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NanoString Technologies and Merck Expand Collaboration to Develop and Commercialize Novel Diagnostic Test to Predict Response to KEYTRUDA® (pembrolizumab)

On February 29, 2016 NanoString Technologies, Inc. (NASDAQ:NSTG), a provider of life science tools for translational research and molecular diagnostic products, reported that it has entered into a collaboration agreement with Merck, known as MSD outside the US and Canada, through a subsidiary, to develop and commercialize a novel diagnostic assay to predict response to Keytruda (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, NanoString Technologies, FEB 29, 2016, View Source [SID:1234509285]).

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Under the terms of the collaboration agreement, NanoString will be responsible for seeking regulatory approval for and commercialization of the diagnostic test. NanoString will be eligible to receive up to $24 million for technology access and near-term milestones, in addition to development funding and other potential regulatory milestone payments.

Previously, the companies had engaged in a research collaboration to develop an assay to evaluate the potential to predict benefit from KEYTRUDA. The expanded collaboration is for the development and commercialization of the selected gene expression signature on NanoString’s nCounter Dx Analysis System as a diagnostic assay to predict response to KEYTRUDA in multiple tumor types.

"We look forward to working with NanoString on the development of their diagnostic assay to help identify patients who are most likely to benefit from KEYTRUDA in multiple additional tumor types," said Dr. Eric Rubin, vice president, oncology early-stage development, Merck Research Laboratories.

"We are excited to expand our collaboration with Merck to develop this novel assay for predicting response to anti-PD-1 therapies such as KEYTRUDA. We believe this gene signature has the potential to become the basis for a universally available assay that serves as the ‘gold standard‘ for informing treatment with immuno-oncology therapies," said Brad Gray, President and Chief Executive Officer of NanoString Technologies. "This collaboration solidifies NanoString’s position as the leader in immuno-oncology biomarker signatures, and builds on our ongoing research collaborations with MD Anderson and the Cancer Immunotherapy Trials Network."

Under the terms of the expanded collaboration agreement, NanoString retains the flexibility to independently develop and commercialize additional indications for the resulting diagnostic assay. In particular, this signature could form the basis for a comprehensive immuno-oncology test with the ability to direct use of multiple therapeutic classes, alone or in combination.

Exelixis and Ipsen Enter into Exclusive Licensing Agreement to Commercialize and Develop Novel Cancer Therapy Cabozantinib in Regions Outside the United States, Canada and Japan

On February 29, 2016 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext: IPN; ADR: IPSEY) jointly reported an exclusive licensing agreement for the commercialization and further development of cabozantinib, Exelixis’ lead oncology drug (Press release, Exelixis, FEB 29, 2016, View Source [SID:1234509277]).

Under the agreement, Ipsen will have exclusive commercialization rights for current and potential future cabozantinib indications outside of the United States, Canada and Japan. This agreement includes rights to COMETRIQ, which is currently approved in the European Union (EU) for the treatment of adult patients with progressive, unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). The companies have agreed to collaborate on the development of cabozantinib for current and potential future indications. Exelixis will maintain exclusive commercial rights for cabozantinib in the United States and Canada, and continue its discussions to partner commercial rights in Japan.

Under the agreement, Exelixis will receive a $200 million upfront payment. Exelixis is eligible to receive regulatory milestones, including $60 million upon the approval of cabozantinib in Europe for advanced renal cell carcinoma (RCC) and $50 million upon the filing and approval of cabozantinib in Europe for advanced hepatocellular carcinoma (HCC), as well as additional regulatory milestones for potential further indications. The agreement also includes up to $545 million of potential commercial milestones and provides for Exelixis to receive tiered royalties up to 26% on Ipsen’s net sales of cabozantinib in its territories.

Marc de Garidel, Chairman and Chief Executive Officer of Ipsen said: "The robust results from the METEOR study in advanced renal cell carcinoma demonstrate that cabozantinib has the potential to become a key oncology product in Europe. This transaction will help Ipsen accelerate the growth of the company and strengthen its oncology footprint in Europe. We are excited to bring cabozantinib to patients and clinicians around the world."

Future commercial indications for cabozantinib could include advanced HCC, the subject of CELESTIAL, an Exelixis-sponsored phase 3 pivotal trial for which top-line results are anticipated in 2017. Additional earlier-stage studies are under way through Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP), and its ongoing Investigator-Sponsored Trial (IST) program. Through these two programs, there are more than 45 ongoing or planned studies including trials in advanced RCC, bladder cancer, colorectal cancer, non-small cell lung cancer, and endometrial cancer.

