On September 9, 2015 BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine company developing targeted and programmable therapeutics called AccurinsTM, treported that patient dosing is underway in the iNSITE 2 trial, a global, phase 2, two-stage clinical trial of BIND-014 in patients with four tumor histologies (Press release, BIND Therapeutics, SEP 9, 2015, View Source [SID:1234507417]). Schedule your 30 min Free 1stOncology Demo! These diseases (cholangiocarcinoma [bile duct cancer], advanced cervical cancer, advanced bladder cancer, and advanced squamous cancer of the head and neck) each affect fewer than 200,000 patients in the U.S., making investigational drugs for these diseases candidates for orphan drug designation by the U.S. Food and Drug Administration. Stage 1 data readout for the iNSITE 2 trial is expected in the first half of 2016.
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"The dosing of the first patient in the iNSITE 2 trial further expands the clinical development opportunities of BIND-014," said Hagop Youssoufian, M.Sc., M.D., chief medical officer at BIND Therapeutics. "It also represents a new milestone for the first targeted nanoparticle to enter the clinic by utilizing a rigorous biomarker program that can become a useful aid for more reliable patient selection in the future. The orphan tumor types that we have chosen for iNSITE 2 are all cancers with high unmet need and limited treatment options, representing potential opportunities for rapid development. Our choice was also guided by the activity seen with BIND-014 in our phase 1 trial and the historical role of docetaxel in treating these tumors."
The open-label, phase 2, multi-center two-stage iNSITE 2 clinical trial is designed to determine the activity, safety and tolerability of BIND-014 and will enroll up to 160 patients. In addition, an imaging and biomarker program that can potentially inform the future clinical utility of BIND-014 is also planned. Additional information on this study can be found at: View Source
Kancera evaluates immuno-oncology drug candidate
On September 8, 2015 Kancera reported it has entered into an agreement with Acturum Life Science AB in order to evaluate and further develop the unique Fractalkine inhibitor AZD8797 (Press release, Kancera, SEP 8, 2015, View Source [SID:1234511323]). Published research points to that Fractalkine signaling probably contributes to the growth and spread of tumors and the pain that often affects cancer patients. In addition, the presence of Fractalkine has been proposed to be associated with a lack of efficacy of immuno-oncology drugs. Taken together, these findings provide a new perspective of Fractalkine signaling as a target for cancer drug development. Kancera will now evaluate how efficiently the Fractalkine inhibitor AZD8797 may stop tumor growth and relieve severe pain.
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Originally, the candidate drug AZD8797 was successfully developed by AstraZeneca in Södertälje as an effective inhibitor of Fractalkine signaling. The present documentation of AZD8797 includes drug properties, safety, toxicology, and production. Kancera’s assessment is that this documentation is likely to meet requirements for an application to undertake clinical trials against cancer. AstraZeneca originally developed AZD8797 against multiple sclerosis and showed effect of AZD8797 in a preclinical model of the disease (see the publication in PNAS April 8, 2014 vol. 111, no. 14, p 5409). Acturum Life Science acquired the rights to the Fractalkine project from AstraZeneca as part of Acturum’s acquisition of the research facility in Södertälje. However, AstraZeneca has retained the rights to develop Fractalkine inhibitors against respiratory diseases.
The agreement with Acturum Life Science gives Kancera right to evaluate AZD8797 in preclinical studies and then to acquire the project. This agreement entails no expenses for Kancera apart from investments in the patent portfolio and in the scientific evaluation.
If Kancera chooses to acquire the Fractalkine project, following the preclinical evaluation phase, the total payment to Acturum will consist of 6 million Kancera shares divided into three tranches, which are due at pre-defined success-milestones. Accordingly, the two companies share the risk in the product development through the first study in man. Kancera intends to apply for orphan drug designation, covering the Fractalkine inhibitor, in order to ensure at least 10 years of exclusivity on the market in Europe and 7 years in the United States.
