Peregrine Pharmaceuticals Provides Update on Planned Expansion of Bavituximab Clinical Program

On June 1, 2015 Peregrine Pharmaceuticals, Inc. (Nasdaq:PPHM) (Nasdaq:PPHMP), provided a corporate update on its immuno-oncology pipeline, its wholly-owned contract manufacturing business, Avid Bioservices, as well as anticipated upcoming milestones. This update outlines the expansion of the bavituximab clinical pipeline with a focus on exploring expanded indications and combinations in lung and breast cancers (Press release, Peregrine Pharmaceuticals, JUN 1, 2015, View Source [SID:1234505178]). These new trials build on recently published clinical data of bavituximab in combination with paclitaxel in HER2 negative breast cancer and clinical translational and preclinical data presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting that support the potential combination of bavituximab with the anti-PD-1 checkpoint inhibitor, nivolumab (marketed as Opdivo). These clinical trials are expected to begin enrollment later this year.

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"With many exciting near-term opportunities for Peregrine and Avid, we are pleased to share several strategic decisions aimed at expanding the potential clinical indications for bavituximab. These new trials represent large market opportunities for the bavituximab clinical program that can add significant value," said Steven King, president and chief executive officer of Peregrine. "As we near completion of enrollment in the SUNRISE pivotal Phase III trial by year-end, we are looking to expand bavituximab’s market potential and market position in key indications that are supported by strong clinical, translational, and preclinical data. Taken together with the research collaboration we announced last week, we believe we are setting the stage for many significant value driving events throughout 2015 and into 2016."

SUNRISE Phase III Pivotal Trial

The company’s Phase III SUNRISE (Stimulating ImmUne RespoNse thRough BavItuximab in a PhaSE III Lung Cancer Study) is an approximately 600 patient trial that continues to enroll at over 150 sites worldwide. Completion of enrollment is anticipated by calendar year-end. This Phase III, randomized, double-blind, placebo-controlled clinical trial is designed to evaluate the safety, tolerability and efficacy of bavituximab as a second-line treatment in patients with non-squamous, non-small cell lung cancer (NSCLC). Enrollment is proceeding according to plan with two planned interim efficacy analyses which will be reviewed by the trial’s Independent Data Monitoring Committee (IDMC). The first interim analysis, which will be conducted when 33% of the targeted overall survival events are reached, is for futility and the second interim analysis, for futility or superiority, will be conducted at 50% of events. As these analyses are event driven, the exact timing of each is unknown, however the company plans to provide updates as these events are reached. For additional information about the SUNRISE trial, please visit www.sunrisetrial.com or ClinicalTrials.gov using the Identifier NCT01999673.

Beyond SUNRISE: Exploring Checkpoint Inhibitor Combinations in Lung Cancer

Joe Shan said: "Following recent encouraging preclinical data supporting the combination of bavituximab with immune checkpoint inhibitors, today we are supplementing our strategy in lung cancer with the second clinical trial to emerge from our Immuno-Oncology Development Program, a combination trial of bavituximab with nivolumab, an immune checkpoint inhibitor of PD-1. Specifically, recent preclinical data show that the addition of bavituximab could result in turning patients that do not respond to monotherapy into patient responders. This supports our long held knowledge of the synergistic properties of the combination of bavituximab and chemotherapies, thus making this new trial the next logical step."

The company plans to initiate an open-label multi-center, randomized Phase II trial of the anti-PD-1 monoclonal antibody nivolumab (marketed as Opdivo) versus nivolumab plus bavituximab in patients with previously treated locally advanced or metastatic NSCLC. Enrollment will include patients with squamous and non-squamous NSCLC who have not received a prior PD-L1 or PD-1 inhibitor. The primary endpoint of this trial will be overall response rate (ORR) with secondary endpoints including tumor response and duration, progression free survival, overall survival (OS) and safety. The trial is in the final stages of design and the details of which will be made available once details are completed. Trial initiation is anticipated in the second half of 2015.

Leveraging Positive Data in Breast Cancer

"Today we are pleased to be detailing our strategy in breast cancer which is built upon very promising data which were recently published in the peer-reviewed journal Cancer Medicine," said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine Pharmaceuticals. "The clinical development pathway that we are outlining today is based upon the strong clinical experience that supports synergies between bavituximab and docetaxel and paclitaxel, our deep and consistently positive clinical experience in breast cancer to date, as well as the support of leading breast cancer physicians."

