On July 6, 2015 ImmunoCellular Therapeutics reported the establishment of an agreement with Novella Clinical (Novella), to conduct the phase 3 registration trial of ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, JUL 6, 2015, View Source [SID:1234506167]). Schedule your 30 min Free 1stOncology Demo! Novella is a full-service, global clinical research organization (CRO) providing clinical trial services to small to mid-sized oncology companies. The ICT-107 phase 3 trial will include approximately 120 clinical sites in the US, Europe and Canada, and will recruit about 400 patients with newly diagnosed glioblastoma. ImmunoCellular anticipates initiating the phase 3 trial in the fourth quarter of 2015. Know more, wherever you are: "Establishing this agreement with Novella Clinical moves us one more critical step forward in the implementation of our phase 3 ICT-107 registrational trial," said Andrew Gengos, ImmunoCellular Chief Executive Officer. "Novella’s special expertise in oncology clinical trials, combined with their strong international network, experience working with oncology cooperative groups, and reputation for high quality, efficiency and cost-effectiveness, make them an excellent partner for our ICT-107 program. We are rapidly building the infrastructure for our phase 3 program and remain on track to initiate the trial later this year."
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Novella’s President Richard Staub added, "We are proud and very pleased to be selected to support this proprietary oncology immunotherapy platform for glioblastoma. We look forward to working alongside ImmunoCellular to navigate the development and successful execution of this pivotal program to ultimately benefit patients."
Author: [email protected]
Encorafenib-Based Regimens Show Promising Clinical Activity In BRAF-Mutant Colorectal Cancer Patients
On July 6, 2015 Array BioPharma reported Array BioPharma’s wholly-owned RAF inhibitor, encorafenib, was showcased this past weekend at the 2015 ESMO (Free ESMO Whitepaper) World Congress of Gastrointestinal Cancer during an oral presentation (Press release, Array BioPharma, JUL 6, 2015, View Source;p=RssLanding&cat=news&id=2064825 [SID:1234506165]).
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At the meeting, data were shared from a Phase 1b trial and preliminary data from a 100-patient randomized Phase 2 expansion of that trial testing the combination of encorafenib and cetuximab, an EGFR inhibitor, with or without the addition of alpelisib (BYL719) 1, an investigational PI3K inhibitor in patients with BRAF-mutant colorectal cancer (BRAFmut CRC). Results from the study indicate that these combinations can be administered with good tolerability and show promising clinical activity in this patient population with high unmet medical needs. Patient enrollment is now complete in the Phase 2 study.
The preliminary Phase 2 results show an objective response rate (complete or partial response) and disease control rate (complete or partial response or stable disease) of 29% and 81%, respectively, for patients receiving the combination of encorafenib and cetuximab (encorafenib doublet), and 35% and 79%, respectively, for patients receiving the combination of encorafenib, cetuximab and alpelisib (encorafenib triplet).
Across both the encorafenib doublet and triplet treatment groups, most treatment related adverse events were grade 1 or 2 with few grade 3 or 4 adverse events. The most frequent treatment related adverse events across all grades for the encorafenib doublet were fatigue (36%), nausea (31%), lipase increased (24%), diarrhea (21%) and decreased appetite (21%), while for the encorafenib triplet they were diarrhea (39%), nausea (37%), fatigue (33%) and hyperglycemia (31%).
These results are consistent with the Phase 1b portion of the trial and are encouraging when compared to currently available therapies for BRAFmut CRC patients, as well as with other recently published investigational approaches in this population. Historically, response rates are very low for either single-agent EGFR or RAF inhibitor therapy in patients with BRAFmut CRC, which suggests a synergistic effect for the combination of encorafenib and cetuximab in this population.
"The combination of encorafenib and cetuximab demonstrated promising activity in this hard-to-treat subset of colorectal cancer patients," said Josep Tabernero, M.D., Head of the Medical Oncology Department at the Vall d’Hebron University Hospital and the Director of the Vall d’Hebron Institute of Oncology. "It is critical to identify new, effective treatments for BRAF mutant colorectal cancer patients, and I look forward to rapid development of this combination in a subsequent clinical trial."
