On April 28, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that results from the international, randomized, double-blind, placebo-controlled TOURMALINE-MM1 Phase 3 clinical study, evaluating once-weekly oral NINLARO (ixazomib) capsules plus lenalidomide and dexamethasone versus placebo plus lenalidomide-dexamethasone in patients with relapsed and/or refractory multiple myeloma, have been published in the prestigious New England Journal of Medicine (NEJM) (Press release, Takeda, APR 27, 2016, View Source [SID:1234511534]).

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NINLARO was recently approved by the U.S. Food and Drug Administration (FDA), based on the pivotal TOURMALINE-MM1 data, in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

"NEJM has published the results of the first Phase 3 study supporting an all-oral triplet regimen containing a proteasome inhibitor in multiple myeloma. With the emergence of long-term treatment as a preferred approach for multiple myeloma, it is crucial that we investigate more ways to improve treatment sustainability for patients," said study co-author and lead investigator Philippe Moreau, M.D., University of Nantes, France. "The TOURMALINE-MM1 results demonstrated that ixazomib in combination with lenalidomide and dexamethasone is an effective and tolerable oral regimen with a manageable safety profile for patients with relapsed and/or refractory multiple myeloma."

"The publication of the Phase 3 TOURMALINE-MM1 trial results is another important milestone for patients and physicians. This reflects invaluable efforts from our researchers, the study investigators, the patients and their families," said Dixie-Lee Esseltine, MD, FRCPC, Vice President, Oncology Clinical Research, Takeda. "The publication concluded that the addition of ixazomib to lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. We look forward to sharing additional ixazomib data from our ongoing TOURMALINE studies over the next few years."

TOURMALINE-MM1, a double-blind, placebo-controlled trial including 722 patients, is the first Phase 3 study with an oral proteasome inhibitor. As reported in NEJM, the trial results demonstrated a statistically significant and clinically meaningful (35%) extension of PFS (HR 0.74; p = 0.01; median PFS: 20.6 months vs. 14.7 months in control group; median follow-up 14.7 months). A benefit in PFS was observed with the ixazomib regimen across pre-specified patient subgroups, including patients with poor prognosis, such as elderly patients, those who have received two or three prior therapies, those with advanced stage disease, and those with high-risk cytogenetic abnormalities. Overall response rates were 78% in the ixazomib arm versus 72% in the placebo group and at least very good partial response rates were 48% versus 39%. The median time to response was 1.1 months in the ixazomib arm versus 1.9 months in the placebo group, and median duration of response was 20.5 versus 15.0 months, respectively. In the ixazomib and placebo groups, frequencies of serious adverse events (47% vs. 49%) and on-study deaths (4% vs. 6%) were similar; 74% and 69% of patients experienced grade ≥3 adverse events. Grade 3 and 4 thrombocytopenia was more frequent in the ixazomib (12 and 7%) vs. placebo group (5 and 4%). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group, and no grade 4 events were reported). Please see below for the full U.S. prescribing information of NINLARO (ixazomib) capsules.

Data from TOURMALINE-MM1 were previously presented at the 57th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida.

NINLARO is currently under review by the European Medicines Agency (EMA). Takeda has also submitted applications for approval of ixazomib to additional health authorities around the world.

About NINLARO (ixazomib) capsules
NINLARO (ixazomib) is the first and only oral proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is administered orally, once-weekly 4 mg fixed dose on days 1, 8, and 15 of a 28-day treatment cycle. NINLARO also received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.

The comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of five ongoing pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. This trial is currently ongoing, and patients continue to be treated to progression and will be evaluated for long-term outcomes.

TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma

TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)

TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT

TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis

In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

For additional information on the studies please visit www.clinicaltrials.gov. To learn more about NINLARO, please visit www.NINLARO.com or call 1-844-N1POINT (1-844-617-6468).

Important Safety Information

WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle.

Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for severe symptoms.

Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms.

Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification.

Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in
< 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly during treatment and adjust dosing as needed.

Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) in the NINLARO regimen and greater than the placebo regimen, respectively, were diarrhea (42%, 36%), constipation (34%, 25%), thrombocytopenia (78%, 54%; pooled from adverse events and laboratory data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%).

SPECIAL POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.
Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.
Lactation: Advise women to discontinue nursing while on NINLARO.
DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers.

Please see the accompanying NINLARO full Prescribing Information.

About Multiple Myeloma

Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies. These malignant plasma cells have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with more than 26,000 new cases in the U.S. and 114,000 new cases globally per year.

On April 27 2016 Servier reported that the European Commission (EC) has granted marketing authorization for LONSURF (trifluridine/tipiracil), formerly known as TAS-102, in the European Union (EU) for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents (Press release, Servier, APR 27, 2016, View Source [SID:1234511504]).

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LONSURF is an oral anticancer drug, comprising the combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity.

"Data from the pivotal RECOURSE study provides evidence that LONSURF may offer patients with refractory metastatic colorectal cancer extended survival as well as a reduction in risk of death compared to placebo," said Professor Eric Van Cutsem, MD, PhD, Digestive Oncology, University Hospitals Leuven in Belgium. "The combination of trifluridine and tipiracil in LONSURF works by directly attacking the DNA of the tumor cells which reduces the growth of cancer cells. This approach fights the cancer differently to other previously given treatments, allowing us to delay cancer progression rather than cycling back through therapies that have already been used."

"With this approval, we are delivering on a promise to bring a new treatment to patients with advanced metastatic colorectal cancer across Europe," said Dr. U. Marion Schrenk, Head of Global Medical Strategy, Oncology at Servier. "We are excited about this important milestone, which demonstrates Servier’s commitment to improving the lives of patients living with cancer. LONSURF has also been shown to prolong progression-free survival and preserve performance status, allowing patients to make time for more moments that matter."

The decision from the EC follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending the approval of LONSURF in February 2016.1 Both the CHMP opinion and the EC decisions were based on data from the international, double-blind, placebo-controlled Phase III RECOURSE study, which investigated the efficacy and safety of LONSURF with best supportive care (BSC) compared to placebo with BSC in 800 patients with previously treated mCRC. The study met the primary endpoint of statistically significant improvement in overall survival (OS).

About RECOURSE

RECOURSE is an international, double-blind, placebo-controlled Phase III study, which investigated the efficacy and safety of LONSURF with BSC compared to placebo with BSC in 800 patients with previously treated mCRC, among which 403 were treated in Europe.3 The study met the primary endpoint of statistically significant improvement in OS. Results demonstrated a 32% reduction in risk of death compared to BSC (HR=0.68; 95% CI: 0.58 to 0.81 p<0.001). An updated OS analysis in 89% of events, presented at ASCO (Free ASCO Whitepaper) GI 2016, confirmed the clinically meaningful and statistically significant survival benefit of LONSURF with BSC compared to placebo with BSC. This translates into a 31% relative reduction in the risk of death (HR=0.69; 95% CI: 0.59 to 0.81; p<0.0001) and an improvement of 2 months in the median OS. The median OS was 7.2 months for LONSURF with BSC vs 5.2 months for placebo with BSC, this translated into 1-year survival rates of 27.1% and 16.6%, respectively.

The most frequently observed side effects (≥ 30%) in patients receiving LONSURF were neutropenia, nausea, decreased appetite, diarrhea, fatigue, anemia, thrombocytopenia, increase in total bilirubin, alkaline phosphatase and ASAT levels, and leucopenia.

About Metastatic Colorectal Cancer

There remains a high unmet need in the treatment of colorectal cancer (CRC), which was the second leading cause of cancer-related deaths in Europe in 2012, responsible for 215,000 deaths.4 Approximately 25% of patients with CRC present with metastases at initial diagnosis and almost 50% of patients with CRC will develop metastases.5 This contributes to the high mortality rates reported for CRC; the 5-year survival rate of patients diagnosed with stage IV mCRC is about 11%.