The company plans to initiate a Phase II/III open-label trial of physician’s choice of either docetaxel or paclitaxel with or without bavituximab in patients with locally advanced or metastatic HER2 negative breast cancer. The primary endpoint for the Phase II trial will be ORR. Results from this trial are expected to inform decisions on future studies in breast cancer and add value to the overall program. The initiation of this trial is anticipated in the second half of 2015.

Fiscal Year End Cash Position

Peregrine today reported $68 million in cash and cash equivalents, as of fiscal year ended April 30, 2015. The company will review full financial results for the fourth quarter and fiscal year 2015 during its quarterly call on Tuesday, July 14, 2015 after the close of markets, details of which will be included in a forthcoming press release.

Avid Bioservices’ Expansion on Track and Strongly Positioned to Meet Increased Client Demand

In December 2014, the company announced the expansion of Avid’s Current Good Manufacturing Practice (cGMP) current manufacturing capacity with a build out that is utilizing an existing 40,000 square foot facility located adjacent to the company’s current campus. Designed to more than double Avid’s current manufacturing capacity, this state-of-the-art biotechnology facility will employ an innovative and flexible modular clean room design and the latest in single-use technologies to meet the growing needs of Avid’s existing and future clients as well as the planned commercialization of bavituximab. Avid’s new facility is anticipated to be ready for cGMP production of biotechnology products in July 2015.

Added Steve King: "We are very pleased with the rapid progress by which this expansion is advancing as this is a key component to further demonstrating Avid as a leading provider of high quality biotechnology contract manufacturing services. The design and the features that we have employed in this expansion will truly be an integral part to the future growth of this unique part of our business. We look forward to sharing specific details on the expansion upon its formal unveiling later this year."

Novartis highlights CTL019 data showing its potential in the treatment of specific types of hard-to-treat non-Hodgkin lymphoma

On June 1, 2015 Novartis reported highlighting data from an ongoing Phase II clinical study of CTL019, an investigational chimeric antigen receptor (CAR) T cell therapy, that indicate its potential in the treatment of specific types of hard-to-treat non-Hodgkin lymphoma (Press release, Novartis, JUN 1, 2015, View Source [SID:1234505197]). Findings from the ongoing study conducted by the University of Pennsylvania’s Perelman School of Medicine (Penn) in adults with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) found an overall response rate (ORR) of 100% in patients with FL and 50% in patients with DLBCL[1].

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Thirteen of 19 evaluable patients responded to the therapy. Eleven achieved a complete response (CR) and two experienced a partial response (PR) to treatment[1]. These results will be presented in an oral session at the 51st American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Monday, June 1 (Abstract #8516, June 1, 3:24 p.m. CDT)[1].

"The results from this ongoing study of CTL019 are encouraging, as we now have data through six months showing that patients may have achieved durable overall response rates," said lead investigator Stephen Schuster, M.D., associate professor, division of Hematology/Oncology at the University of Pennsylvania, Abramson Cancer Center. "These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas."

Study results include 19 adult patients (12 with DLBCL and seven with FL) who were evaluable for response[1]. The study found that six patients with a PR to treatment at three months achieved a CR by six months[1]. Two patients with a PR experienced disease progression at 6 and 12 months after treatment[1]. Median patient follow-up is 274 days for the patients with DLBCL and 290 days for the patients with FL[1]. In the study, two patients developed cytokine release syndrome (CRS) of grade 3 or higher at peak T cell expansion[1].

"These new CTL019 findings are inspiring as we continue clinical research with our collaborators at the University of Pennsylvania, with the goal of altering the course of cancer care and treating areas of critical unmet need," said Usman Azam, Global Head, Cell & Gene Therapies Unit, Novartis Pharmaceuticals. "As Novartis initiates the Phase II multi-center global study of CTL019, this reinforces our commitment to furthering the new frontier of cell and gene therapies."

Additional CTL019 data being presented at ASCO (Free ASCO Whitepaper) include the preliminary safety and efficacy findings of a Phase I study investigating the use of CTL019 in the treatment of multiple myeloma (Abstract #8517, June 1, 3:36 p.m. CDT)[2]. This study adds to the growing body of data on CARTs and supports the advancement of the expanding pre-clinical and early clinical research pipeline at Novartis.