Since AZD8797 already meets the pharmaceutical properties Kancera considers necessary for the biological evaluation of the effect against cancer, the project can be run without significantly affecting the resource allocation to Kancera’s other projects.
"The agreement with Acturum provides Kancera with a technically strong candidate drug in an dynamic field of drug discovery. We are thereby set to evaluate how the promising research on Fractalkine can be translated into a new effective immune-oncology treatment" says Thomas Olin, CEO of Kancera.
Peter Sjöstrand, representing Acturum Life Science AB and its main shareholder FAM (the Wallenberg Foundations’ investment company) continues, "the agreement with Kancera provides the best conditions for a professional evaluation and further development of the Fractalkine project in a very important medical area. Since Acturum is committed to keep the Kancera shares received as payment for the project for at least five years, the agreement is also the start of a long-term commitment in Kancera. "
About the Fractalkine project
Fractalkine is an immune regulatory factor that sends signals via the CX3CR1 receptor, also called G-protein coupled receptor 13 (GPCR13). In the healthy individual, Fractalkine and its receptor regulate migration of immune cells from the blood capillary wall into areas where the immune system is needed. Animal studies show that Fractalkine and its receptor are not essential for survival and that important immune functions remain intact indicating that inhibition of the Fractalkine signaling by a drug probably will be tolerated without significant adverse effects. Fractalkine and its receptor have been linked to the growth and proliferation of pancreatic, breast and prostate cancer. Also, cancer cells that have the Fractalkine receptor on their surface migrate towards nerve ends that have Fractalkine on their surface. Thus, cancer cells are led to surround and apply pressure on nerves and thereby cancer pain may arise. Another proposed mechanism for how Fractalkine and its receptor affect the development of tumors is that they contribute to the transformation of the body’s macrophages from being a threat against the cancer (the M1 form) to supporting the cancer (the M2 form). This mechanism is also suggested as a predictive factor for responsiveness to the new immuno-oncology drugs that act through PD-1 and PD-L1 such as nivolumab, pembrolizumab and pidilizumab. During 2014 and 2015 studies have been published demonstrating that the absence of Fractalkine in tumor cells is a significant marker for how successful the immuno-oncology treatment is expected to be (see e.g. the publication in Nature on November 27, 2014, Vol. 515, pp 563). In the light of these observations, there are good reasons to further study if inhibition of the Fractalkine signaling with AZD8797 has the potential to increase the proportion of patients responding to the new immuno-oncology drugs that act through PD-1 and PD-L1.
Aduro Biotech Completes Enrollment in Phase 2b ECLIPSE Trial in Metastatic Pancreatic Cancer
On September 8, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that it has completed enrollment in the Phase 2b ECLIPSE trial of its novel LADD and GVAX immunotherapies being developed for the treatment of metastatic pancreatic cancer. The randomized, controlled three-arm trial enrolled 303 patients in the United States and Canada (Press release, Aduro BioTech, SEP 8, 2015, View Source;p=RssLanding&cat=news&id=2085917 [SID:1234507460]). Top line results are expected in the first half of 2016.
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ECLIPSE was designed to evaluate the safety, immune response and efficacy of the combination immunotherapy of CRS-207 and GVAX Pancreas compared to chemotherapy. The trial also included a treatment arm to evaluate CRS-207 as a monotherapy. The primary endpoint of the trial is overall survival in the primary cohort of patients who have received two or more prior therapies for metastatic disease. A second cohort of patients who received one prior therapy for metastatic disease is also being evaluated.
"This is a significant clinical trial in the pancreatic cancer field which has the potential to yield important information on the role of Aduro’s immunotherapy combination in this indication," said Vincent Picozzi, M.D., director of the Pancreatic Center of Excellence at the Virginia Mason Clinic. "Very few therapeutic options exist for metastatic pancreatic cancer patients, especially after initial chemotherapy, and this field could benefit greatly from more varied and attractive therapy options."
