SID:1234500747]). The SPA provides agreement that the Phase 3 trial design adequately addresses objectives that would support the regulatory submission for drug approval.

Full details of the Phase 3 clinical trial will be released at the launch of the study, which is expected to occur before the end of the year. In this randomized controlled trial, patients will receive either TG-1101 plus ibrutinib or ibrutinib alone. The trial will enroll approximately 330 patients, with approximately the first two-thirds of the patients included in the ORR assessment. As per the SPA, the Company plans to use the ORR data from the trial as the basis for submission of a Biologics License Application (BLA) for accelerated approval for TG-1101. All patients will then be followed for PFS assessment, which is designed to support full approval.

Additionally, the Company reported that enrollment into the CLL cohort of its ongoing combination Phase 2 study of TG-1101 plus ibrutinib is now closed. The Company expects it will have over 30 CLL patients evaluable for safety and efficacy available for presentation at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) this December.

Dr. Jeff Sharman, Medical Director of Hematology Research for the US Oncology Network, and currently the lead investigator on the Company’s Phase 2 combination trial of TG-1101 plus ibrutinib, will be the Study Chair for this Phase 3 trial. Dr. Sharman commented, “We have been very pleased with the safety and activity profile of the combination seen thus far in our Phase 1/2 trial, and are excited to lead this important clinical trial. Combining a glycoengineered anti-CD20 monoclonal antibody with ibrutinib has the potential to materially increase the number of patients benefitting from treatment with ibrutinib therapy. The Phase 2 trial has enrolled very quickly throughout our clinical research network with patients, physicians, and nurses recognizing the benefits of this study.”

Michael S. Weiss, Executive Chairman and Interim Chief Executive Officer of TG Therapeutics, stated, “The TG-1101 SPA agreement is a major milestone for us as it represents the first clearly defined development and regulatory pathway for the approval of TG-1101 for the treatment of CLL. As we’ve mentioned previously, reaching agreement with the FDA on this combination trial with ORR as a primary endpoint for accelerated approval was our number one priority. We are thrilled to get this first SPA in place earlier than anticipated, which puts us in an excellent position to build out the remainder of our registration program for both TG-1101 and TGR-1202. We would like to thank the FDA for its invaluable guidance throughout this process. The speed at which the FDA reviewed the submission demonstrates a real commitment to drive novel medicines to the patients who need them as rapidly as possible.” Mr. Weiss continued, “We look forward to launching this trial by year end and are excited to continue to work with Dr. Sharman, the entire US Oncology team, and all investigators, who have been instrumental in our development of this important combination.”

Merck Discontinues Clinical Development Program of Tecemotide as a Monotherapy in Stage III Non-Small Cell Lung Cancer

On September 12, 2014 Merck reported that its biopharmaceutical division Merck Serono will discontinue the clinical development program of its investigational MUC1 antigen-specific cancer immunotherapy tecemotide (also known as L-BLP25) as a monotherapy in Stage III non-small cell lung cancer (NSCLC) (Press release Merck KGaA, SEP 12, 2014, View Source [SID:1234500739]).

Luciano Rossetti, Global Head of Research & Development at Merck Serono, said: “While the data from the exploratory subgroup analysis in the START trial1 generated a reasonable hypothesis to warrant additional study, the results of the recent trial in Japanese patients decreased the probability of current studies to reach their goals. Therefore, we have decided to discontinue the development of tecemotide as a monotherapy in NSCLC in order to refocus our efforts on other promising candidates in our pipeline, like our anti-PD-L1 antibody MSB0010718C. Merck Serono remains committed to developing new treatment options for patients with difficult-to-treat cancers.”