Novartis has initiated a Phase II multi-center global study of CTL019 in pediatric patients with r/r acute lymphoblastic leukemia (ALL). This study has opened in the United States, with the intention of expanding into other countries as soon as possible. Further, Novartis has begun to process patient cells at its cell processing facility in Morris Plains, N.J., and will utilize the facility in the Phase II multi-center global study. The facility is the first US Food and Drug Administration (FDA)-approved Good Manufacturing Practices quality site for a cell therapy.

Novartis and Penn have an exclusive global collaboration to research, develop and commercialize CAR T cell therapies for the investigational treatment of cancers. In July 2014, the FDA designated CTL019 as a Breakthrough Therapy for the treatment of pediatric and adult patients with r/r ALL under the Penn Investigational New Drug application (IND). Breakthrough Therapy designation is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. Novartis holds the worldwide rights to CARs developed through the collaboration with Penn for all cancer indications, including the lead program, CTL019.

About CTL019
CTL019 uses CAR technology to reprogram a patient’s own T cells to "hunt" cancer cells that express specific proteins, called CD19. After they have been reprogrammed, the T cells (now called CTL019) are re-introduced into the patient’s blood; they proliferate and bind to the targeted CD19+ cancer cells and potentially kill these tumor cells.

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

About Cytokine Release Syndrome
After CTL019 infusion, cytokine release syndrome (CRS) may occur when the engineered cells become activated and multiply in the patient’s body resulting in the release of cytokines. During CRS, patients typically experience varying degrees of flu-like symptoms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. CRS severity correlates with disease burden. Additionally, CRS also can occur in other non-CAR therapy settings including some monoclonal antibodies.

FDA Accepts Supplemental Biologics License Application (sBLA) for KEYTRUDA® (pembrolizumab), Merck’s Anti-PD-1 Therapy, in Advanced Non-Small Cell Lung Cancer, and Grants Priority Review

On June 1, 2015 Merck reported that the U.S. Food and Drug Administration (FDA) has accepted for review the supplemental Biologics License Application (sBLA) for Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), for the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on or after platinum-containing chemotherapy and an FDA-approved therapy for EGFR or ALK genomic tumor aberrations, if present (Press release, Merck & Co, JUN 1, 2015, View Source [SID:1234505194]). The FDA granted Priority Review with a PDUFA, or target action, date of October 2, 2015; the sBLA will be reviewed under the FDA’s Accelerated Approval program.

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"Today’s announcement reflects our commitment to accelerate the development of immunotherapeutic approaches to treat lung cancer, one of the most deadly malignancies," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We believe that data submitted to the FDA illustrate the significant potential of KEYTRUDA to treat advanced non-small cell lung cancer – and we look forward to working with the FDA to bring our anti-PD-1 therapy to patients afflicted with this devastating cancer."

The sBLA submission was based in part on data from KEYNOTE-001 – including patients with greater than or equal to 50 percent of tumor cells positive for PD-L1 expression – which were presented at the 2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (link). These data also served as the basis for the FDA Breakthrough Therapy designation for KEYTRUDA in advanced NSCLC. Merck has filed for approval of KEYTRUDA monotherapy at a dose of 2 mg/kg every three weeks, which is the currently approved dose for advanced melanoma.

As previously announced, a Premarket Approval Application (PMA) was submitted by Dako North America, Inc., an Agilent Technologies Company, for an immunohistochemistry companion diagnostic test that detects PD-L1 expression, PD-L1 IHC 22C3 PharmDx.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast, and prostate cancers combined. The two main types of lung cancer are NSCLC and SCLC. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year relative survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be four percent.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-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 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 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.

Findings Presented at 2015 ASCO Annual Meeting Add to Breadth of KEYTRUDA® (pembrolizumab) Data; Anti-Tumor Activity Now Demonstrated in 13 Different Tumor Types

On June 1, 2015 Merck reported the first-time presentation of findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in multiple, difficult-to-treat cancers, including advanced small cell lung cancer (SCLC), esophageal cancer and ovarian cancer from the KEYNOTE-028 Phase 1b study (Press release, Merck & Co, JUN 1, 2015, View Source [SID:1234505182]). These data, which were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, May 29 – June 2, 2015, build upon Merck’s broad and fast-growing immuno-oncology clinical development program for KEYTRUDA.