"In Ipsen, Exelixis has an ideal partner to maximize the potential for cabozantinib to have a positive impact on the treatment of cancer on a global basis," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "Ipsen’s established international oncology marketing presence, late-stage clinical development expertise and shared vision with Exelixis for the franchise potential of cabozantinib will accelerate cabozantinib’s commercialization in its territories, while Exelixis remains focused on our launch in the United States. While our immediate priority will be on advanced renal cell carcinoma, Exelixis and Ipsen are committed to exploring and potentially developing cabozantinib in a variety of cancer settings."

Cabozantinib is a small molecule therapy that inhibits the activity of tyrosine kinases including VEGF receptors, MET, AXL, and RET. Following positive results from the METEOR global phase 3 pivotal trial, the tablet form of cabozantinib is the subject of pending U.S. and EU regulatory applications for use as a treatment for advanced RCC in patients who have received one prior therapy. In the EU, the Marketing Authorization Application (MAA) for cabozantinib in advanced RCC has been accepted and granted accelerated assessment. With this designation, the MAA is eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by the EMA). Exelixis plans to transfer sponsorship of this MAA to Ipsen. Exelixis also anticipates transitioning the commercialization rights to COMETRIQ outside the U.S. from Exelixis’ current international partner for COMETRIQ, Swedish Orphan Biovitrum AB (Sobi), to Ipsen, in accordance with the terms of its agreement with Sobi. In March 2014, the capsule form of cabozantinib was approved by the European Commission under the trade name COMETRIQ for the treatment of patients with progressive, unresectable, locally advanced or metastatic MTC.

About the METEOR Phase 3 Clinical Trial

METEOR is a global, randomized open-label trial that compares cabozantinib to everolimus, a standard of care therapy, in 658 patients with advanced RCC whose disease progressed following treatment with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI). The trial’s primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival (OS) and objective response rate (ORR). Patients were randomized 1:1 to receive 60 mg of cabozantinib or 10 mg of everolimus daily, and were stratified based on number of prior VEGFR TKI therapies and on commonly applied RCC risk criteria. No crossover was allowed.

As published in the New England Journal of Medicine, the trial met its primary PFS and secondary ORR endpoints.1 Cabozantinib demonstrated a 42% reduction in the rate of disease progression or death as compared with everolimus, with median PFS of 7.4 months versus 3.8 months for everolimus (Hazard Ratio [HR]=0.58, 95% Confidence Interval [CI] 0.45-0.75, p<0.001).

Following a pre-planned interim analysis that showed a strong trend in OS favoring cabozantinib (HR=0.67, 95% CI 0.51-0.89, p=0.005) but did not reach statistical significance, Exelixis undertook a second interim analysis after consulting with regulatory authorities. The results of this second interim analysis demonstrated a highly statistically significant and clinically meaningful increase in OS for cabozantinib. Exelixis has shared these data with regulators and intends to present them at a medical conference later this year.

Cabozantinib’s safety profile was similar to that of other VEGFR TKIs in this patient population. The incidence of adverse events (any grade), regardless of causality, was 100% with cabozantinib and more than 99% with everolimus. Serious adverse events occurred in 40% of cabozantinib patients and 43% of everolimus patients. The rate of treatment discontinuation due to adverse events was low (~10%) in both treatment arms.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.2 Clear cell RCC is the most common type of kidney cancer in adults.3 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.4

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second- and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,5 two small-molecule therapies and an immune checkpoint inhibitor have been approved. The currently approved small-molecule agents have shown little differentiation in terms of efficacy, demonstrating only modest PFS benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

About Cabozantinib

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic MTC, and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the NDA and MAA for advanced RCC.

Cabozantinib inhibits the activity of tyrosine kinases including VEGF receptors, MET, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.
COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
Wound complications have been reported with COMETRIQ.
COMETRIQ treatment results in an increase in hypertension.
Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.
Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.
Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.

AstraZeneca reports top-line result of tremelimumab monotherapy trial in mesothelioma

On February 29, 2016 AstraZeneca and MedImmune, its global biologics research and development arm, reported that DETERMINE, the Phase IIb clinical trial of 10 mg/kg tremelimumab monotherapy in second or third-line treatment of unresectable malignant mesothelioma, did not meet its primary endpoint of overall survival (Press release, AstraZeneca, FEB 29, 2016, View Source [SID:1234509273]).

Robert Iannone, Senior Vice President, Head of Immuno-Oncology, Global Medicines Development at AstraZeneca, said: "We are disappointed that tremelimumab monotherapy did not demonstrate a survival benefit in this patient population with no approved medicines beyond first-line treatment. However, we remain confident in tremelimumab’s clinical activity in combination, as shown in our recently published Study 006 trial of tremelimumab and durvalumab in non-small cell lung cancer."

