On January 18, 2018 Kite, a Gilead Company (Nasdaq: GILD), reported it has entered into a clinical trial collaboration with Pfizer, Inc. to evaluate the safety and efficacy of the investigational combination of Yescarta (axicabtagene ciloleucel) and Pfizer’s utomilumab, a fully humanized 4-1BB agonist monoclonal antibody, in patients with refractory large B-cell lymphoma (Press release, Kite Pharma, JAN 18, 2018, View Source;p=irol-newsArticle&ID=2327256 [SID1234523300]). A multi-center Phase 1/2 study sponsored by Kite is expected to begin in 2018. The results of this study will be used to evaluate options for further development of this combination, or similar combinations between Kite’s engineered T cell products and utomilumab.

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Yescarta is the first chimeric antigen receptor T (CAR T) cell therapy to be indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for patients with primary central nervous system lymphoma.

Utomilumab, also known as PF-05082566, is an investigational 4-1BB agonist that has been shown in preclinical models to enhance T cell mediated immune responses. Pfizer is currently investigating utomilumab in both hematologic cancers and solid tumors as a single agent and in combination with other anti-cancer therapies. Evidence also suggests that 4-1BB, a costimulatory protein expressed on activated T cells, is upregulated upon exposure to CD19-expressing tumor cells. Utomilumab could potentially enhance T cell proliferation and activity by augmenting the CD28 costimulatory domain of Yescarta with exogenous 4-1BB signaling.

"Kite is committed to realizing the full potential of Yescarta and other cell therapy technologies across a range of cancers," said David Chang, MD, PhD, Worldwide Head of Research and Development and Chief Medical Officer at Kite. "We are pleased to collaborate with Pfizer on this study with utomilumab, which adds to the growing number of combination approaches we are exploring with Yescarta for patients living with lymphoma."

The combination of Yescarta and utomilumab is investigational and has not been proven safe and effective.

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.

Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with Yescarta. In Study 1, CRS occurred in 94% (101/108) of patients receiving Yescarta, including ≥ Grade 3 (Lee grading system) CRS in 13% (14/108) of patients. Among patients who died after receiving Yescarta, four had ongoing CRS events at the time of death. The median time to onset was 2 days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

Neurologic Toxicities

Neurologic toxicities, that were fatal or life-threatening, occurred following treatment with Yescarta. Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks of Yescarta infusion, with a median time to onset of 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities occurred in 31% of patients.

The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta.

Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

Yescarta REMS

Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are:

Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities.

Further information is available at www.YescartaREMS.com or 1-844-454-KITE (5483).

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of Yescarta. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

Serious Infections

Severe or life-threatening infections occurred in patients after Yescarta infusion. In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines.

Febrile neutropenia was observed in 36% of patients after Yescarta infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated.

Viral Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in (28%) of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Yescarta. In Study 1, hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment with Yescarta and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment with Yescarta.

Secondary Malignancies

Patients treated with Yescarta may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving Yescarta are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions

The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia.

The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections.

U.S. Indication for Yescarta

Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitation of Use: Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

On January 18, 2018 MacroGenics, Inc. (NASDAQ:MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported presentation of data from its clinical trial of margetuximab plus pembrolizumab for patients with advanced gastric and gastroesophageal junction (GEJ) cancers in a poster session at the 2018 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in San Francisco, California (Press release, MacroGenics, JAN 18, 2018, View Source [SID1234523293]). The poster was titled "Phase 1b/2 Study of Margetuximab Plus Pembrolizumab in Advanced HER2+ Gastroesophageal Junction or Gastric Adenocarcinoma."

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This Phase 1b/2 open-label, dose escalation study evaluates margetuximab, an Fc-optimized anti-HER2 monoclonal antibody, in combination with pembrolizumab, an anti-PD-1 antibody. The trial seeks to characterize the safety, tolerability, maximum tolerated dose, and preliminary anti-tumor activity of this combination. Enrolled patients had relapsed or refractory advanced HER2+ gastric or GEJ cancer with disease progression after or resistance to treatment with trastuzumab plus chemotherapy. Study patients were enrolled irrespective of PD-L1 expression status.

A Phase 1b dose escalation segment of the study tested dose levels of 10 and 15 mg/kg margetuximab in combination with a flat dose of 200 mg pembrolizumab every three weeks. After completion of dose escalation, Phase 2 dose expansion cohorts were enrolled, including a 30 patient cohort in North America and a 30 patient cohort in Asia. Sixty dose expansion patients received margetuximab at 15 mg/kg and 200 mg of pembrolizumab every three weeks.

