On August 23, 2017 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported that patient enrollment has been completed in the Company’s Phase 2b METRIC study of glembatumumab vedotin in patients with metastatic triple negative breast cancers that overexpress gpNMB (Press release, Celldex Therapeutics, AUG 23, 2017, View Source [SID1234520304]). Glembatumumab vedotin is an antibody-drug conjugate that targets and binds to gpNMB, a protein expressed by multiple tumor types, including breast cancer. Overexpression of gpNMB has been shown to promote the migration, invasion and metastasis of the disease. It is highly expressed in triple negative breast cancers, where it is associated with increased risk of recurrence and poor clinical outcome.

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"We are extremely grateful to the METRIC investigators and the patients and families who supported this trial," said Anthony Marucci, Co-Founder, President and Chief Executive Officer of Celldex Therapeutics. "Patients with triple negative breast cancer have very limited treatment options. We believe glemba holds significant promise as a potential new targeted treatment for patients with this devastating disease and look forward to topline data, likely in the second quarter of 2018."

The METRIC study is a randomized Phase 2b study of glembatumumab vedotin in patients with metastatic triple negative breast cancers that overexpress gpNMB. In this indication, overexpression is defined as greater than or equal to 25% of tumor cells testing positive for gpNMB. Patients are randomized 2 to 1 to either glembatumumab vedotin or to capecitabine, also known by the tradename Xeloda, as a comparator. In total, 327 patients were enrolled into METRIC. The primary endpoint of the study is progression-free survival (PFS), which is defined as the time from randomization to the earlier of disease progression or death due to any cause. The study calls for 203 progression events for evaluation of the primary endpoint, which will be assessed based on an independent, central reading of patient scans. The sum of the data, including the secondary endpoints of response rate, overall survival, duration of response and safety, will be important in assessing clinical benefit. The Company projects that topline primary endpoint data should be available in the second quarter of 2018, but it could occur earlier or later based on the rate of events in the study.

Xeloda is a registered trademark of Genentech, Inc.

About Glembatumumab Vedotin

Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer with an initial focus in triple negative disease, stage III and IV melanoma, squamous cell lung cancer and uveal melanoma.

On August 23, 2017 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) and Nippon Shinyaku Co., Ltd. (TOKYO: 4516) reported that Chugai filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW), for glycoengineered type II anti-CD20 monoclonal antibody, obinutuzumab (genetical recombination) which was co-developed by the two companies for the treatment of "CD20-positive B-cell follicular lymphoma (FL)" in Japan (Press release, Chugai, AUG 23, 2017, View Source [SID1234520300]).

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"Combination therapy of rituximab and chemotherapy has been used as the standard treatment for CD20-positive B-cell FL for a long time. As a new treatment option, Obinutuzumab was confirmed to be more beneficial than the conventional treatment with rituximab for the treatment of FL," said Dr. Yasushi Ito, Chugai’s Senior Vice President, Head of Project & Lifecycle Management Unit. "We are committed to deliver obinutuzumab to patients as early as possible to contribute to the access to better treatments in Japan."

Dr. Kazuya Mori, Nippon Shinyaku’s Corporate Officer, Head of R&D Administration Div. said "I am very glad that a new drug application for our co-developed product, obinutuzumab, was filed. By adding this new product to our lineup in the area of hematologic malignancies, on which we are focusing, we will make utmost efforts to meet the demands of the clinical setting and contribute to the treatment of patients."

This filing was based on the results of the GALLIUM study, a global phase III clinical study conducted by Roche and participating from Japan and other several clinical studies.
The GALLIUM study is a global Phase III open-label, multi-center, randomized two-arm study that evaluated the efficacy and safety of obinutuzumab plus chemotherapy followed by obinutuzumab alone (obinutuzumab arm) compared with rituximab plus chemotherapy followed by rituximab alone (rituximab arm) in 1,401 patients with previously untreated CD20-positive advanced non-Hodgkin’s lymphoma. The primary endpoint of the study was investigator-assessed progression free survival (PFS) in 1,202 patients with FL. The secondary endpoints were PFS assessed by an independent review committee (IRC), overall survival (OS), safety, and other endpoints.