In addition to investigation as monotherapy for patients with mesothelioma, tremelimumab is being studied in combination with AstraZeneca’s anti-PD-L1 investigational immunotherapy durvalumab in multiple tumour types, including non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, bladder, pancreatic, gastric and liver cancers. Preclinical data have suggested that targeting both PD-L1 and CTLA-4 may have additive or synergistic effects.1 In the recently published Study 006, combination treatment with durvalumab and tremelimumab demonstrated antitumour activity in patients with locally advanced or metastatic NSCLC, irrespective of PD-L1 status.2

The Company will complete a full evaluation of the final DETERMINE data, which will be submitted for presentation at an upcoming medical meeting in 2016.

NOTES TO EDITORS

1 Stewart et al. Preclinical modeling of immune checkpoint blockade (P2012). J Immunol 2013: 190 (1 Meeting Abstracts): Abstract 214.7. 

2 Antonia S, et al. Safety and antitumour activity in a Phase 1b study of combined checkpoint blockade with anti- PD-L1 (durvalumab) and anti-CTLA-4 (tremelimumab) in non-small cell lung cancer. The Lancet Oncology. Available at http://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00544-6.pdf. Accessed February 2016.

3 Delgermaa V et al. Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ. 2011 Oct 1;89(10):716-24, 724A-724C

4 Driscoll T et al. The global burden of disease due to occupational carcinogens. Am J Ind Med. 2005 Dec;48(6):419-31.

About Mesothelioma

Mesothelioma is a rare and deadly form of cancer that affects the lining of the lungs or abdomen. There is a high unmet medical need for mesothelioma treatments, with median overall survival 9 to 12 months after initial diagnosis.3 The disease causes approximately 43,000 deaths per year globally.4 In 2015, tremelimumab was granted Orphan Drug Designation by the U.S. Food and Drug Administration.

About the DETERMINE trial

DETERMINE (NCT01843374) is a randomised, double-blind, placebo-controlled Phase IIb global trial with 571 patients across multiple countries. The trial evaluated the safety and efficacy of tremelimumab versus placebo in the treatment of unresectable pleural or peritoneal malignant mesothelioma.

About Tremelimumab

Tremelimumab is an investigational, selective human antibody directed against cytotoxic T- lymphocyte-associated protein 4 (CTLA-4). By blocking the activity of CTLA-4, tremelimumab "releases the brakes" on T cell activation and boosts the immune response against cancer cells. Tremelimumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with durvalumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers. In 2015, the U.S. Food and Drug Administration granted tremelimumab Fast Track Designation and Orphan Drug Designation as a potential treatment for malignant mesothelioma, an aggressive, rare form of cancer that affects the lining of the lungs and abdomen.

About Durvalumab

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 expression enables tumours to evade detection from the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 on T cells, countering the tumour’s immune- evading tactics. Durvalumab is being developed alongside other immunotherapies to activate the patient’s immune system to attack the cancer. Durvalumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with tremelimumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers. In 2015, durvalumab received Fast Track Designation for the treatment of patients with PD-L1–positive metastatic SCCHN, and in 2016, durvalumab was granted Breakthrough Designation by the U.S. Food and Drug Administration as a potential treatment for metastatic urothelial bladder cancer.

8-K – Current report

On February 29, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "The Company"), reported that it is initiating a protocol titled, "A Phase 1 Study to Assess the Safety, Tolerability and Effectiveness of PV-10 Chemoablation of Neuroendocrine Tumours (NET) Metastatic to the Liver in the Reduction of Biochemical Markers and Symptoms Caused by Secretory Products (Filing, 8-K, Provectus Pharmaceuticals, FEB 29, 2016, View Source [SID:1234509272])."

The 12-patient phase 1 study will run up to 48 months with interim data anticipated at the half-way point of the two-cohort study. Patients in the first of the two successive cohorts will receive PV-10 to a single NET tumor in their liver, while patients in the second cohort may receive PV-10 to multiple NET tumors.

Timothy Price, M.D. will serve as principal investigator for the study at The Queen Elizabeth Hospital in Woodville, South Australia.
Dr. Price explained, "The primary endpoint of our study will be assessment of safety and tolerability of PV-10 in the treatment of these metastatic NETs. Our secondary endpoints address preliminary efficacy, disease symptoms and biomarkers, and include assessments of Objective Response Rate (ORR) of injected and uninjected tumors; change in tumor biomarkers (somatostatin receptor expression, chromogranin A and 5-hydroxyindole acetic acid); change in NET symptoms assessed by standard quality of life instruments; and possible change in peripheral blood mononuclear cells (PBMCs)."