Acceptable tolerability was observed in the safety population of 67 patients. Grade 3 or higher treatment-related adverse events (TRAE) occurred in 11.9% of patients. The most common TRAE of any grade was fatigue (14.9%).

As of the December 4, 2017 data cut-off date, responses were evaluable from 51 patients, including 25 with gastric and 26 with GEJ cancer. The Overall Response Rate (ORR) was higher in patients with gastric vs. GEJ cancer (32% vs. 4%). ORR across all patients in the study was 18% (six confirmed and three unconfirmed patients). Similarly, Disease Control Rate (including partial responses and stable disease) was higher in patients with gastric vs. GEJ cancer (72% vs. 38%). Median progression-free survival was also higher in patients with gastric vs. GEJ cancer (5.5 vs. 1.4 months).

"We are encouraged by the tolerability and anti-tumor activity of this novel, chemotherapy-free regimen combining margetuximab with an anti-PD-1 mAb for treatment of patients with advanced HER2+ gastric cancer," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "We are expanding the study by enrolling 25 additional gastric cancer patients and will continue to evaluate biomarkers, including HER2 and PD-L1 expression, to determine the patients who are most likely to benefit from margetuximab plus anti-PD-1 therapy. We expect to provide an update on these data later this year and define future development options for this regimen in the context of existing standard-of-care."

The poster presented at the 2018 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium is available for download from the Events & Presentations page on MacroGenics’ website at View Source

About Margetuximab

Margetuximab is an Fc-optimized monoclonal antibody that targets the human epidermal growth factor receptor 2, or HER2 oncoprotein. HER2 is expressed by tumor cells in breast, gastric, gastroesophageal, bladder and other forms of solid tumor cancers, making it a key marker for biologic therapy. The Phase 1b/2 study of margetuximab in gastric and gastroesophageal cancer incorporates pembrolizumab, which is provided by Merck & Co., under a previously announced arrangement. MacroGenics is also studying margetuximab as a potential treatment for metastatic breast cancer in a Phase 3 study called SOPHIA, for which an interim futility analysis is expected to be completed by the end of January 2018.

On January 18, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that updated phase 1 safety and efficacy data for DS-8201, an investigational HER2-targeting antibody drug conjugate (ADC), in a subgroup of patients with HER2-expressing gastric cancer previously treated with trastuzumab and chemotherapy were presented during a poster session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in San Francisco, California (Press release, Daiichi Sankyo, JAN 18, 2018, View Source [SID1234523291]).

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Updated preliminary subgroup analysis results in 44 of 45 efficacy evaluable patients with HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma previously treated with trastuzumab and chemotherapy showed that DS-8201 demonstrated a confirmed overall response rate of 45.5 percent (20 of 44 patients) and a disease control rate of 81.8 percent (36 of 44 patients). Median duration of response was 7.0 months (95 percent CI: NR). The Kaplan-Meier estimate of median progression-free survival was 5.8 months (95 percent CI: 3.0, 8.3). A total of 17 out of 44 patients were continuing to receive treatment at the time of data cut-off.

"Gastric cancer can be difficult to treat due to its molecular complexity, and currently there are no HER2- targeted therapies or antibody drug conjugates approved for HER2-positive advanced gastric cancer that progresses following treatment with trastuzumab," said Toshihiko Doi, MD, PhD, Department of Experimental Therapeutics, National Cancer Center Hospital East. "These phase 1 results are encouraging and demonstrate the importance of continuing to study the potential of DS-8201 in treating HER2-positive gastric cancer. The pivotal phase 2 study is currently underway."

A subgroup analysis of 23 patients previously treated with CPT-11 (irinotecan) showed that DS-8201 demonstrated a confirmed overall response rate of 43.5 percent (10 of 23 patients) and a disease control rate of 82.6 percent (19 of 23 patients). Median duration of response was 6.9 months (95 percent CI: NR).

The Kaplan-Meier estimate of median progression-free survival for this subgroup of patients was 4.1 months (95 percent CI: 2.5, 8.3).

"These data from patients with HER2-positive gastric cancer who have failed HER2-targeted therapy combined with chemotherapy, and for many who also failed irinotecan as a systemic chemotherapy suggest that the ADC technology of DS-8201 appears able to deliver on what it was specifically researched and innovated for: a smart chemotherapy approach to tumors expressing some degree of HER2 receptors, regardless of prior treatment with a topoisomerase I inhibitor," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "A comprehensive translational research effort is planned and underway to further understand the biological basis for the observed activity, including the role of tumor heterogeneity and HER2 expression, the mechanisms of resistance that may have contributed to failing prior lines of treatment, and factors more directly related to the unique pharmacological profile of DS-8201."