1 alpelisib (BYL719) is an investigational Novartis Pharmaceuticals compound.
About Colorectal Cancer
Colorectal cancer is the third most common cancer among men and women in the United States, with approximately 132,000 new cases and nearly 50,000 deaths from the disease projected in 2015. BRAF mutations occur in approximately 10% percent of patients with colorectal cancer and predict for a poor response to standard therapies and an overall poorer prognosis relative to patients without these mutations.
About RAF and encorafenib
RAF is a key protein kinase in the MAPK signaling pathway that regulates several key cellular activities including proliferation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers, such as melanoma, colorectal, lung and thyroid cancers. Encorafenib is a selective, small molecule, oral inhibitor which targets the RAF enzyme in this pathway. It is currently being developed in eleven active clinical trials, including the COLUMBUS trial, a Phase 3 study of encorafenib and binimetinib (MEK inhibitor) for patients with BRAF mutant melanoma. Array expects updated BRAF melanoma data from the Phase 2 combination trial (LOGIC-2) of binimetinib, encorafenib and a third agent (LEE011, BKM120, BFJ398 or INC280) will be submitted to a scientific conference later this year.
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ArQule Announces Interim Phase 2 Study Results for Tivantinib in Combination with Cetuximab in Patients with MET-High, KRAS Wild Type Colorectal Cancer Presented at ESMO World Congress on Gastrointestinal Cancer 2015
On July 6, 2015 ArQule reported interim data from an ongoing investigator-initiated Phase 2 clinical trial with tivantinib in combination with cetuximab in patients with MET-High, KRAS wild-type metastatic colorectal cancer (CRC) NCT01892527 who recently progressed on anti-EGFR antibodies (Press release, ArQule, JUL 6, 2015, View Source [SID:1234506164]). These data were presented on Friday, July 3rd at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) World GI 2015 (abstract number O-008) by Dr. Lorenza Rimassa, MD, Deputy Director, Medical Oncology Unit at Humanitas Cancer Center, in Rozzano (Milan, Italy). Schedule your 30 min Free 1stOncology Demo! "Considering that in CRC objective response rate (ORR) often correlates with overall survival (OS) benefit, the preliminary results obtained combining tivantinib with cetuximab are encouraging," said Dr. Rimassa. "Since all patients enrolled in this trial were MET-High and had recently progressed on a combination regimen including cetuximab or panitumumab, the data may support the hypothesis that MET inhibition can reverse resistance to EGFR inhibitors as well as the need for rigorous tissue collection procedures at enrollment to allow for a more robust correlative outcome assessment related to the MET pathway."
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The primary endpoint of the trial is ORR in the biomarker defined population. Secondary study endpoints are progression-free survival (PFS), overall survival (OS) and safety. The ESMO (Free ESMO Whitepaper) World GI presentation included data from 21 patients enrolled in Stage 1 of this trial. One patient, still on therapy, experienced a complete response (CR) and 2 patients experienced durable confirmed partial responses (PRs). Stable disease was observed in 8 patients, including 2 short duration PRs, for an overall Disease Control Rate (CR + PR + SD) of 52.4%. Having met the Stage 1 endpoint (≥2 confirmed responses), the trial continued to Stage 2 and has recently completed enrollment.
Adverse events were in line with those historically reported, including skin toxicity attributed to cetuximab, and neutropenia attributed to tivantinib. Neutropenia was addressed timely with growth factors and dose adjustments.
The trial is a 2-stage, investigator-initiated study testing tivantinib plus cetuximab after recent progression on anti-EGFR antibodies. The trial is coordinated by the Humanitas Cancer Center in Milan, Italy. Stage 1 enrolled 21 patients, and Stage 2 recently completed enrollment of 20 additional patients. Final results from the 41 patients enrolled are expected by the end of 2015.
About Colorectal Cancer (CRC)
Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. and is the third most common cancer in men and women. According to the National Cancer Institute, it is estimated that more than 132,000 new cases of colorectal cancer will be diagnosed in 2015, and an estimated 49,700 deaths from the disease will occur this year. The estimated incidence rate was 42.4 per 100,000 people during the period 2008-2012.