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"The breadth and depth of the data being shared at ASCO (Free ASCO Whitepaper) reinforces the potential for the broad clinical activity that we have seen with KEYTRUDA in multiple types of cancer," said Dr. Roy Baynes, senior vice president and head of global clinical development, Merck Research Laboratories. "Our goal is to help people with cancer and these data are furthering our understanding of which patients may be more likely to benefit from our anti-PD-1 therapy."

As of ASCO (Free ASCO Whitepaper), data presented has demonstrated anti-tumor activity with KEYTRUDA in 13 different tumor types. Registrational trials are planned or ongoing in eight different tumor types, as monotherapy and in combination with other therapies. KEYTRUDA was the first anti-PD-1 therapy approved in the United States and is currently indicated at a dose of 2 mg/kg administered 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. Please see below for complete indication and selected safety information for KEYTRUDA.

About the KEYNOTE-028 Phase 1b Study

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study evaluated patients with PD-L1 positive advanced solid tumors that have not responded to current therapy or for which current therapy is not appropriate.

Early Findings from Advanced Small Cell Lung Cancer Cohort (Abstract #7502)

These early findings from 20 heavily pre-treated patients with advanced SCLC, presented on Saturday, May 30 by Dr. Patrick Ott, Dana-Farber Cancer Institute, demonstrated an overall response rate (ORR) (confirmed and unconfirmed) of 35 percent (n=7/20) (95% CI, 15-59) (per RECIST v1.1). At the time of the analysis, six of seven responses were ongoing. The median follow-up duration for evaluable patients was 21 weeks (range, 2-48). Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 14 patients. Grade 3-4 investigator-assessed, treatment-related adverse events were asthenia (n=1) and blood bilirubin increased (n=1). Some patients experienced adverse events of special interest, including autoimmune thyroiditis (n=1, Grade 2) and colitis (n=1, Grade 5). There was one treatment-related death (colitis).

Early Findings from Advanced Esophageal Cancer Cohort (Abstract #4010)

These early findings from 23 heavily pre-treated patients with advanced esophageal cancer, presented in a clinical science symposium on Sunday, May 31 by Dr. Toshihiko Doi, National Cancer Center Hospital East, Kashiwa, Japan, demonstrated an ORR (confirmed and unconfirmed) of 30.4 percent of patients (n=7/23) (95% CI, 13.2-52.9) (per RECIST v1.1). In patients with squamous cell carcinoma, the ORR was 29.4 percent (n=5/17) and in patients with adenocarcinoma, the ORR was 40 percent (n=2/5). The median duration of response was 40 weeks (0.1+ to 40), with six of seven responses ongoing. Tumor shrinkage was achieved in 52.2 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in nine patients. All investigator-assessed, treatment-related adverse events were Grade 3 and included lymphocyte count decreased (n=2), decreased appetite (n=1), liver disorder (n=1), and pruritic rash (n=1). Some patients experienced adverse events of special interest (Grade 2), including hypothyroidism (n=2) and adrenal insufficiency (n=1). There were no treatment-related deaths.

Early Findings from Advanced Ovarian Cancer Cohort (Abstract #5510)

These early findings from 26 heavily pre-treated patients with advanced ovarian cancer, which will be presented in a clinical science symposium on Monday, June 1 by Dr. Andrea Varga, Gustave Roussy Institute, Villejuif, France, demonstrated an ORR (confirmed and unconfirmed) of 11.5 percent of patients (n=3/26) (95% CI, 2.4-30.2) (per RECIST v1.1). Additionally, there was a disease control rate (DCR) of 34.6 percent (n=9/26) (95% CI, 17.2-55.7). At the time of the analysis, the median duration of response had not been reached (27.9-36.3). Tumor shrinkage was achieved in 23 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 18 patients. One Grade 3-4 treatment-related adverse event occurred (transaminases increased). Some patients experienced adverse events of special interest, including hyperthyroidism (n=2), hypothyroidism (n=3), myositis (n=1) and pancreatitis (n=1). There were no treatment related deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-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 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 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.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In 2012, there were an estimated 1.8 million new cases of lung cancer diagnosed worldwide. SCLC accounts for about 10-15 percent of all lung cancer cases.