Updated preliminary safety data for this subgroup of trastuzumab-treated HER2-expressing gastric cancer patients were also reported. The most common adverse events (>30 percent, any grade) included nausea (71.1 percent), decreased appetite (64.4 percent), platelet count decreased (33.3 percent), white blood cell count decreased (33.3 percent) and constipation (31.1 percent). Grade 3 adverse events occurring in >10 percent of patients included anemia (24.4 percent), neutrophil count decreased (15.6 percent), platelet count decreased (13.3 percent) and white blood cell count decreased (11.1 percent). Grade 4 adverse events included platelet count decreased (4.4 percent), white blood cell count decreased (4.4 percent) and neutrophil count decreased (4.4 percent). Three patients discontinued treatment due to treatment-emergent adverse events (pneumonia, decreased appetite, and pneumonitis). Two potential cases of interstitial lung disease (ILD) were reported by the investigators (one grade 1 and one grade 3) in gastric cancer subjects and together with all reported or suspected ILD cases are being assessed by an independent ILD adjudication committee. These include two cases of potential Grade 5 pneumonitis previously reported in the breast cancer cohorts.

Based on these phase 1 data, patients are currently being enrolled in the pivotal, phase 2 open-label DESTINY-Gastric01 study investigating the safety and efficacy of DS-8201 in patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two prior regimens including fluoropyrimidine agent, platinum agent and trastuzumab. For more information about this study, visit www.ClinicalTrials.gov.

Unmet Need in Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide, with nearly one million new cases reported in 2012.1 Approximately one in five gastric cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells.2 HER2-expressing gastric cancer is an area of unmet medical need as advances in the treatment of the disease have been limited, largely due to its genetic complexity and heterogeneity.3 Currently, there are no approved HER2-targeting therapy options for patients with HER2-positive advanced gastric cancer after treatment with trastuzumab.

About the DS-8201 Phase 1 Study

The open-label, two-part phase 1 study is currently evaluating DS-8201 in patients with advanced/

unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of the study was to assess the safety and tolerability of DS-8201 and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.4

In the dose expansion part of the phase 1 study, DS-8201 is given to patients with HER2-positive advanced or metastatic breast cancer or gastric cancer, HER2 low-expressing breast cancer or other HER2-expressing or mutant solid tumors. Patient enrollment in the two breast cancer cohorts and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan. For more information about the study, please visit ClinicalTrials.gov.

About DS-8201

DS-8201 is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in pivotal phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (T-DM1) (DESTINY-Breast01), pivotal phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01), and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science Franchise, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/

immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: DS-8201, an antibody drug conjugate (ADC) for HER2-expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com

On January 18, 2018 Cellular Biomedicine Group Inc. (NASDAQ: CBMG) (CBMG or the Company), a leading clinical-stage biopharmaceutical firm engaged in the development of immunotherapies for cancer, reported its plan to configure part of its facility in Shanghai with GE Healthcare’s FlexFactory platform, which is expected to be designed to speed up manufacturing timelines for its cell therapy clinical trials and commercial launch (Press release, Cellular Biomedicine Group, JAN 18, 2018, View Source [SID1234523290]).

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There are more than 900 regenerative medicine trials underway globally, including trials in cell and gene therapy, a 19 percent increase since 2016.[1] Despite the increased number of precision medicine trials, gaps exist in how to manufacture these precise therapies to meet demand. Scalable integrated solutions to support the transition from clinical trials to commercialization have been limited. Many of the multiple cell therapy manufacturing process steps[2] remain largely unintegrated and manual, with open transfers between steps increasing contamination risk. To address these challenges and allow for reproducible manufacturing of cell therapies, GE Healthcare has developed FlexFactory for cell therapy, a scalable, semi-automated end-to-end platform.

"This is a productivity revolution in the CAR-T space – this new generation of semi-automated and standardized CAR-T manufacturing capabilities created by GE Healthcare and CBMG may allow cell therapy to provide an optimal platform and opportunity for general oncology patients. This long-term collaboration with GE could help us utilize digital technology, semi-automation and analytics, in an effort to reduce overall costs, and deliver treatments to patients more efficiently," said Tony (Bizuo) Liu, Chief Executive Officer, CBMG. GE Healthcare’s FlexFactory solution would support CBMG by providing process development and training services, cell processing equipment, semi-automation capabilities, and digital connectivity solutions – all of which support current good manufacturing practices (cGMP)-compliant manufacturing. CBMG plans to use its FlexFactory to speed up its timelines for commercializing its CAR T-cell therapies, targeting various blood and solid tumor cancers.