"The fight against metastatic pancreatic cancer continues to be arduous," said Dirk G. Brockstedt, Ph.D., senior vice president of research and development at Aduro. "We are encouraged by data from long-term survivors in our Phase 2a clinical trial and look forward to results from our Phase 2b ECLIPSE trial. We would like to thank our investigators, and more importantly the patients and their families, for their participation and support in our trials and development of our technologies in this indication."
The ECLIPSE trial was initiated following a Phase 2a trial which demonstrated efficacy of the immunotherapy combination with CRS-207 and GVAX Pancreas compared to GVAX Pancreas alone in a randomized, controlled, multi-center trial in metastatic pancreatic cancer patients. Results of the Phase 2a clinical trial, published in the Journal of Clinical Oncology (JCO), indicated the median overall survival of Arm A patients receiving the combination regimen of CRS-207 and GVAX Pancreas was 6.1 months compared to 3.9 months for Arm B patients receiving GVAX monotherapy (HR=0.5930, one-sided p=0.0172).
Overall, the combination immunotherapy was well-tolerated. Of the 93 patients enrolled, the most common Grade 3 adverse events were transient lymphopenia, fevers, elevated liver enzymes and fatigue.
In 2014, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for Aduro’s pancreatic cancer combination treatment consisting of CRS-207 and GVAX Pancreas based on results from the Phase 2a clinical trial of patients with metastatic pancreatic cancer. According to the FDA, Breakthrough Therapy designation is for a drug candidate that treats a serious or life-threatening condition for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint over available therapies.
About CRS-207
CRS-207 is one of a family of product candidates based on Aduro’s live-attenuated, double-deleted (LADD) Listeria monocytogenes immuno-oncology platform that are designed to induce potent innate and adaptive immune responses. CRS-207 has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian and gastric cancers.
About GVAX Pancreas
GVAX Pancreas is one of a family of GVAX immunotherapies derived from human cancer cell lines that are genetically modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune system-stimulating cytokine. GVAX Pancreas is derived from human pancreatic cancer cell lines and is designed to activate specific T cell immunity to pancreatic cancer antigens, including mesothelin.
Five Prime Therapeutics Initiates Patient Dosing in Phase 1a/1b Trial Evaluating the Immunotherapy Combination of FPA008 and OPDIVO (nivolumab) in Six Tumor Types
On September 8, 2015 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing novel protein therapeutics for cancer and inflammatory diseases, reported that it has initiated patient dosing in the Phase 1a/1b clinical trial evaluating the immunotherapy combination of FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R), with OPDIVO (nivolumab), Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor, in six tumor types (Press release, Five Prime Therapeutics, SEP 8, 2015, View Source [SID:1234507422]).
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FPA008 and OPDIVO are part of a new class of cancer treatments known as immunotherapies that are designed to harness the body’s own immune system to fight cancer. FPA008 targets macrophages and monocytes, which are activated or elevated in multiple disease settings. In cancer, tumor-associated macrophages suppress the immune system’s ability to kill cancer cells. OPDIVO is approved in the United States, Japan and the European Union for metastatic melanoma, and in the United States and European Union for squamous non-small cell lung cancer. OPDIVO is being evaluated as a mono therapy, as well as in combination with other agents, across multiple tumor types in more than 50 clinical trials. Preclinical data suggest that combining antibodies targeting PD-1 and CSF1R may lead to an enhanced anti-tumor immune response compared to either drug alone.
"We hope that targeting tumor suppressing macrophages in addition to a known immune checkpoint will allow us to harness more of the immune system’s anticancer activity, and will make durable responses a reality for more of our patients," said Julie Brahmer, M.D., Associate Professor of Oncology and Interim Director at the Sidney Kimmel Comprehensive Cancer Center (Johns Hopkins Bayview campus) and a Principal Investigator for the trial. "We look forward to participating in this trial, which will generate important information about the potential of this immunotherapy combination across a number of tumor types, including many where patients have few effective treatments."
