On April 5, 2016 Merck and Pfizer (NYSE:PFE) reported the treatment of the first patient in a Phase III study of avelumab*, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, in an advanced renal cell carcinoma (RCC) setting (Press release, Pfizer, APR 5, 2016, View Source [SID:1234510394]).

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The study, JAVELIN Renal 101, is the first pivotal trial investigating avelumab in combination with INLYTA (axitinib), a tyrosine kinase inhibitor (TKI), in patients with previously untreated advanced RCC, and the only Phase III trial currently evaluating an anti-PD-L1 immunotherapy in combination with a vascular endothelial growth factor (VEGF)-receptor TKI in this setting. The 5-year survival rate for patients with distant metastatic RCC is approximately 12 percent.1

"Pfizer has a strong heritage in the treatment of metastatic RCC, and through the strategic alliance with Merck, we aim to further accelerate the development of potential therapies to help improve the lives of patients living with this disease," said Chris Boshoff, M.D., PhD., Vice President and Head of Early Development, Translational and Immuno-Oncology at Pfizer Oncology. "As renal cell carcinoma is an immunogenic type of tumor that can respond to immunotherapy and to anti-angiogenic treatment, there is a strong scientific rationale for combining avelumab with INLYTA and we believe that this combination may help improve outcomes for patients with this cancer."

JAVELIN Renal 101 is a multicenter, international, randomized (1:1), open-label Phase III trial designed to evaluate the potential superiority, assessed by the progression-free survival (PFS), of first-line avelumab combined with INLYTA compared with SUTENT(sunitinib malate) monotherapy, an oral, small-molecule, multi-targeted receptor TKI, in patients with unresectable, locally advanced or metastatic RCC with clear cell component. The study will enroll 583 patients across approximately 170 sites in Asia, Europe, Latin America and North America.

"The first patient receiving treatment in this pivotal trial marks an important milestone in the strategic immuno-oncology alliance between Merck and Pfizer," said Alise Reicin, M.D., Head of Global Clinical Development at the biopharma business of Merck. "As part of the JAVELIN clinical development program, we are exploring the potential of innovative, rational combination therapies, which combine avelumab with other treatment modalities to address significant unmet needs that exist in challenging cancers, such as advanced renal cell carcinoma."

The clinical development program for avelumab now includes more than 1,600 patients who have been treated across more than 15 tumor types.

INLYTA is currently approved in the United States for the treatment of advanced RCC after failure of one prior systemic therapy. INLYTA is also approved by the European Medicines Agency for use in the European Union in adult patients with advanced RCC after failure of prior treatment with SUTENT or a cytokine. Following its approval in 2012, INLYTA has become a standard of care for second-line advanced RCC and has been used by an estimated 12,000 metastatic renal cell carcinoma patients in the United States.2 INLYTA is under investigation in combination with avelumab for the indication studied in this Phase III trial.

*Avelumab is the proposed International Non-proprietary Name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

About Renal Cell Carcinoma

Renal cell carcinoma accounts globally for 2-3% of all malignancies.3 As of 2012, more than 338,000 new cases of kidney cancer were diagnosed per year worldwide.4 In general, higher incidence rates of renal cell carcinoma occur in Eastern Asia, North America and Central/Eastern Europe.5 Early-stage renal cancers tend to have a better prognosis, compared with advanced/metastatic renal cancers.6

The five-year survival rate for localized kidney and renal pelvis cancer is approximately 90%.1 The five-year overall survival rate for patients with distant metastatic RCC is approximately 12%.1

In the past 7 years, major advances have been made in the improvement of clinical outcomes with the introduction of new therapies.7 The introduction of these therapies has extended median survival rates for metastatic renal cell carcinoma.7

About Avelumab

Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

About INLYTA (axitinib)

INLYTA is indicated for the treatment of advanced RCC after failure of one prior systemic therapy. INLYTA, a kinase inhibitor, is an oral therapy that is designed to inhibit tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors 1, 2 and 3; these receptors can influence tumor growth, vascular angiogenesis and progression of cancer (the spread of tumors).

Selected Safety Information for INLYTA (axitinib)

Hypertension including hypertensive crisis has been observed. Blood pressure should be well-controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events.

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA.

No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST and bilirubin before initiation of, and periodically throughout, treatment.

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA.

The most common (≥20%) adverse reactions are diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.

The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

For more information on INLYTA and Pfizer Oncology, including Full Prescribing Information, please visit www.pfizer.com.

About SUTENT (sunitinib malate)

SUTENT is an oral multi-kinase inhibitor that works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer. SUTENT was approved in 2006 and is indicated for the treatment of advanced/metastatic renal cell carcinoma.