"With the rate in which cell therapies are moving through clinical trials, we understand how critentre for Commercialization of Regenerative Medicine (CCRM), a leader in developing and commercializing regenerative medicine technologies and cell and gene therapies, GE Healthcare expects to provide CBMG with process development services. The combined GE and CCRM process development team is comprised of 35 scientists and engineers with expertise in advanced therapeutic cell technologies, helping bridge the gap between research protocols and industrial manufacturing. GE and CCRM expects to support CBMG in increasing process efficiency by establishing a robust process development effort focused on simplifying, integrating and automating the manufacturing workflow.

"CCRM and GE Healthcare established the Centre for Advanced Therapeutic Cell Technologies, or CATCT, to industrialize cell manufacturing and accelerate the efforts of companies working with cell and gene therapies. The partnership between CBMG and GE is an exciting opportunity for the team at CCRM to demonstrate its process development skills and knowledge in overcoming cell therapy production challenges. We look forward to enabling CBMG in its efforts to commercialize its CAR T-cell therapy to treat patients with various blood and solid tumor cancers," said Michael May, President and CEO, CCRM.

On January 18, 2018 Amgen (NASDAQ: AMGN) and Allergan plc. (NYSE: AGN) reported that the European Commission (EC) has granted marketing authorization for MVASI (biosimilar bevacizumab) (Press release, Amgen, JAN 18, 2018, View Source;p=RssLanding&cat=news&id=2327358 [SID1234523289]). MVASI is the first biosimilar bevacizumab approved by the EC and is approved for the treatment of certain types of cancers, including in combination with fluoropyrimidine-based chemotherapy for metastatic carcinoma of the colon or rectum; in combination with paclitaxel for metastatic breast cancer; in combination with platinum-based chemotherapy for unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC); in combination with erlotinib for unresectable advanced, metastatic or recurrent non-squamous NSCLC; in combination with interferon alfa-2a for advanced and/or metastatic renal cell cancer; in combination with carboplatin and paclitaxel, carboplatin and gemcitabine, and paclitaxel, topotecan, or pegylated liposomal doxorubicin for advanced, platinum-sensitive, or platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; and in combination with paclitaxel and cisplatin, or alternatively, paclitaxel and topotecan for persistent, recurrent, or metastatic carcinoma of the cervix.

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"The European Commission’s approval of MVASI marks a significant milestone for both Amgen and the oncology community, providing a biosimilar for a medicine which is used across multiple types of cancer," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "MVASI is the first targeted cancer biosimilar from Amgen’s portfolio approved in Europe, underscoring our commitment to delivering high-quality medicines that address some of the most serious illnesses."

Amgen and Allergan are committed to developing high-quality biosimilars with a robust analytic and clinical package. The EC approved MVASI based on a comprehensive data package that demonstrated MVASI and bevacizumab are highly similar, with no clinically meaningful differences in terms of the efficacy, safety and immunogenicity between the products. Clinical studies included results from a Phase 3 trial in patients with non-squamous NSCLC.

"MVASI is the first product from our collaboration with Amgen to receive marketing authorization from the European Commission, highlighting the success of our joint commitment to developing cancer biosimilars," said David Nicholson, chief research and development officer at Allergan. "We look forward to our continued work with Amgen and to providing important medicines to patients in the future."

Approval from the EC grants a centralized marketing authorization with unified labeling in the 28 countries that are members of the European Union (EU). Norway, Iceland and Liechtenstein, as members of the European Economic Area, will take corresponding decisions on the basis of the decision of the EC.

In September 2017, MVASI became the first anti-cancer biosimilar, as well as the first biosimilar bevacizumab, to be approved by the U.S. Food and Drug Administration (FDA). Amgen and Allergan are collaborating on the development and commercialization of four oncology biosimilars. Amgen has a total of 10 biosimilars in its portfolio, two of which have been approved by the EC.

About MVASI (biosimilar bevacizumab) in the EU

MVASI is a biosimilar to bevacizumab, a recombinant immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to vascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2, thus inhibiting establishment of new blood vessels necessary for the maintenance and growth of solid tumors.

MVASI, in combination with fluoropyrimidine-based chemotherapy, is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum.

MVASI, in combination with paclitaxel, is indicated for first-line treatment of adult patients with metastatic breast cancer.

MVASI, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent NSCLC other than predominantly squamous cell histology.

MVASI, in combination with erlotinib, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous NSCLC with Epidermal Growth Factor Receptor (EGFR) activating mutations.