The company’s decision to discontinue the current clinical program in NSCLC, which includes the Phase III START2 and INSPIRE studies, follows recent results from a planned analysis of EMR 63325-009, a randomized, double-blind, placebo-controlled Phase I/II study in Japanese patients with Stage III unresectable, locally advanced NSCLC who had received concurrent or sequential chemoradiotherapy (CRT), with a minimum of two cycles of platinum-based chemotherapy and radiation dose ≥50 Gy. Of the patients included in the Phase II part of the study, the majority had received concurrent CRT. The results indicate that no effect has been observed for either the primary endpoint, overall survival (OS), or for any of the secondary endpoints (progression-free survival [PFS], time to progression [TTP] and time to treatment failure). An analysis of the reported adverse events has not identified a clinically meaningful difference in the frequency between treatment groups. Although the trial was not powered to demonstrate a statistically significant difference in benefit between the two arms, Merck Serono made the recommendation to stop the investigational treatment for patients in the EMR 63325-009 study in Japan.

Merck Serono has made the decision to discontinue all other Merck Serono-sponsored clinical trials with tecemotide in NSCLC worldwide. Those patients on active treatment with tecemotide can undergo an individual assessment by their treating physician and apply to receive further treatment outside of the studies. The company will continue to supply tecemotide for ongoing investigator-sponsored trials in other indications in accordance with Merck’s agreements with the sponsors of these studies.

Merck Serono continues to evaluate a number of investigational compounds for difficult-to-treat cancers, and remains committed to improving the lives of cancer patients and their families.

Lilly Announces CYRAMZA™ Phase III Second-Line Colorectal Cancer Trial Meets Primary Endpoint of Overall Survival

On September 12, 2014 Eli Lilly reported that the RAISE trial, a Phase III study of ramucirumab (CYRAMZA) in combination with chemotherapy in patients with metastatic colorectal cancer (mCRC), met its primary endpoint of overall survival (Press release Eli Lilly, SEP 12, 2014, View Source [SID:1234500738]). The global, randomized, double-blind study compared ramucirumab plus FOLFIRI to placebo plus FOLFIRI as a second-line treatment in patients with mCRC after treatment with bevacizumab, oxaliplatin and a fluoropyrimidine in the first-line setting.

RAISE showed a statistically significant improvement in overall survival in patients treated with ramucirumab plus FOLFIRI compared to placebo plus FOLFIRI. The study also showed a statistically significant improvement in progression-free survival in the ramucirumab-plus-FOLFIRI arm compared to the placebo-plus-FOLFIRI arm. The most common ( > 5% incidence) grade > /=3 adverse events occurring at a higher rate on the ramucirumab-plus-FOLFIRI arm compared to the control arm were neutropenia, fatigue, hypertension, and diarrhea.

Despite advances in treating colorectal cancer in recent years, the mortality rate remains significant. It is the fourth leading cause of cancer death worldwide and the second leading cause of cancer death in the U.S.

“Patients with metastatic colorectal cancer – particularly those in the second-line setting – continue to need new treatment options that improve survival,” said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. “We are pleased that the RAISE study demonstrated a survival benefit and are hopeful that ramucirumab will become a new anti-angiogenic treatment option after first-line bevacizumab-containing therapy for metastatic colorectal cancer patients.”

Lilly plans to present data from the RAISE trial at a scientific meeting in 2015 and expects to initiate regulatory submissions in the first half of 2015.

Dr. Gaynor added, “We now have four Phase III ramucirumab trials that improved survival in three of the world’s most common and deadly cancers–gastric, lung, and colorectal–supporting global regulatory submissions in multiple indications. The RAISE data also build on Lilly’s growing presence in gastrointestinal cancer therapy.”

Ramucirumab is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. VEGF Receptor 2 is an important mediator in the VEGF pathway.i,ii In an in vivo animal model, ramucirumab inhibited angiogenesis. Angiogenesis is a process by which new blood vessels form to supply blood to normal healthy tissues as well as tumors, enabling the cancer to grow.