With respect to the primary endpoint, as the median PFS was not reached, the results showed that obinutuzumab arm reduced the risk of disease progression, recurrence or death in patients with FL by 34 percent (HR=0.66, 95% CI: 0.51-0.85, p=0.0012, stratified log-rank test, Data cut-off: January 31, 2016) compared to rituximab arm. Concerning secondary endpoints, the median PFS assessed by the IRC was not reached as well, the risk of disease progression, recurrence or deaths decreased by 29% (HR=0.71, 95% CI: 0.54-0.93], p=0.0138, stratified log-rank test, Data cut-off: January 31, 2016). The median OS did not reach in both arms due to small numbers of events. As for safety, the adverse events (AEs) expressed in both arms in the GALLIUM study were consistent with previous reports. The Grade 3 or higher AEs which was observed in 5% or more frequently for obinutuzumab arm than rituximab arm was neutropenia (43.9% for obinutuzumab arm vs. 37.9% for rituximab arm).

Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells, same as rituximab which is recommended as a treatment of non-Hodgkin’s lymphoma in treatment guidelines in Japan and overseas. Obinutuzumab is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.

In Japan, the prevalence of malignant lymphoma was reported to be approximately 27,000 and the number of deaths due to the disease was reported to be approximately 11,000 in 20121, 2). Since the cases of Hodgkin’s lymphoma is reported to account for approximately 8 to 10% of the cases of malignant lymphoma in Japan3), the prevalence of non-Hodgkin’s lymphoma is estimated to be approximately 24,000 and the number of deaths from this condition is estimated to be approximately 10,000. The prevalence of and deaths from malignant lymphoma tend to increase in recent years1, 2), and a same tendency is seen in patients with non-Hodgkin’s lymphoma.

Chugai and Nippon Shinyaku will work for the early approval to provide obinutuzumab as a new treatment option for patients with CD20-positive B-cell follicular lymphoma and medical professionals.

August 22, 2017 – Curtana Pharmaceuticals, a privately-held, preclinical-stage biopharmaceutical company, reported that it has completed a pre-investigational new drug (IND) meeting with the U.S. Food and Drug Administration (FDA) (Press release, Curtana Pharmaceuticals, AUG 22, 2017, View Source [SID1234520419]). The purpose of the meeting was to discuss the proposed clinical development program for treating newly diagnosed adult glioblastoma (GBM) patients with Curtana’s lead product candidate, CT-179, including the Phase 1 clinical study design. In addition, a clinical development plan for CT-179 in pediatric patients with newly diagnosed high grade glioma (HGG) was proposed.

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Curtana submitted their meeting package to the FDA on May 19, 2017. In written responses, the FDA addressed the company’s questions related to the design of the first-in-human Phase 1 study in adult patients with newly diagnosed GBM. The FDA also provided greater clarity on the data collection requirements in pediatric patients. Last, the Agency provided guidance regarding Curtana’s submission for fast track (FT) designation. Curtana anticipates submitting this IND application in the first half of 2018.

"We are very excited by the FDA’s response and general acceptance of our clinical trial design to study CT-179 in newly diagnosed GBM patients in combination with the standard of care treatments, temozolomide and radiation," said Gregory Stein, M.D., MBA, and Chief Executive Officer. "This is a much-needed departure from the typical development process, which is to first test a new drug as monotherapy in patients with recurrent disease, a strategy that provides safety data, but is frequently unsuccessful in providing adequate evidence of activity. Our goal is to get CT-179 as quickly as possible to adult and pediatric patients with these devastating brain cancers. We applaud the FDA’s acknowledgement of the difficulty treating gliomas and their willingness to be innovative and we will continue to work diligently with the Agency to move our lead product candidate into clinical trials."

Glioblastoma is the most common and most aggressive of the malignant primary brain tumors in adults. According to the American Brain Tumor Association, an estimated 12,390 new cases of GBM are predicted in 2017. Conventional therapeutic approaches for GBM, including surgery, chemotherapy and radiation therapy, target the tumor bulk, but have limited effect on the glioma cancer stem cells (CSCs), which are responsible for the recurrence of disease that occurs in most GBM patients. Accordingly, GBM represents a significant unmet clinical need as the median survival is less than 15 months and five-year survival rate is less than 10%.