About Esophageal Cancer

Esophageal cancer is a type of cancer that begins in the inner layer (mucosa) of the esophagus and grows outward. There are two main types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. In 2012, there were an estimated 456,000 new cases of esophageal cancer and 400,000 esophageal cancer deaths worldwide, making it the eighth most common cancer.

About Ovarian Cancer

Ovarian cancer is a type of cancer that begins in the ovaries. There are three main types of ovarian tumors: epithelial ovarian tumors, ovarian germ cell tumors, and ovarian stromal tumors. In 2012, there were an estimated 239,000 new cases of ovarian cancer and 152,000 ovarian cancer deaths worldwide.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells. Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 (PD-1), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present. When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells – a type of cancer-killing immune cell – allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung and bladder cancer. High levels of PD-L1 expression are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches.

Merck and Dynavax Announce New Collaboration Investigating the Combination of Immuno-Oncology Therapies

On June 1, 2015 Merck and Dynavax Technologies reported they have entered into two clinical trial collaboration agreements to investigate the potential synergistic effect of combining immunotherapies from both companies’ pipelines: Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), and its investigational anti-interleukin-10 (anti-IL-10) immunomodulator, MK-1966, with Dynavax’s investigational toll-like receptor 9 (TLR9) agonist, SD-101 (Press release, Dynavax Technologies, JUN 1, 2015, View Source [SID:1234505159]).

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SD-101, KEYTRUDA, and MK-1966 are immunotherapies designed to enhance the body’s own defenses in fighting cancer. SD-101 is designed to mediate anti-tumor effects by triggering both innate and adaptive immune responses, including the induction of high levels of Type 1 interferon to stimulate recruitment of T-cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. MK-1966 is an investigational anti-IL-10 immunomodulator designed to neutralize the immune-suppressive environment for tumors. The collaboration includes multiple studies that will evaluate:

Safety and efficacy of combining SD-101 with KEYTRUDA in patients with advanced melanoma; this Phase 1b/2, multicenter, open-label study is expected to be initiated in the second half of 2015.
Safety and efficacy of combining SD-101 with MK-1966 in patients with solid or hematological malignancies; this Phase 1 study is expected to be initiated in the second half of 2015.
"The collaboration with Dynavax is rooted in Merck’s commitment to advancing breakthrough science in the field of immuno-oncology in order to address the complex interplay between the immune system and cancer," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early stage development, Merck Research Laboratories. "We are pleased that this latest collaboration not only investigates the potential of KEYTRUDA as a combination therapy, but also includes our new immunomodulator candidate, MK-1966."

"Our interest in working with Merck on these clinical collaborations was propelled by the synergistic activity we have seen when SD-101 is combined with checkpoint inhibitors in preclinical models," said Eddie Gray, chief executive officer of Dynavax. "These collaborations with Merck will facilitate our objective to demonstrate SD-101’s potential to complement multiple therapeutic modalities and thereby provide benefit to patients."

Under the terms of the agreement, Dynavax will sponsor and fund the SD-101 and KEYTRUDA study. Merck will sponsor and fund the SD-101 and MK-1966 study. The agreements include provisions where the parties may agree to extend either collaboration to include a Phase 3 clinical trial. Additional details of the agreements between Dynavax and Merck, through a subsidiary, were not disclosed.

About SD-101

SD-101 is a proprietary, second-generation, TLR9 agonist CpG-C class oligodeoxynucleotide. SD-101 activates multiple anti-tumor activities of innate immune cells and activates plasmacytoid dendritic cells to stimulate T cells specific for antigens released from dying tumor cells. TLR9 agonists such as SD-101 enhance T and B cell responses and provide potent Type 1 interferon induction and maturation of plasmacytoid dendritic cells to antigen-presenting cells. SD-101 is being evaluated in several Phase 1/2 oncology studies to assess its preliminary safety and activity.

About MK-1966

MK-1966, an investigational anti-interleukin-10 (anti-IL-10) immunomodulator, is designed to neutralize the immune-suppressive environment for tumors. MK-1966 blocks the activity of IL-10 which is known to down modulate the immune activation that is needed to kill tumor cells in the tumor microenvironment. These effects include decrease in cytokine production, upregulation of T regulatory cell activity and downregulation of antigen presenting cell activity. Based on preclinical data, co-administration of an anti-IL-10 with a TLR9 agonist may provide clinical benefit in the treatment of certain cancers.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-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 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 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.