Cancer Research UK, Cancer Research Technology And Asterias Biotherapeutics Partner To Trial Immunotherapy Vaccine For Lung Cancer

On September 11, 2014 CANCER RESEARCH UK and Cancer Research Technology (CRT), the charity’s development and commercialisation arm, have reached an agreement with Asterias Biotherapeutics, Inc. (OTCBB: ASTY), a biotechnology company in the emerging field of regenerative medicine, to take forward Asterias’ novel immunotherapy treatment AST-VAC2 into clinical trials in subjects with non-small cell lung cancer (Press release BioTime, SEP 11, 2014, View Source;p=RssLanding&cat=news&id=1966042 [SID:1234500740]).

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AST-VAC2 represents the tenth treatment to enter Cancer Research UK’s Clinical Development Partnerships* (CDP) scheme, with six having progressed into the clinic to date. CDP is a joint initiative between Cancer Research UK’s Drug Development Office (DDO) and Cancer Research Technology, to develop promising anti-cancer agents which pharmaceutical companies do not have the resources to progress through early phase clinical trials.

AST-VAC2 is a non-patient specific (allogeneic) cancer vaccine designed to stimulate patients’ immune systems to attack telomerase, a protein that is expressed in over 95 percent of cancers but is rarely expressed in normal adult cells.

The vaccine was developed following successful early phase clinical trials of a similar, patient specific (autologous) Asterias vaccine, called AST-VAC1, which was derived from patients’ blood cells and tested in prostate cancer and acute myeloid leukemia.

Unlike AST-VAC1, and other autologous (patient specific) vaccines that are developed from a patient’s own cells, AST-VAC2 is derived from human embryonic stem cells (hESCs), meaning it can be produced on a large scale and stored ready for use, rather than having to produce a specific version of the drug for each patient.

The trial of AST-VAC2 will evaluate the safety and toxicity of the vaccine, feasibility, stimulation of patient immune responses to telomerase and AST-VAC2, and clinical outcome after AST-VAC2 administration in patients with resected early-stage lung cancer and in patients with advanced forms of the disease.

Pedro Lichtinger, Asterias’ chief executive officer, said: "The Asterias collaboration with Cancer Research UK’s Drug Development Office and CRT represents a major step in advancing our proprietary dendritic cell platform for the potential benefit of patients.

"AST-VAC2 is based on a specific mode of action that is complementary and potentially synergistic to other immune therapies. We are delighted to partner with Cancer Research UK to advance this important platform through Phase 1/2 clinical trials. Cancer Research UK’s Drug Development Office has the global recognition of having the quality, capability and track record of successfully advancing development programs. We are excited about the possibility of favorably impacting the lives of patients across multiple cancers and are proud to be working with Cancer Research UK."

Under the agreement, Asterias will complete development of the manufacturing process for AST-VAC2. Cancer Research UK will then produce the vaccine and conduct the phase 1/2 clinical trial in the UK. On completion of the clinical trial, Asterias will have an exclusive first option to acquire a license to the data from the trial on pre-agreed terms including an upfront payment, milestones and royalties on sales of products. If Asterias declines this option, CRT will then have an option to obtain a license to Asterias’ intellectual property to continue the development and commercialisation of AST-VAC2 and related products in exchange for a revenue share to Asterias of development and partnering proceeds.

Dr. Jane Lebkowski, president of research and development at Asterias, said: "The use of human embryonic stem cells to derive allogeneic dendritic cells for cancer immunotherapy has the potential to dramatically improve the scalability, consistency, and feasibility of cellular cancer vaccines. We believe this collaboration will enable the acceleration of clinical studies of AST-VAC2 and the collection of important proof-of-concept data for the entire human embryonic stem cell-derived dendritic cell immunotherapy platform."

Nigel Blackburn, Cancer Research UK’s Director of Drug Development, said: "Recent advances in cancer immunotherapy have demonstrated the exciting potential of these treatments to improve outcomes in devastating diseases such as lung cancer. Better treatment options for lung cancer are badly needed and it is through collaborations such as this that we can save more lives sooner."