Selected Safety Information for SUTENT (sunitinib malate)

Boxed Warning/Hepatotoxicity: Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.

Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

Given the potential for serious adverse reactions (ARs) in nursing infants, a decision should be made whether to discontinue nursing or SUTENT.

Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. Use SUTENT with caution in patients who are at risk for, or who have a history of, these events. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies.

SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsades de Pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered.

Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

There have been (<1%) reports, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS).

Hemorrhagic events, including tumor-related hemorrhage such as pulmonary hemorrhage, have occurred. Some of these events were fatal. Perform serial complete blood counts (CBCs) and physical examinations.

Cases of Tumor Lysis Syndrome (TLS) have been reported primarily in patients with high tumor burden. Monitor these patients closely and treat as clinically indicated.

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported in patients who received SUTENT as monotherapy and in combination with bevacizumab. Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was discontinued.

Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Perform baseline and periodic urinalysis during treatment, with follow-up measurement of 24-hour urine protein as clinically indicated. Interrupt SUTENT and dose-reduce if 24-hour urine protein is ≥3 g; discontinue SUTENT in cases of nephrotic syndrome or repeat episodes of urine protein ≥3 g despite dose reductions.

Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of EM, SJS, or TEN are present, SUTENT treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, treatment must not be re-started. Necrotizing fasciitis, including fatal cases, has been reported, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.

SUTENT has been associated with symptomatic hypoglycemia, which may result in loss of consciousness or require hospitalization. Reductions in blood glucose levels may be worse in patients with diabetes. Check blood glucose levels regularly during and after discontinuation of SUTENT. Assess whether antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

The most common adverse reactions (≥20%) are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding.

For more information on SUTENT and Pfizer Oncology, including Full Prescribing Information, including Boxed warning, please visit www.pfizer.com.

On April 05, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, and Merck & Co., Inc. (NYSE:MRK), reported that they have completed the first two dose-escalation cohorts and launched the third dose-escalation cohort in their KEYNOTE-046 clinical trial (Press release, Advaxis, APR 5, 2016, View Source [SID:1234510393]).

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The Phase 1/2 study is evaluating the combination of ADXS-PSA (ADXS31-142) and KEYTRUDA (pembrolizumab), the first anti-PD-1 (programmed death receptor-1) therapy approved in the United States, in patients with previously treated, metastatic castration-resistant prostate cancer (mCRPC).

The KEYNOTE-046 trial is the first-in-human study of Advaxis’ Lm immunotherapy candidate for prostate cancer. It is the second study initiated to evaluate the use of KEYTRUDA in the treatment of advanced prostate cancer.

"We are one step closer to evaluating our Lm platform in combination with a PD-1 antibody and are excited to launch this next cohort," said Daniel J. O’Connor, President and Chief Executive Officer at Advaxis. "We are thrilled to continue our collaboration with Merck in pursuit of finding a treatment option for a form of prostate cancer where few options exist."

KEYNOTE-046 is a multicenter, dose determining, open-label Phase 1/2 study designed to evaluate the safety and efficacy of ADXS-PSA as a monotherapy and in combination with KEYTRUDA in 51 mCRPC patients. Part A of the study is a dose escalating study designed to establish the maximum tolerated dose of ADXS-PSA as a monotherapy. Part B of the study will commence mid-year and evaluate ADXS-PSA in combination with KEYTRUDA, followed by an expansion cohort phase. The primary objective is to evaluate the safety and tolerability of the two immunotherapies, with the secondary objective to evaluate anti-tumor activity and progression-free survival.

The companies plan to submit an abstract to a major medical meeting on the dose-escalation portion of the study in the second half of the year. Further information about KEYNOTE-046 can be found on ClinicalTrials.gov, using Identifier NCT02325557.

About Prostate Cancer

Prostate cancer is the second most common form of cancer affecting men in the United States: an estimated one in seven will be diagnosed with prostate cancer in his lifetime. The American Cancer Society estimates that approximately 180,890 new cases of prostate cancer will be diagnosed and about 26,120 men are expected to die of the disease this year.

