On November 1, 2016 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM) and Ospedale Pediatrico Bambino Gesù (OPBG), a leading European pediatric research center and hospital, reported that they have entered into an expanded collaboration focused on preclinical and clinical development of CD19 and other CAR T and TCR therapeutics engineered with Bellicum’s CaspaCIDe molecular safety switch technology (Press release, Bellicum Pharmaceuticals, NOV 1, 2016, View Source [SID1234516154]).

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The two organizations agreed to jointly develop CARs and other cell therapies discovered by OPBG and engineered with Bellicum’s CaspaCIDe safety switch, which is designed to reduce or eliminate cells that become toxic or are no longer needed. Under terms of this agreement, Bellicum agreed to provide financial support to the research collaboration in exchange for exclusive worldwide rights to commercialize certain cell therapies that are developed, while OPBG maintains rights for research purposes. OPBG will conduct research and clinical studies of CAR T and TCR therapeutics in pediatric patients, with initial CD19 CAR T and GD2 CAR T clinical trials in pediatric acute lymphoblastic leukemia and neuroblastoma patients, respectively, expected to start in 2017. In addition, OPBG agreed to manufacture European clinical trial supplies for the investigational programs, as well as Bellicum’s PRAME-targeted TCR, BPX-701, in its GMP facility.

"The Ospedale Pediatrico Bambino Gesù is among the world’s leading cell and gene therapy research centers and hospitals, and we are enthusiastic about working with them to develop controllable engineered T-cell therapies," commented Tom Farrell, President and CEO of Bellicum Pharmaceuticals. "This agreement builds on our highly successful clinical development collaboration with OPBG on BPX-501, our CaspaCIDe-enabled T-cell therapy in clinical development for patients undergoing haploidentical hematopoietic stem cell transplant. OPBG has developed several exciting and innovative new cell therapies, including a CD19 CAR T cell that we believe will be highly differentiated by virtue of our clinically validated CaspaCIDe safety switch."

"We have a highly productive and synergistic relationship with Bellicum, and look forward to building on our present research collaboration," commented Dr. Mariella Enoc, President of the Board of Directors of OPBG. "The combination of Bellicum’s innovative safety switch technology and our cell and gene therapy expertise, clinical study network and GMP vector and cell manufacturing capabilities, makes this an ideal partnership to rapidly advance controllable cell therapies that could benefit children and adults with life-threatening cancers throughout the world."

On November 1, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported that it has completed the niraparib rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for the maintenance treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy (Press release, TESARO, NOV 1, 2016, View Source [SID1234516152]).

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The niraparib NDA is supported by data from the ENGOT-OV16/NOVA trial, a double-blind, placebo-controlled, international Phase 3 study that enrolled 553 patients with recurrent ovarian cancer who were in response to their most recent platinum-based chemotherapy. This trial was designed to assess progression free survival (PFS) in patients who were assigned to one of two cohorts based upon germline BRCA mutation status, as determined by the Myriad BRACAnalysis CDx test. Within the cohort of patients who were not germline BRCA mutation carriers (non-gBRCAmut), tumor samples were assessed for HRD status using the Myriad myChoice HRD test.

The ENGOT-OV16/NOVA trial successfully achieved its primary endpoint in both patient cohorts, demonstrating that niraparib treatment significantly prolonged PFS compared to control. The full results of the ENGOT-OV16/NOVA trial were presented in detail at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen on October 8, 2016 and were published simultaneously in The New England Journal of Medicine. Based upon the results of this trial, the indication proposed in the NDA provides for the use of niraparib regardless of tumor biomarker status, and it is anticipated that the BRACAnalysis CDx and myChoice HRD tests would be available to physicians as complementary diagnostics.

"TESARO is working daily to benefit the many women living with ovarian cancer," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "Our niraparib NDA and MAA submissions represent a significant step in our efforts to bring meaningful therapies to these patients."