About MET and tivantinib (ARQ 197)
Tivantinib is an orally administered, selective inhibitor of MET, a receptor tyrosine kinase, which is currently in Phase 2 and Phase 3 clinical trials. In healthy adult cells, MET can be present in normal levels to support natural cellular function, but in cancer cells, MET can be inappropriately and continuously activated. When abnormally activated, MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The activation of certain cell signaling pathways, including MET, has also been associated with the development of resistance to anti-EGFR (epidermal growth factor receptor) antibodies such as cetuximab and panitumumab.
Pre-clinical data have demonstrated that tivantinib inhibits MET activation in a range of human tumor cell lines and shows anti-tumor activity against several human tumor xenografts. In clinical trials to date, treatment with tivantinib has been generally well tolerated and has shown clinical activity in the tumors studied. Tivantinib has not yet been approved for any indication in any country.
In December 2008, ArQule and Daiichi Sankyo signed a license, co-development and co-commercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan.
IPC, the comprehensive cancer center of Marseille, and INNATE PHARMA collaborate on translational research for novel immune checkpoint inhibitors
On July 6, 2015 Paoli Calmettes Institute (IPC) reported it has initiated a collaboration with Innate Pharma to conduct translational research aimed at identifying specific populations of patients with hematological cancers who may benefit most from treatment with Innate Pharma’s novel proprietary antibodies, and to identify associated biomarkers (Press release, Innate Pharma, JUL 6, 2015, View Source [SID:1234506163]). Schedule your 30 min Free 1stOncology Demo! Nicolai Wagtmann, Chief Science Officer of Innate Pharma, said: "This agreement strengthens our translational research capabilities, at the core of our drug development process. IPC is a leading center in hematology-oncology with deep understanding in immunology and capabilities in immune monitoring. Early-stage testing of Innate Pharma’s promising antibodies on patient samples will greatly optimize subsequent clinical development by better identifying the most relevant indications, patient populations and biomarkers". Know more, wherever you are: Pr. Patrice Viens, Chief Executive Officer of IPC, stated that "This new R&D collaboration with Innate Pharma further expands a long-lasting relationship which started with lirilumab, a fully human monoclonal antibody blocking the interaction between Killer-cell immunoglobulin-like receptors (KIR) on NK cells with their ligands on tumor cells. IPC conducted the "first-in-man study" of lirilumab and continues to be involved in the development of this drug. IPC and Innate Pharma are also involved in other partnerships within the frame of the Marseille SIRIC* and of Marseille Immunopole **".
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The collaboration will operate under the direction of Pr. Daniel Olive, Head of the Immunity and Cancer research team and of the immune monitoring platform at IPC, and Pascale André, Senior Director, R&D, at Innate Pharma. It will also involve drug-discovery research teams and experts in translational research at IPC, including Pr. Norbert Vey and Pr. Anthony Gonçalvès, and other scientists with expertise in converting promising drug discoveries into clinical treatments for cancer patients.
Under the terms of the collaboration agreement, IPC will test Innate Pharma’s new therapeutic antibodies in immuno-oncology using IPC’s extensive biological resource collection. Innate Pharma’s antibodies are designed to block immune checkpoints, one of the most promising classes of drugs in oncology. These immune checkpoints interfere with the natural defense mechanisms of our immune system against cancer and regulate immunosuppressive mechanisms. Their blockade can unleash the patient’s immune system to recognize and eliminate cancer cells. However, only a fraction of patients respond to current immune checkpoint inhibitors, and identifying the population of patients most likely to respond to various checkpoint blockers would be of great interest. This R&D collaboration will facilitate the development of novel therapeutic antibodies by identifying the best suited patient population and indications for a given drug.