About ADXS-PSA

ADXS-PSA is an Lm Technology product candidate that is a multi-function immunotherapy designed to target prostate cancer. ADXS-PSA combines potent innate immune stimulation, triggering of STING receptors, and induction of T-cell response targeting prostate specific antigen (PSA) with tumor microenvironment effects. In a preclinical analysis this approach also inhibits the Treg and myeloid-derived suppressor cells (MDSCs) that contribute to immunologic tolerance of prostate cancer. Preclinical studies have shown ADXS constructs to be synergistic with checkpoint inhibitors like Keytruda.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 70 clinical trials – across more than 30 tumor types and over 8,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at View Source and the Medication Guide for KEYTRUDA at View Source

On April 5, 2016 Bellicum Pharmaceuticals Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported the presentation of interim data from the lead site in Bellicum’s ongoing BP-004 Phase 1/2 clinical trial during the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Valencia, Spain (Press release, Bellicum Pharmaceuticals, APR 5, 2016, View Source [SID:1234510391]).

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Studies with BPX-501 were selected for two oral presentations, including one during the Presidential Symposium session where significant findings from the meeting are featured.

In the ongoing BP-004 clinical trial, malignant and nonmalignant pediatric patients receive a haploidentical, T cell-depleted hematopoietic stem cell transplant (HSCT) followed by an add-back of BPX-501 donor T cells. The trial is designed to evaluate whether this regimen is safe and improves immune reconstitution, infection control and overall outcomes.

In an oral presentation reviewing the preliminary outcomes from the BP-004 clinical trial in 17 high-risk pediatric patients with blood cancers, the data showed that BPX-501 cells expand in vivo and persist over time, contributing to adaptive immunity. There was no transplant-related mortality due to infections, GvHD or other transplant-related complications. Additionally, the relapse rate to date compares favorably with that of historical controls, with 16 of 17 patients in the trial with acute leukemias showing disease-free outcomes. The median follow-up period to date for these patients was approximately seven months.

In a feature presentation during the Presidential Symposium session, initial outcomes for nonmalignant patients were reviewed. The data included children with genetic diseases including Fanconi anemia (5), beta thalassemia major (5), severe combined immunodeficiency (SCID or "bubble boy" disease) (5), Wiskott-Aldrich Syndrome (4) and other orphan diseases (5). All 24 children treated remain disease-free with no treatment-related mortality (median follow-up period of approximately seven months), consistent with earlier results presented at ASH (Free ASH Whitepaper) 2015.

"These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant," said lead investigator Dr. Franco Locatelli, Director, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome. "Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease."

"In both malignant and nonmalignant patients, the results show that treatment with BPX-501 appears safe, well-tolerated, and provides important immune benefits," commented Tom Farrell, President and CEO of Bellicum Pharmaceuticals. "These data also demonstrate high BPX-501 cell viability, expansion and persistence, and that the improvement of immune reconstitution is sustained. We look forward to sharing more results as these data mature, and providing updates following our plan to meet with the U.S. FDA and EMA during the second quarter of this year."

A copy of the slides presented at the meeting is available in the Events & Presentations section of bellicum.com.

About BPX-501

BPX-501 is an adjunct T cell therapy of genetically modified donor T cells incorporating Bellicum’s proprietary CaspaCIDe safety switch. The product candidate is designed to provide a safety net to eliminate the BPX-501 alloreactive T cells should severe GvHD occur, enabling physicians to more safely perform haploidentical stem cell transplants by adding back the BPX-501 genetically engineered T cells to speed immune reconstitution and provide control over viral infections.

BP-004 Clinical Trial Design

In December 2014, Bellicum initiated BP-004, a Phase 1/2 clinical trial in children with leukemias, lymphomas, or orphan inherited blood disorders, such as severe combined immunodeficiency (SCID), Wiskott-Aldrich Syndrome, beta thalassemia and sickle cell disease, all chronic life-long disorders for which HSCT is curative. The trial is being conducted in both European and U.S. pediatric transplant centers and plans to enroll up to 90 patients. The open label dose escalation trial is evaluating whether BPX-501 T cells from a haploidentical donor, typically the child’s mother or father, administered following a T-depleted HSCT, are safe and can enhance immune reconstitution.

On April 5, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its European regional headquarters Eisai Europe Ltd. (Location: U.K.) has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on anticancer agent Halaven (eribulin mesylate) for treatment of adult patients with unresectable liposarcomas who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease (Press release, Eisai, APR 5, 2016, View Source [SID:1234510390]).

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Halaven is the first and only single agent to demonstrate an overall survival (OS) benefit in a Phase III trial in patients with advanced, recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma). Following approval for use in the treatment of metastatic breast cancer in the EU, this marks the second indication for which Halaven has received a positive CHMP opinion based on a statistically significant extension of OS.