About LONSURF

LONSURF is currently available in Japan for the treatment of unresectable advanced or recurrent CRC and in the United States for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine -, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.6,7,8 LONSURF is an oral anticancer drug, comprising the combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity and differs from fluoropyrimidines. FTD is an antineoplastic nucleoside analog, which is incorporated directly into DNA, thereby interfering with the function of DNA. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme, thymidine phosphorylase.

In June 2015, Servier entered into an exclusive license agreement with Taiho Pharmaceutical Co., Ltd. for the co-development and commercialization of LONSURF. Under the terms of the agreement, Servier has the rights to co-develop and commercialize LONSURF in Europe and other countries outside of the United States, Canada, Mexico and Asia. Taiho Pharmaceutical retains the right to develop and commercialize LONSURF in the United States, Canada, Mexico, and Asia and to manufacture and supply the product.

On April 27, 2016 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company developing checkpoint antibodies and cancer vaccines, reported that the first patient has been dosed in the company’s Phase 1 clinical trial of AGEN1884, an anti-CTLA-4 checkpoint (CPM) antibody (Press release, Agenus, APR 27, 2016, View Source [SID:1234511496]).

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The open-label, multicenter trial in patients with advanced or refractory cancer is designed to evaluate the safety of AGEN1884 and determine the estimated maximum tolerated dose.

"Advancing AGEN1884 into the clinic is an important milestone for Agenus," said Garo Armen, PhD, Chairman and CEO of Agenus. "Since the acquisition of 4-Antibody two years ago, we have completed additional strategic acquisitions and formed new collaborations considerably strengthening our antibody research and development capabilities."

AGEN1884 is an anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) checkpoint antibody that enables the immune system to find and destroy cancer cells. It is the first of a series of CPMs, discovered using Agenus’ proprietary platform, to enter clinical development. Anti-CTLA-4 antibodies have been highly efficacious in treating cancer and curative in some patients for whom standard of care has proven unsuccessful. Recent clinical data also suggests that anti-CTLA-4 antibodies are emerging as a central component of combination immunotherapeutic regimens for fighting cancer.

Agenus has in-house technologies for rapid discovery and development of CPMs using its integrated mammalian, yeast and phage display platforms. The company also possesses the capability to generate optimal cell lines and manufacture GMP grade antibodies and vaccines.

"We expect additional checkpoint antibodies from our portfolio to commence clinical trials during the course of this year. We believe our CPMs, vaccines and adjuvants will provide advantages in advancing the fight against cancers. This effort will be particularly enhanced by our ability to combine these agents as required," said Robert B. Stein, MD, PhD, Agenus’ President, Research & Development.

This Phase 1 clinical trial is taking place at leading centers in the United States, including The Ohio State University Comprehensive Cancer Center and the Comprehensive Cancer Center of Northwestern University. AGEN1884 was developed under a Collaborative Research and Development Agreement between Ludwig Cancer Research, 4-Antibody AG and Recepta Biopharma S.A.

About Checkpoint Antibodies

Promising clinical data from trials employing monoclonal antibodies that bind to checkpoint molecules, such as CTLA-4 and programmed death receptor-1 (PD-1), have generated considerable excitement in the field of cancer immunotherapy. These molecules serve as checks employed by the body to prevent a runaway immune response, which can be debilitating and even deadly. Unfortunately, these necessary mechanisms of control can hinder the anti-cancer immune response. They can be harnessed by cancer cells as a defense against immune attack. Agenus is developing a broad pipeline of antibodies that bind to key checkpoint proteins and activate or block their activities for use in cancer therapy.

On April 27, 2016 Celldex Therapeutics, Inc. (Nasdaq:CLDX) reported that it has initiated an open-label Phase 1/2 safety and tolerability study of glembatumumab vedotin in patients with unresectable stage IIIB or IV, gpNMB-expressing, advanced or metastatic squamous cell carcinoma (SCC) of the lung, who have progressed on prior platinum-based chemotherapy (Press release, Celldex Therapeutics, APR 27, 2016, View Source [SID:1234511479]).

