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.