Curtana’s lead clinical candidate, CT-179, is a highly potent inhibitor of Olig2, a transcription factor that is not actively expressed in the vast majority of normal adult brain cells or in normal tissues outside the brain. However, Olig2 is markedly over-expressed in GBM; specifically, in the cancer stem cells (CSCs) that have been shown to be an important factor in tumorigenesis, driving tumor growth, invasion into normal brain tissue, and recurrence. The drug is orally bioavailable, readily crosses the blood-brain barrier, achieves very high concentrations in the brain, and significantly prolongs survival in animal models of brain cancer. When combined with standard of care temozolomide and radiation, CT-179 dramatically inhibits tumor growth and prolongs survival compared to either treatment alone, in relevant animal models.

On August 22, 2017 The Alliance Foundation Trials, LLC (AFT), in conjunction with Pfizer and six international cancer research groups, reported the launch of PATINA – a randomized, open-label, Phase 3 clinical study of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor palbociclib (also known as IBRANCE) (Press release, Pfizer, AUG 22, 2017, View Source [SID1234520297]). The PATINA trial will evaluate palbociclib in combination with anti-HER2 therapy and endocrine therapy versus standard therapy as a first-line treatment for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. The trial randomized its first patient on July 26, 2017.

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"The PATINA trial offers an exciting opportunity for a new global collaborative initiative among clinical trial groups aimed at improving the treatment of women with metastatic breast cancer," said Monica M. Bertagnolli, MD, President and Chief Executive Officer of Alliance Foundation Trials, LLC, and group chair and principal investigator of the Alliance for Clinical Trials in Oncology. "Our partnership with the Mastering Breast Cancer Initiative, PrECOG, the German Breast Group, Fondazione Michelangelo, SOLTI Breast Cancer Research Group and the Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) makes this trial available to patients across the U.S., Europe, Australia and New Zealand. PATINA is the first study of the Mastering Breast Cancer Initiative which is an umbrella organization that includes multiple clinical trials whose participants will contribute medical information and biological specimens for future research. This initiative was created in order to understand the natural history of breast cancer and how it evolves over time with the overall goal to develop new treatments for this patient population."

In the U.S., IBRANCE is indicated for the treatment of HR+, HER2-negative (HER2-) advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy. Since its initial FDA approval in 2015, more than 60,000 patients have been treated with IBRANCE in the U.S. alone.

Pre-clinical data and preliminary results from early phase clinical trials point to the potential efficacy of palbociclib when combined with anti-HER2 therapies and endocrine therapy. About 10-15% of patients with metastatic breast cancer are HR+, HER2+.1 Palbociclib is currently not approved for use in this patient population in any country.

"The current PATINA study is built on strong pre-clinical and clinical rationale demonstrating the potential of palbociclib when given in combination with endocrine therapy and anti-HER2 therapies," said Otto Metzger, MD, principal investigator of the trial for AFT and Medical Oncologist at the Dana-Farber Cancer Institute in Boston. "We hope that this trial will show that the addition of palbociclib to the first-line treatment of HR+, HER2+ disease will help delay the onset of therapeutic resistance to endocrine therapy, complement the benefits of anti-HER2 therapy and ultimately improve patient outcomes. The study also includes a comprehensive molecular characterization of the disease when patients enter the study and at the time of disease progression."

"We are pleased to partner with these prominent research groups to explore the use of palbociclib in first-line HR+, HER2+ disease," said Charles Hugh-Jones, MD FRCP, Chief Medical Officer, Pfizer Oncology. "PATINA is the first randomized, Phase 3 trial of a CDK 4/6 inhibitor in this setting. Collaborations of this kind are critical to advance our understanding of how we can treat breast cancer, and they represent an important part of Pfizer’s clinical development program for palbociclib."