"We are excited about the potential of FPA008 as a novel immuno-oncology therapeutic and about combining it with OPDIVO in this clinical collaboration with Bristol-Myers Squibb. We believe that targeting the CSF1R and PD-1 pathways in tandem may produce a synergistic treatment effect against a variety of tumors," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "Five Prime looks forward to enrolling this study, as it will provide us a wealth of information about this novel therapeutic combination and will further guide our development of FPA008 in oncology."
During Phase 1a, Five Prime will evaluate the safety, pharmacokinetics and biomarkers of escalating doses of FPA008 as a monotherapy, as well as in combination with the approved 3 mg/kg dose of nivolumab. Approximately 30 patients with advanced cancers are expected to be enrolled during the Phase 1a part of the study and both drugs will be administered every two weeks. In the Phase 1b part of the study, Five Prime will evaluate the safety, tolerability and preliminary efficacy of the selected dose of FPA008 in combination with nivolumab in approximately 240 patients, as a front-line therapy for melanoma; as second-line therapy for squamous cell carcinoma of the head and neck, pancreatic cancer, and malignant glioma; as a second- or third-line therapy for non-small cell lung cancer (NSCLC); and as a third-line therapy for colorectal cancer. Tumor biopsies will be obtained both pre-treatment and one month post-treatment in a subset of patients to analyze the immune response within the tumor microenvironment, and Five Prime will use this analysis to further guide FPA008’s development in oncology.
Under the terms of the clinical collaboration, BMS made a one-time payment of $30 million to Five Prime and is responsible for external study costs, the costs for OPDIVO, and half of the costs for FPA008 used in the Phase 1b part of the trial. The study design will be described in further detail in a trial-in-progress presentation at the International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper), to be held September 16-19, 2015 in New York City. Five Prime expects to complete Phase 1a dose escalation and expand into Phase 1b with the selected dose of FPA008 in late 2015 or early 2016.
About FPA008
FPA008, Five Prime’s antibody that inhibits colony stimulating factor-1 receptor (CSF1R), targets macrophages and monocytes, which are activated or elevated in multiple disease settings. In cancer, tumor-associated macrophages suppress the immune system’s ability to kill cancer cells. In joint diseases, such as PVNS and RA, synovial macrophages play a central role in the disease process. Five Prime is evaluating the immunotherapy combination of FPA008 and OPDIVO (nivolumab), Bristol-Myers Squibb’s investigational PD-1 immune checkpoint inhibitor, in six tumor types in a Phase 1a/1b clinical trial. Five Prime is also conducting a Phase 1/2 trial of FPA008 in pigmented villonodular synovitis (PVNS), a joint tumor driven by the CSF1 pathway and an orphan disease, and a Phase 1 study in rheumatoid arthritis.
FDA grants Roche's alectinib Priority Review for specific type of ALK-positive lung cancer
On September 8, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s New Drug Application (NDA) and granted Priority Review for alectinib (known as Alecensa in Japan and the U.S.), an oral investigational anaplastic lymphoma kinase (ALK) inhibitor, for the treatment of people with ALK-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib (Press release, Hoffmann-La Roche , SEP 8, 2015, View Source [SID:1234507421]). Alectinib was granted Breakthrough Therapy Designation by the FDA in June 2013 for people with ALK-positive NSCLC whose disease progressed on crizotinib.
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"Alectinib was granted Priority Review by the FDA based on results from two studies showing the medicine shrank tumours in people with ALK-positive NSCLC that progressed on crizotinib," said Sandra Horning, M.D., Roche’s Chief Medical Officer and Head of Global Product Development. "There is a need for new treatment options in this patient population, especially because the disease often spreads to the brain at progression."
A Priority Review designation is granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible. The NDA for alectinib includes data from two Phase II studies (NP28761 and NP28673), and the FDA will make a decision on approval by 4 March 2016.
ALEX, an ongoing, global randomised Phase III study is comparing alectinib to crizotinib as an initial (first-line) treatment for people with advanced NSCLC whose tumours were characterised as ALK-positive by a companion immunohistochemistry (IHC) test developed by Roche Diagnostics.