Cancer Research UK, Cancer Research Technology and Asterias Biotherapeutics partner to trial immunotherapy vaccine for lung cancer

On September 11, 2014 Cancer Research UK and Cancer Research Technology (CRT), the charity’s development and commercialisation arm, reported an agreement with Asterias Biotherapeutics, Inc. (OTCBB: ASTY), a biotechnology company in the emerging field of regenerative medicine and a subsidiary of BioTime, Inc. (NYSE MKT: BTX), to take forward their novel immunotherapy treatment AST-VAC2 into clinical trials with non small cell lung cancer patients (Press release, Cancer Research Technology, SEP 11, 2014, View Source [SID1234523224]).

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This is the tenth treatment to enter Cancer Research UK’s Clinical Development Partnerships* (CDP) scheme, with six having progressed into the clinic to date. CDP is a joint initiative between Cancer Research UK’s Drug Development Office (DDO) and Cancer Research Technology, to develop promising anti-cancer agents which pharmaceutical companies do not have the resources to progress through early phase clinical trials.

AST-VAC2 is a non-patient specific (allogeneic) cancer vaccine designed to stimulate patients’ immune systems to attack telomerase, a protein that is expressed in over 95 percent of cancers but is rarely expressed in normal adult cells.

The vaccine was developed following successful early phase trials of a similar Asterias drug, called AST-VAC1, which was designed to treat acute myeloid leukemia and derived from patients’ blood cells.

Unlike AST-VAC1, and other autologous (patient specific) vaccines that are developed from a patient’s own cells, AST-VAC2 is derived from human embryonic stem cells (hESCs), meaning it can be produced on a large scale and stored ready for use, rather than having to produce a specific version of the drug for each patient.

The trial of AST-VAC2 will evaluate the safety and toxicity of the vaccine, feasibility, stimulation of patient immune responses to telomerase and AST-VAC2, and clinical outcome after AST-VAC2 administration in patients with either resected early-stage, or advanced forms of lung cancer.

Pedro Lichtinger, Asterias’ chief executive officer, said: "The Asterias collaboration with Cancer Research UK’s Drug Development Office represents a major step in advancing our proprietary dendritic cell platform for the potential benefit of patients.

"AST-VAC2 is at the forefront of cell-based immune therapies. It is based on a unique mode of action that is complementary and potentially synergistic to other immune therapies. We are delighted to partner with Cancer Research UK to advance this important platform through Phase 1/2 clinical trials. Cancer Research UK’s Drug Development Office has the global recognition of having the quality, capability and track record of successfully advancing development programs. We are excited about the possibility of favorably impacting the lives of patients across multiple cancers and are proud to be working with Cancer Research UK."

Under the agreement, Asterias will complete development of the manufacturing process for AST-VAC2. Cancer Research UK will then produce the vaccine and conduct the phase 1/2 clinical trial. On completion of the clinical trial, Asterias will have an exclusive first option to acquire the data from the trial. If Asterias declines this, CRT will then have an option to obtain a license to Asterias’ intellectual property to continue the development and commercialisation of AST-VAC2 and related products in exchange for a revenue share to Asterias of development and partnering proceeds.

Dr Jane Lebkowski, president of R&D at Asterias, said: "The use of human embryonic stem cells to derive allogeneic dendritic cells for cancer immunotherapy has the potential to dramatically improve the scalability, consistency, and feasibility of cellular cancer vaccines. We believe this collaboration will enable the acceleration of clinical studies of AST-VAC2 and the collection of important proof-of-concept data for the entire hESC-DC immunotherapy platform."

Nigel Blackburn, Cancer Research UK’s Director of Drug Development, said: "Recent advances in cancer immunotherapy have demonstrated the exciting potential of these treatments to improve outcomes in devastating diseases such as lung cancer. Better treatment options for lung cancer are badly needed and it is through collaborations such as this that we can save more lives sooner."