Navidea Reports Clinical Data Demonstrating Manocept™ Agent Localizes in Multiple KS Lesions
On July 2, 2015 Navidea Biopharmaceuticals and its subsidiary, Macrophage Therapeutics reported that imaging results from the Manocept clinical trial in Kaposi’s Sarcoma (KS) and other preclinical studies were presented at the 18th International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents in Hollywood, Florida (Press release, Navidea Biopharmaceuticals, JUL 2, 2015, View Source;p=RssLanding&cat=news&id=2064415 [SID:1234506023]). The clinical imaging study, using Tc 99m tilmanocept, a Manocept platform product, in both HIV+ and HIV- patients suggests that KS tumor lesions, both cutaneous and suspected extra-cutaneous sites, can be easily visualized and mapped, demonstrating that this technique may potentially provide a means for routine patient assessment. The results also show that use of Manocept represents a potential therapeutic pathway for targeting tumor associated macrophages (TAMs). Manocept agents are designed to target CD206, which is highly expressed on TAMs and the KS tumor itself. As a potential therapeutic, Manocept could be used as a precision vehicle to deliver payloads to tumor sites throughout the body.
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"These pre-clinical and clinical studies support using Kaposi’s sarcoma as a model tumor system for evaluating therapeutic approaches for the Manocept platform in other forms of solid tumors," commented Michael Tomblyn, M.D., Navidea’s Chief Medical Officer. "They provide evidence that Manocept agents can target CD206 and are internalized into tumor associated macrophages and tumor cells. This along with clinical observations that demonstrate tilmanocept can be used to image KS tumors both externally and internally indicates excellent potential for immunotherapeutic utility."
"Using a targeted imaging agent like tilmanocept in this group of HHV8+patients represents an elegant approach to potentially detect internal KS lesions that would previously be difficult or impossible to non-invasively locate," commented Toby Maurer, M.D., FAAD, Professor of Dermatology at the University of California, San Francisco (UCSF), and Chief of Dermatology at San Francisco General Hospital and Trauma Center, who co-led the clinical study at UCSF with Michael S. McGrath, M.D., PhD. "Further, the specificity and the ability to quantify tumor burden could enable regular patient evaluations and monitoring of therapeutic effectiveness addressing important unmet patient needs."
Five Human Herpes Virus8 positive (HHV8+) patients (4 HIV+, 1HIV-) were enrolled in the NAV03-12 study. Patients received a single subcutaneous injection of Technetium Tc 99m tilmanocept in the region of a cutaneous KS lesion and imaging was performed at 1, 4 and 24-hours post-injection to visualize localization of tilmanocept. Results represented by whole body Single-Photon Emission Computed Tomography (SPECT/CT) imaging scans from study patients were presented. Collectively, the scans show localization of tilmanocept and detected multiple cutaneous lesions in the extremities, face and genitalia, as well as extra-cutaneous localization found in the nasopharynx, lymph nodes and brain. Results also indicate that KS lesions are anatomically linked in chains by and within the lymph ducts. The study concludes that both HIV+ and HIV- patients have pan-tumor expression of CD206, strongly suggests tilmanocept crosses the blood brain barrier and that a Manocept-drug conjugate may have the potential as a therapeutic with high target effect and low off-target concerns.
The data from these studies also suggest a novel theory on the genesis of KS in which KS arises from an HHV8 infected macrophage type cell and its interaction with the lymphatic system. This interaction provides the means for access of the KS through CD206 receptor for diagnosis, evaluation, and potential therapy using the Manocept platform.
Navidea and Macrophage Therapeutics plan a webcast to provide investors with a complete look at the data being presented at the International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents conference on July 7, 2015 at 1:00 pm EDT. Webcast details will be available on the Navidea website.
About the Manocept CD206-targeting platform
The Manocept platform is predicated on the ability to specifically target the CD206 mannose receptor expressed on macrophages. Macrophages play important roles in many disease states and are an emerging target in many disorders. This flexible and versatile platform acts as an engine for purpose-built molecules that may enhance diagnostic accuracy, clinical decision-making, targeted treatments and ultimately patient care. As a diagnostic tool, the Manocept technology has the potential to utilize a breadth of imaging modalities, including SPECT, PET, intra-operative and/or optical-fluorescence detection. By adding a therapeutic agent on the Manocept molecular backbone, there is the potential to develop novel, targeted immunotherapies specifically designed to selectively deliver an agent that can kill or alter disease-associated macrophages. Navidea’s FDA-approved precision diagnostic imaging agent, Lymphoseek (technetium 99m tilmanocept) injection, is representative of the platform’s ability to successfully exploit this mechanism and offer the potential for development of new CD206-targeted diagnostic agents and therapeutics.