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial), a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial), and a Phase 3 trial for the treatment of patients with germline BRCA-mutated, metastatic breast cancer (the BRAVO trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab and niraparib plus bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

In September, the FDA granted Fast Track designation to niraparib. The FDA Fast Track designation is designed to facilitate the development and expedite the review of medicines that are intended to treat serious conditions and address unmet medical needs. As part of the Fast Track program, the FDA allows for the submission of completed portions of an NDA on an ongoing or rolling basis.

Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA, European Medicines Agency (EMA), or any other regulatory agencies.

The most common (≥10%) treatment-emergent grade 3/4 adverse events in the niraparib arm were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%) with treatment discontinuation for these events of 3.3%, 1.4% and 1.9%, respectively. Thrombocytopenia was not associated with grade 3/4 bleeding events. The majority of these hematological laboratory abnormalities occurred within the first three cycles; following dose modifications the incidence of these lab abnormalities decreased and thrombocytopenia and neutropenia were infrequent beyond cycle 3. The rates of MDS/AML in the niraparib (1.4%) and control (1.1%) arms were similar. There were no deaths among patients during study treatment.

About Ovarian Cancer
Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and more than 65,000 women are diagnosed annually in Europe. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years. If approved, niraparib may address the difficult "watchful waiting" periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.

On November 1, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported that the Company has entered into a definitive agreement to acquire Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel, antibody-based drugs targeting receptor tyrosine kinases (RTKs) (Press release, Celldex Therapeutics, NOV 1, 2016, View Source [SID1234516140]). Focused primarily in oncology and backed by prominent thought leaders in RTK biology, Kolltan has reported clinical and preclinical data that its drug candidates can help overcome tumor resistance mechanisms associated with current tyrosine kinase inhibitors and seen in patients who have failed other cancer therapies. Celldex believes Kolltan’s clinical candidates and preclinical platform are highly compatible with the Company’s scientific approach and can be developed independently and in combination with Celldex’s existing product candidates.

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"Celldex is committed to driving innovation in oncology to meet the needs of patients and their families," said Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics. "The acquisition of Kolltan provides Celldex with a truly unique platform of antibodies targeting receptor tyrosine kinases which we believe are highly compatible with our pipeline. We believe this acquisition complements our leadership position in immuno-oncology and enhances our ability to develop targeted therapeutic regimens to dramatically improve patient outcomes."

"Kolltan’s programs targeting KIT, ErbB3 and TAM receptors potentially address major challenges surrounding tumor resistance mechanisms in cancer biology," said Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan Pharmaceuticals. "Celldex’s leadership and their scientific team played an instrumental role in building the antibody field during their tenure at Medarex and used this expertise to create a leading pipeline in immuno-oncology at Celldex. We firmly believe Celldex is uniquely positioned to advance our antibody portfolio targeting RTKs to improve outcomes for patients and create optimal value for our shareholders."

Kolltan’s portfolio includes:

KTN0158 — a humanized monoclonal antibody that is a potent inhibitor of KIT activation in tumor cells and mast cells; currently in a Phase 1 dose escalation study in refractory gastrointestinal stromal tumors (GIST). KTN0158 prevents KIT activation by blocking receptor dimerization. This mechanism may be effective even in tumors harboring the most common resistant mutations to Gleevec and is unlikely to drive resistance. Preclinical data demonstrate that KIT inhibition in certain immune cells with KTN0158 enhances the activity of checkpoint blockade. This mechanism may also be effective with other immunotherapies, in particular with Celldex’s CD27 agonist, varlilumab.

KTN3379 — a human monoclonal antibody designed to block the activity of ErbB3 (HER3); clinical activity including meaningful responses and stable disease has been observed in a Phase 1b study in cetuximab (Erbitux) refractory patients in head and neck squamous cell carcinoma and in BRAF-mutant non-small cell lung cancer (NSCLC). The proposed mechanism of action for KTN3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It also has a favorable pharmacologic profile, including a longer half-life relative to other drug candidates in this class. KTN3379 also has potential to work well in combination with other targeted and cytotoxic therapies to directly kill tumor cells. Tumor cell death and the ensuing release of new tumor antigens could serve as a focus for combination therapy with immuno-oncology approaches, even in refractory patients.