The CHMP’s positive opinion is based on the results from Phase III study (Study 309)1 comparing the efficacy and safety of Halaven versus dacarbazine in 452 patients (aged 18 or over) with locally advanced or recurrent and metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen. Halaven demonstrated a statistically significant extension in the study’s primary endpoint of OS over the comparator treatment dacarbazine (Halaven median OS: 13.5 months vs dacarbazine median OS: 11.5 months; Hazard Ratio (HR) 0.77 [95% CI=0.62-0.95], p=0.0169). For patients with liposarcoma, Halaven demonstrated a significant improvement in OS over dacarbazine (Halaven, median OS: 15.6 months vs dacarbazine, median OS: 8.4 months; HR 0.51 [95% CI=0.35-0.75]).
In this study, the most common treatment-emergent adverse events (incidence greater than or equal to 25%) in patients treated with Halaven were fatigue, neutropenia, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia, which was consistent with the known side-effect profile of Halaven.

Halaven is a halichondrin class microtubule dynamics inhibitor with a distinct binding profile. Recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.2 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.3 Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries including Japan and countries in Europe and the Americas. Halaven was approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen in January 2016, and was approved in Japan for the treatment of soft tissue sarcoma in February 2016. Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissue (fat, muscle, nerves, fibrous tissues and blood vessels). Approximately 29,000 patients in Europe are diagnosed with soft tissue sarcoma each year or about 1% of all cancers diagnosed in Europe. Liposarcoma is one of the most common forms of soft tissue sarcoma. As outcomes are poor for patients with advanced disease, it remains a disease with significant unmet medical need.

Through obtaining this additional approval, Eisai aims to enhance the clinical value of Halaven to contribute further toward addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

< Notes to editors >

1. About Halaven
Halaven is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally Halaven is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Halaven is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.2 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.3
Halaven was first approved in November 2010 in the United States as a treatment for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries worldwide, including Japan and countries in the Europe, Americas and Asia. In Japan, Halaven has been approved to treat inoperable or recurrent breast cancer and was launched in the country in July 2011. Halaven has also been approved in countries in Europe and Asia indicated as a treatment for patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.
Regarding soft tissue sarcoma, Halaven was approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen in January 2016, and was approved in Japan for the treatment of soft tissue sarcoma in February 2016. Applications seeking approval for use in the treatment of soft tissue sarcoma are currently under review in Switzerland, Russia, Australia, Brazil, and Malaysia. Furthermore, Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

2. About Study 3091
Conducted primarily in Europe and the United States, Study 309 was a multicenter, open-label, randomized Phase III study comparing the efficacy and safety of Halaven versus dacarbazine in 452 patients (aged 18 or over) with locally advanced, recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen. Patients received either Halaven (1.4 mg/m2 administered intravenously on Day 1 and Day 8) or dacarbazine (850–1200 mg/m2 administered intravenously on Day 1) every 21 days until disease progression.
From the results for the study, Halaven demonstrated a statistically significant extension in the study’s primary endpoint of overall survival (OS) over the comparator treatment dacarbazine (Halaven median OS: 13.5 months vs dacarbazine median OS: 11.5 months; Hazard Ratio (HR) 0.77 [95% CI=0.62-0.95], p=0.0169). Furthermore, in the study’s secondary endpoints, there was no statistically significant difference found between Halaven and dacarbazine in either progression-free survival (PFS) (median PFS: 2.6 months in both arms) or progression-free rate at 12 weeks (PFR12wks) (Halaven PFR12wks: 33% vs dacarbazine PFR12wks: 29%).
For patients with liposarcoma, Halaven demonstrated a statistically significant improvement in OS over dacarbazine (Halaven, median OS: 15.6 months vs dacarbazine, median OS: 8.4 months; HR 0.51 [95% CI=0.35-0.75]).
In this study, the most common treatment-emergent adverse events (incidence greater than or equal to 25%) in patients treated with Halaven were fatigue, neutropenia, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia, which was consistent with the known side-effect profile of Halaven.

3. About Soft Tissue Sarcoma
Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissue (including fat, muscle, nerves, fibrous tissues and blood vessels). Approximately 12,000 patients in the United States and 29,000 patients in Europe are diagnosed with soft tissue sarcoma each year. According to a patient survey conducted by Japan’s Ministry of Health, Labour and Welfare, there are approximately 4,000 patients with soft tissue sarcoma in Japan. As the structures where the tumors originate are diverse, there are various types of soft tissue sarcoma, and the most common types include leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. While treatment of soft tissue sarcoma is focused on curative surgery, if the stage of the disease is advanced, treatment then becomes a combination of chemotherapy and radiation therapy. As outcomes are poor for patients with advanced disease, it remains a disease with significant unmet medical need.