About the NP28761 and NP28673 Studies
Results from the Phase II NP28761 and NP28673 studies were recently presented at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).
NP28761 is a North American, single-arm, open-label, multicentre trial evaluating the safety and efficacy of alectinib in 87 people with ALK-positive NSCLC whose disease progressed on crizotinib.
– Response assessment by an independent review committee (IRC) showed that alectinib shrank tumours (objective response rate, ORR) in 47.8% (95% confidence interval [CI] 35.6%-60.2%) of people treated with alectinib, as measured by Response Evaluation Criteria in Solid Tumours (RECIST v1.1).
– Investigator assessment showed that alectinib shrank tumours in this group of people with a similar response rate (ORR of 46.0%, [95% CI 35.2%-57.0%]).
– Activity was also observed in the central nervous system (CNS), as shown by a CNS ORR by IRC of 68.8% (95% CI 41.3%-89.0%) in people whose disease had already spread to the brain or other parts of the CNS at study entry.
– People whose tumours shrank in response to alectinib continued to respond for a median of 7.5 months (duration of response [DOR], immature data).
– The immature median progression-free survival (PFS) was 6.3 months (95% CI 5.5 months–not estimable) based on 40% of events.
In study NP28761, alectinib demonstrated a safety profile consistent with that observed in previous studies.
– The most common Grade 3 or higher adverse events were increased muscle enzymes (increased blood levels of creatine phosphokinase; 8%), increased liver enzymes (alanine aminotransferase; 6%, and aspartate aminotransferase; 5%) and shortness of breath (dyspnea; 3%).
NP28673 is a global, single-arm, open-label, multicentre trial evaluating the safety and efficacy of alectinib in 138 people with ALK-positive NSCLC whose disease progressed on crizotinib.
– An IRC analysis showed that alectinib shrank tumours (ORR of 50.0%, [95% CI 40.8%-59.1%]) in this group of people, as measured by RECIST.
– Assessment by investigator was consistent with the IRC and also showed that alectinib shrank tumours in this group of people (ORR of 47.8%, [95% CI 39.3%-56.5%]).
– Activity was also observed in the CNS, as shown by a CNS ORR by IRC of 57.1% (95% CI 39.4%-73.7%) in people whose disease had already spread to the brain or other parts of the CNS at study entry.
– People who achieved a response continued to respond for a median of 11.2 months (DOR, immature data based on 33% of events, [95% CI 9.6 months-not estimable]).
– The median PFS for people who received alectinib was 8.9 months (95% CI 5.6 months-11.3 months) based on 58% of events.
Alectinib demonstrated a safety profile in study NP28673 consistent with that observed in previous studies.
– The most common Grade 3 or higher adverse event was shortness of breath (dyspnea; 4%).
About alectinib
Alectinib (RG7853/AF-802/RO5424802/CH5424802) is an oral medicine created at Chugai Kamakura Research Laboratories for certain people with NSCLC whose tumours are identified as ALK-positive. ALK-positive NSCLC is often found in younger people who have a light or non-smoking history. The people whose NSCLC is ALK-positive almost always have adenocarcinoma.
Early studies with alectinib have shown activity on brain metastases, indicating that the drug may be taken up in the brain. The brain is protected by the Blood-Brain Barrier, a network of tightly joined cells that line the inside of the blood vessels in the brain and spinal cord. One of the ways the Blood-Brain Barrier prevents molecules from affecting the brain is to actively eject them from the barrier through a process known as ‘active efflux’. The active efflux system does not recognise alectinib, which means that it may travel into and throughout brain tissue.
The Global Phase III studies of alectinib include a companion test developed by Roche Diagnostics. Alectinib is marketed in Japan by Chugai Pharmaceutical, a member of the Roche Group.
About Roche in lung cancer
Lung cancer is a major area of focus and investment for Roche, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have two approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.