MVASI, in combination with interferon alfa-2a, is indicated for first-line treatment of adult patients with advanced and/or metastatic renal cell cancer.

MVASI, in combination with carboplatin and paclitaxel, is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer.

MVASI, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

MVASI, in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin, is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

MVASI, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix.

MVASI EU Important Safety Information

The EU Summary of Product Characteristics for MVASI lists the following Special Warnings and Precautions: gastrointestinal (GI) perforations and fistulae, GI-vaginal fistulae in study GOG-0240, non-GI fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome (PRES), proteinuria, arterial thromboembolism, venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure (CHF), neutropenia and infections, hypersensitivity reactions/infusion reactions, osteonecrosis of the jaw (ONJ), intravitreal use, eye disorders, systemic effects following intravitreal use, and ovarian failure/fertility.

About MVASI (bevacizumab-awwb) in the U.S.

MVASI is a biosimilar to bevacizumab, a recombinant IgG1 mAb that binds to VEGF and inhibits the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2, thus inhibiting establishment of new blood vessels necessary for the maintenance and growth of solid tumors.

MVASI is indicated for the treatment of metastatic colorectal cancer (mCRC), with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment.

MVASI is indicated for the treatment of mCRC, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen. MVASI is not indicated for adjuvant treatment of colon cancer.

MVASI is indicated for the treatment of non-squamous NSCLC, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.

MVASI is indicated for the treatment of glioblastoma, as a single agent for adult patients with progressive disease following prior therapy.

The effectiveness of bevacizumab products in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with bevacizumab products.

MVASI is indicated for the treatment of metastatic renal cell carcinoma with interferon alfa.

MVASI is indicated for the treatment of cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease.

MVASI is currently not available commercially. This is not an offer for sale. The following information is derived from the approved label in the U.S.

MVASI U.S. Important Safety Information

Boxed WARNINGS

Gastrointestinal (GI) Perforations

The incidence of gastrointestinal perforation, some fatal, in bevacizumab product-treated patients ranges from 0.3-3.2%. Fatal outcome was reported in <1% of bevacizumab-treated patients. Discontinue MVASI in patients with gastrointestinal perforation.

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab product-treated patients. Discontinue MVASI in patients with wound dehiscence. The appropriate interval between termination of bevacizumab products and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days after surgery and until the surgical wound is fully healed.

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab products. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 6.9%. Do not administer MVASI to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue MVASI in patients with serious hemorrhage (ie, requiring medical intervention).

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI fistulae (up to 2% in metastatic colorectal cancer)
Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial)
Arterial thromboembolic events (grade ≥3, 2.6%)
Proteinuria (nephrotic syndrome, <1%)
Additional serious adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
Venous thromboembolism (grade 3-4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with chemotherapy and bevacizumab product
Hypertension (grade 3-4, 5%-18%)
Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
Infusion reactions with the first dose of bevacizumab product-treated patients were uncommon (<3%), and severe reactions occurred in 0.2% of patients
Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with MVASI
Pregnancy warning

Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that MVASI may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with MVASI and for 6 months after the last dose of MVASI
Advise nursing women that breastfeeding is not recommended during treatment with MVASI
MVASI may impair fertility
Most Common Adverse Events

Across indications, the most common adverse reactions observed in bevacizumab product-treated patients at a rate of >10% and at least twice the control arm rate were: epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab product was discontinued in 8.4% to 21% of patients because of adverse reactions.
Please see full Prescribing Information, including Boxed WARNINGS, at www.Amgen.com.

About the Amgen and Allergan Collaboration

In December 2011, Amgen and Allergan plc. (then Watson Pharmaceuticals, Inc.) formed a collaboration to develop and commercialize, on a worldwide basis, four oncology antibody biosimilar medicines. This collaboration reflects the shared belief that the development and commercialization of biosimilar products will not follow a pure brand or generic model, and will require significant expertise, infrastructure, and investment to ensure safe, reliably supplied therapies for patients. Under the terms of the agreement, Amgen will assume primary responsibility for developing, manufacturing and initially commercializing the oncology antibody products.

About Amgen Biosimilars

Amgen Biosimilars is committed to building upon Amgen’s experience in the development and manufacturing of innovative human therapeutics to expand Amgen’s reach to patients with serious illnesses. Biosimilars will help to maintain Amgen’s commitment to connect patients with vital medicines, and Amgen is well positioned to leverage its more than 35 years of experience in biotechnology to create high quality biosimilars and reliably supply them to patients worldwide.

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About Amgen’s Commitment to Oncology

Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.