Dr. Eric Wachter, CTO of Provectus, noted, "This protocol is a natural complement to work ongoing in our initial study of hepatic cancers under protocol PV-10-LC-01, which has allowed us to assess PV-10 in a number of tumor types using the method of administration that will be used in this new study. In addition to providing further data on the overall safety of this approach, this study is tailored to NET patients and will allow us to assess potential clinical benefit in terms of objective response and changes in biomarkers and symptoms of these tumors. Patients with metastatic NET tumors are often plagued by persistent diarrhea, flushing, breathing difficulties, abdominal cramping and swelling of the arms and legs. It will be very useful to determine whether PV-10 ablates NET tumors and if ablation has a positive impact on quality of life for patients."

For further information, please visit View Source The study is expected to open for enrollment in March 2016.

About the Queen Elizabeth Hospital

The Queen Elizabeth Hospital (TQEH) is a 311 bed, acute care teaching hospital that provides inpatient, outpatient, emergency and mental health services to a population of more than 250,000 people living primarily in Adelaide’s western suburbs.

Oncothyreon Announces First Patient Dosed in Randomized Phase 2 ONT-380 Combination Trial in Patients with HER2-Positive Breast Cancer

On February 29, 2016 Oncothyreon Inc. (Nasdaq:ONTY), a clinical-stage biopharmaceutical company dedicated to the development of therapeutic products that can improve the lives and outcomes of patients with cancer, reported the dosing of the first patient in a randomized, placebo-controlled Phase 2 trial of ONT-380 in combination with Herceptin (trastuzumab) and Xeloda (capecitabine) (Press release, Oncothyreon, FEB 29, 2016, View Source [SID:1234509270]).

ONT-380 is an oral, HER2-selective, central nervous system (CNS)-active tyrosine kinase inhibitor. The trial is enrolling heavily pretreated patients with advanced HER2-positive breast cancer with or without brain metastases.

"There is a great need for effective, well-tolerated treatments for women with progressing metastatic HER2-positive breast cancer, especially those with metastases to the brain, which develops in up to half of these patients and who are frequently excluded from clinical trials. With no approved therapy for the treatment of brain metastases, options for this patient population are currently limited," said Erika Hamilton, M.D., director, Breast and Gynecologic Cancer Research Program, Sarah Cannon Research Institute. "This trial includes specifically designed endpoints around HER2-positive CNS disease to further explore the activity of ONT-380 in combination with Herceptin and Xeloda on brain metastases and the potential to address this unmet medical need."

"Based on data from our Phase 1b studies, which show that the combination of ONT-380 with other active treatments was well tolerated and resulted in objective responses and prolonged, stable disease, we believe that ONT-380 has the potential to be an important new treatment for HER2-positive breast cancer patients, especially for women with brain metastases," said Christopher S. Henney, chairman and interim CEO of Oncothyreon. "We are excited to advance the development of ONT-380 in the third-line metastatic setting with the initiation of this Phase 2 trial. Additionally, we continue to evaluate opportunities for ONT-380 and to establish the most efficient regulatory path forward."

About the Study

The clinical trial is a Phase 2 randomized, double-blind, placebo-controlled study of ONT-380 in combination with Herceptin and Xeloda in patients with pretreated, unresectable locally advanced or metastatic HER2-positive breast cancer. (ClinicalTrials.gov Identifier: NCT02614794) The trial is expected to enroll approximately 180 patients in multiple centers located in the United States, Canada and Western Europe. Patients must have been previously treated with a taxane, Herceptin, Perjeta (pertuzumab) and Kadcyla (ado-trastuzumab emtansine or T-DM1). Patients with or without brain metastases are eligible, including patients with asymptomatic untreated brain metastases not needing immediate local therapy and patients with previously treated brain metastases.

The trial’s objectives are to assess the efficacy, safety and pharmacokinetics of ONT-380 in combination with Herceptin and Xeloda. The primary endpoint is progression free survival (PFS) based on assessment of both CNS and non-CNS disease. Additional endpoints include time to CNS progression, objective response rate and overall survival.

About ONT-380

ONT-380 is an oral, CNS-active, reversible and selective small molecule HER2 inhibitor being developed for the treatment of metastatic breast cancer. Unlike other approved and investigational treatments, ONT-380 selectively inhibits HER2 without significant inhibition of EGFR (also called HER1), resulting in highly potent inhibition of HER2 while potentially avoiding the side effects associated with dual inhibitors, including skin rash and gastrointestinal toxicities. In addition, ONT-380 has been shown to have durable, objective responses in HER2-positive patients with brain metastases. Brian metastases impact up to 50 percent of women with HER2-positive metastatic breast cancer and represent a major unmet medical need.