A multi-faceted TAM program — a broad antibody discovery effort underway to generate antibodies that modulate the TAM family of RTKs, comprised of Tyro3, AXL and MerTK, which are expressed on tumor-infiltrating macrophages, dendritic cells and some tumors. Research supports TAMs having broad application and potential across immuno-oncology and immunology. In oncology, as with PD-1 and other checkpoints, TAMs regulate the immune response to cancer. Modulation of TAM pathways may provide additional opportunities to develop drugs to overcome resistance mechanisms, especially when used in combination with either Celldex or external product candidates or with existing approved therapies.
Upon closing of the acquisition of Kolltan, Celldex’s clinical pipeline will include seven drug candidates including therapeutic antibodies, antibody-drug conjugates (ADCs) and immune system modulators, which are being tested in a range of difficult-to-treat indications in oncology. This broad pipeline allows for novel combination approaches, several of which are already under study. In addition, Celldex would have two active preclinical programs.

Transaction Terms
Under the terms of the agreement, Celldex will acquire Kolltan in a stock-for-stock transaction, in which the upfront payment represents an equity value of approximately $62.5 million. In addition, Kolltan shareholders are eligible to receive additional payments of up to $172.5 million upon the completion of specific development, regulatory and commercial milestones. The transaction, which is subject to the receipt of Kolltan stockholder approval and other customary closing conditions, is expected to be completed by year-end. The Boards of Directors of both Celldex and Kolltan have unanimously approved the transaction, and Kolltan’s Directors have unanimously recommended that their stockholders approve the transaction. Celldex was advised by Lowenstein Sandler, LLP. Kolltan was advised by Guggenheim and Holland & Knight.

On November 1, 2016 PharmaCyte Biotech, Inc. (OTCQB:PMCB), a clinical stage biotechnology company focused on developing targeted treatments for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that it has submitted a request for a pre-IND meeting with the U. S. Food and Drug Administration (FDA) for its planned clinical trial in locally advanced, inoperable pancreatic cancer (LAPC) (Press release, PharmaCyte Biotech, NOV 1, 2016, View Source [SID1234516138]).

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PharmaCyte has submitted questions to the FDA as part of a pre-IND meeting request where aspects of the content of the Investigational New Drug (IND) application itself (CMC section, clinical trial description, etc.) will be discussed. After the FDA has responded to the questions and issued comments, PharmaCyte must address them to the FDA’s satisfaction. A review of PharmaCyte’s responses by the FDA will then take place at the formal pre-IND meeting where final agreement between PharmaCyte and the FDA on all aspects discussed will be reached. With this information, the IND will be submitted by PharmaCyte and reviewed by the FDA. Once the IND is found to be acceptable to the FDA, patients can be enrolled in PharmaCyte’s clinical trial.

PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said of the meeting request, "We are pleased that PharmaCyte has taken the first step towards regulatory approval in the United States of its therapy for LAPC. When I started to lead this company in January 2014, my first goal was to surround our technology with the best of the best in the biotech sector. I believe we have more than accomplished this goal as we have compiled an internationally renowned team that will lead PharmaCyte into what we expect to be a pivotal human clinical trial. My second goal was to get our therapy to the FDA, and with this pre-IND meeting request, we have accomplished this goal as well. My ultimate goal, of course, was and is to get our pancreatic cancer therapy into clinical trials and approved by the FDA. I feel we are well on our way to accomplishing this goal."

PharmaCyte’s clinical trial in patients with LAPC is designed to meet a clear unmet medical need for those whose cancer no longer responds after 4-6 months of treatment with the combination of Abraxane plus gemcitabine. The trial will be open-label and multi-site in nature, with sites in the U.S. and Europe. Patients with LAPC will be randomized equally into two groups. One group will receive gemcitabine chemotherapy alone, and the other group will receive PharmaCyte’s pancreatic cancer therapy (encapsulated genetically modified live human cells that can activate the cancer prodrug ifosfamide plus low doses of the prodrug to eliminate side effects from the chemotherapy). In addition to comparing the anticancer activity and safety of the two therapies, a major aspect of the trial will be to determine if, and how well, PharmaCyte’s therapy can shrink inoperable tumors so that they become operable.