The PATINA trial is a pivotal, open-label, international, multicenter, randomized Phase 3 study. The trial is open to women or men with HR+, HER2+ metastatic breast cancer following completion of induction with anti-HER2 based chemotherapy. Participants will be randomized (selected by chance) to one of two treatment arms following 6-8 cycles of chemotherapy with anti-HER2 therapy. One study arm will treat patients with palbociclib (at a dose of 125 mg orally once daily for 21 days followed by seven days off treatment in a 28-day cycle) and standard anti-HER2 therapy and endocrine therapy until disease progression. The other study arm will treat patients with standard anti-HER2 therapy and endocrine therapy until disease progression. About 500 participants will be recruited worldwide.

Alliance Foundation Trials, LLC, under the auspices of the Alliance for Clinical Trials in Oncology, has brought together a collaborative group of breast cancer specialists from around the world to team up with a pharmaceutical sponsor to form a public-private cancer research partnership aimed at bringing more innovative therapies to patients in more efficient ways.

For questions about this trial, please contact the PATINA study at [email protected].

Availability

Currently, the new study is open to physicians and medical facilities throughout the U.S. if they are associated with the Alliance Foundation and PrECOG oncology research groups. The study will be available to non-U.S. sites this fall through an extended academic core network that includes the German Breast Group (GBG), Fondazione Michelangelo, SOLTI Breast Cancer Research Group, and the Australia and New Zealand Breast Cancer Trials Group (ANZBCTG).

Information on the PATINA study can be found on the National Institutes of Health (NIH) registry of clinical trials, www.clinicaltrials.gov (Clinicaltrials.gov Identifier: NCT02947685), and on the PATINA website at www.patina-trial.com.

Funding and Sponsorship

Pfizer, the manufacturer of palbociclib (IBRANCE), is providing funding support for this trial. AFT is the global sponsor of this trial which will be conducted in the U.S., Germany, Italy, Spain, Australia, and New Zealand.

On August 22, 2017 Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that the first patient was dosed in the registrational Phase 3 MORPHO trial of gilteritinib, the fourth Phase 3 trial underway in the gilteritinib clinical development program (Press release, Astellas, AUG 22, 2017, View Source [SID1234520296]). The MORPHO trial is a randomized, double-blind, placebo-controlled, multi-center trial that compares gilteritinib to placebo as maintenance therapy over a period of two years following hematopoietic stem cell transplant (HCT) in patients with FLT3 internal tandem duplication (ITD) mutation-positive (FLT3/ITD+) acute myeloid leukemia (AML) and in remission after induction therapy. The primary endpoint is relapse-free survival (RFS), and the study is being conducted in collaboration with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).

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"We know that FLT3+ AML patients face potentially worse outcomes than those with other mutations, and while some patients may experience remission following a stem cell transplant, many unfortunately relapse," said trial investigator and BMT CTN Study co-chair Mark J. Levis, M.D., Ph.D., of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. "Given this reality, it is exciting to study gilteritinib in patients following a stem cell transplant."

Gilteritinib has demonstrated inhibitory activity against FLT3 ITD as well as FLT3 tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in approximately one third of patients with AML. Further, gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.

AML is a cancer that impacts the blood and bone marrow and is most commonly experienced in older adults. According to the American Cancer Society, in 2016 there were an estimated 21,000 new cases of AML diagnosed in the United States and about 10,600 cases resulted in death.

"The initiation of the MORPHO trial is another significant milestone for Astellas and for patients as therapeutic options can be very limited for this FLT3+ AML population," said Steven Benner, M.D., senior vice president and global therapeutic area head, oncology development, Astellas. "We are committed to patients with FLT3+ AML and currently have underway four Phase 3 trials to explore the potential benefit of gilteritinib for patients suffering from such an aggressive form of blood cancer characterized by both genetic and resistance mutations."

Astellas is currently investigating gilteritinib in various AML patient populations through several Phase 3 trials, including the registrational ADMIRAL trial in relapsed/refractory FLT3+ AML.

The safety and efficacy of the agent discussed herein are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated. Information about pharmaceutical products (including products currently in development) which is included in this press release are not intended to constitute an advertisement or medical advice.