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Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets gpNMB, a protein overexpressed by multiple tumor types, including SCC of the lung, where approximately 85 percent of patients overexpress the marker. Overexpression of gpNMB has been shown to promote the invasion and metastasis of cancer and has been associated with poor clinical outcome. Celldex has entered into a collaborative relationship with PrECOG, LLC, which represents a research network established by the Eastern Cooperative Oncology Group (ECOG), and PrECOG, LLC will conduct the study.

"While checkpoint inhibitor therapy has been an important development for patients with squamous cell lung cancer, the majority of patients still require new, effective treatment options—especially targeted therapies," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "gpNMB, the target of glembatumumab vedotin, is strongly expressed in the vast majority of squamous cell lung cancers. Glembatumumab vedotin has consistently induced notable response rates in other difficult to treat cancers that overexpress gpNMB. We hope to elicit similar activity in squamous cell carcinoma and look forward to completing this study."

Glembatumumab vedotin is currently being evaluated in patients with metastatic triple negative breast cancers that overexpress gpNMB in the registrational METRIC study, as well as in a Phase 2 study in patients with advanced melanoma who have progressed after at least one checkpoint inhibitor therapy and, if applicable, BRAF- or MEK-targeted therapy. It has been previously evaluated in a Phase 2 study in advanced breast cancer (the EMERGE study), a Phase 1/2 study in advanced breast cancer and a Phase 1/2 study in patients with unresectable stage III or IV melanoma. Also, Celldex and the National Cancer Institute (NCI) have entered into a Cooperative Research and Development Agreement (CRADA) under which the NCI is sponsoring two studies of glembatumumab vedotin—one in uveal melanoma and one in pediatric osteosarcoma. Both studies are currently open to enrollment.

Study Design
This Phase 1/2 study will enroll patients with gpNMB-positive stage IIIB or IV non-small cell lung cancer (NSCLC) of squamous histology who have previously been treated with platinum-based chemotherapy. gpNMB positivity will be determined by a greater than, or equal to, five percent gpNMB expression in tumor epithelial cells. Glembatumumab vedotin will be administered once every three weeks until disease progression or intolerance. The study is expected to include 10 sites in the United States.

The study will include a dose-escalation phase followed by a two-stage Phase 2 portion (Simon two-stage design). The Phase 1, dose-escalation portion of the study will assess the safety and tolerability of glembatumumab vedotin at the current dose of 1.9 mg/kg and then 2.2 mg/kg in order to determine whether higher dosing is feasible in this population. The first stage of the Phase 2 portion will enroll approximately 20 patients, and if at least two patients achieve a partial response or complete response, a second stage may enroll an additional 15 patients. The primary objective of the Phase 2 portion of the study is to assess the anti-tumor efficacy of glembatumumab vedotin in squamous cell lung cancer as measured by objective response rate (ORR). Secondary objectives of the study include analyses of safety and tolerability and further assessment of anti-tumor activity across a broad range of endpoints.

About Squamous Cell Lung Cancer
Lung cancer is the leading cause of cancer related deaths in the world, with an estimated one million new cases worldwide and around 216,000 in the U.S. annually. Non-small cell lung cancer (NSCLC) represents more than 80 percent of all lung cancers, and squamous cell carcinoma (SCC) of the lung accounts for approximately 30 to 40 percent of NSCLC. While new treatment options, especially targeted therapies, have become available for patients with adenocarcinoma, another type of NSCLC, clinical studies have not identified targeted therapies with major benefits for patients with SCC of the lung. Recent improvements for patients with SCC of the lung include checkpoint immunotherapy; however, not all patients respond to this treatment, and new therapeutic options are needed. Approximately 85 percent of patients with SCC of the lung have tumors that overexpress gpNMB, the target of glembatumumab vedotin.

About Glembatumumab Vedotin
Glembatumumab vedotin (CDX-011) 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, head and neck cancer, uveal melanoma, osteosarcoma, pancreatic cancer and glioblastoma. 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, uveal melanoma and osteosarcoma.