On November 1, 2016 Novartis reported that the US Food and Drug Administration (FDA) accepted the company’s New Drug Application (NDA) for filing and granted Priority Review for LEE011 (ribociclib) as first-line treatment of postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer in combination with letrozole (Press release, Novartis, NOV 1, 2016, View Source [SID1234516136]). The NDA is based on a comprehensive clinical package, including results of the Phase III MONALEESA-2 trial. The trial, which was presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress and published simultaneously in the New England Journal of Medicine, showed LEE011 plus letrozole reduced the risk of progression or death by 44% (HR = 0.556, 95% CI: 0.429-0.720; P = 0.00000329) over letrozole alone, significantly extending progression-free survival (PFS) across all patient subgroups[1]. The company also announced that the EMA has accepted for review the marketing authorization application for LEE011 plus letrozole in the same patient population.

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"These regulatory milestones, along with the FDA Breakthrough Therapy designation granted in August, underscore the need for new treatment options for women living with HR+/HER2- advanced breast cancer," said Bruno Strigini, CEO, Novartis Oncology. "Priority Review allows a shorter review period compared with FDA standard review in the US, helping us to potentially bring LEE011 plus letrozole to patients more quickly. We also are working diligently with the EMA and other Health Authorities to bring this treatment to patients around the world as fast as possible."

FDA Priority Review designation requires the agency to take action on an application within six months of its filing date compared to ten months under standard review[2]. FDA grants Priority Review to applications for new drug candidates that treat serious conditions, such as advanced breast cancer for which there is currently no cure, and if approved, would provide a significant improvement in treatment safety or efficacy[2].

About LEE011 (ribociclib)
LEE011 (ribociclib) is a selective cyclin dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated in a cell, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring cancer cells do not grow uncontrollably.

LEE011 is not approved for any indication in any market at this time. LEE011 was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the MONALEESA Clinical Trial Program
Novartis is continuing to assess LEE011 through the robust MONALEESA (Mammary ONcology Assessment of LEE011’s Efficacy and SAfety) clinical trial program, which includes MONALEESA-2, MONALEESA-3, and MONALEESA-7. These trials are evaluating LEE011 in multiple endocrine therapy combinations across a broad range of patients, including men and premenopausal women.

MONALEESA-2 is a Phase III randomized, double blind, placebo controlled, multicenter global registration trial to evaluate the safety and efficacy of LEE011 in combination with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- advanced breast cancer who received no prior therapy for their advanced breast cancer[1].

The trial randomized 668 patients in a 1:1 ratio stratified by the presence of liver and/or lung metastases at 223 clinical trial sites globally[1]. Patients received LEE011 600 mg/daily (three weeks on and one week off), or placebo, in combination with letrozole 2.5 mg/daily.

The primary endpoint of the trial was PFS[1]. Secondary endpoints included: overall survival, overall response rate, clinical benefit rate, health-related quality of life, safety and tolerability[1].

The MONALEESA-3 trial is evaluating LEE011 in combination with fulvestrant compared to fulvestrant alone in men and post-menopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy.

The MONALEESA-7 trial is investigating LEE011 in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in pre-menopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. Both MONALEESA-3 and MONALEESA-7 are fully enrolled.

About Advanced Breast Cancer
Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease[3]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[4]. Advanced breast cancer comprises metastatic breast cancer (stage 4) and locally advanced breast cancer (stage 3)[4]. Survival rates for women living with advanced breast cancer are lower than those for women with earlier stage disease. The 5-year relative survival rate for stage 3 breast cancer is approximately 72%, while metastatic (stage 4) breast cancer has a 5-year relative survival rate of approximately 22%[5].