On November 20, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data which demonstrated that altiratinib (DCC-2701) provided balanced inhibition of MET, TRK, TIE2 and VEGFR2 kinases (Press release Deciphera Pharmaceuticals, NOV 20, 2014, View Source [SID:1234500992]). Altiratinib exhibited potency against both wild-type and mutant forms of MET and TRK kinases. In in vivo studies, altiratinib was shown to inhibit tumor growth, evasive vascularization, invasion and/or metastasis. In one model an increased overall survival was observed. Altiratinib exhibited anti-tumor activity in a variety of xenograft or allograft tumor models, including melanoma, gastric, lung, colorectal, breast, ovarian and glioblastoma. These data were presented today at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. Altiratinib is currently in a Phase 1 clinical study in cancer patients with solid tumors.

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"In this preclinical data set, the profile observed with altiratinib demonstrated robust and durable inhibition of kinases related to multiple hallmarks of cancer., Our data demonstrate blocking of tumor progression and growth and tumor microenvironment related mechanisms, including evasive vascularization and metastasis in a variety of cancer models," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "We look forward to further evaluation of altiratinib’s anti-cancer activity, including top-line data from our ongoing Phase 1 clinical study in patients with advanced solid tumors which is expected in mid-2015."

In a poster presentation titled "Altiratinib: a balanced inhibitor of MET, TRK, TIE2, and VEGFR2 kinases that exhibits broad anti-tumor and anti-angiogenic activities," Deciphera researchers described data which demonstrated that altiratinib inhibited tumors driven by MET amplification, overexpression, or mutation and also provided the potential for blocking tumor microenvironment angiogenic resistance mechanisms and pro-tumoral effects. Findings from the data include:

Altiratinib potently inhibited MET, TIE2, VEGFR2, and TRK kinases in functional cellular assays, including activity against proliferation, migration, and capillary tube formation, and with sufficient single-digit nanomolar potency such that all of these targets could be effectively inhibited simultaneously in vivo.
Altiratinib exhibited efficacy at preventing tumor growth, as well as inhibiting evasive vascularization, pro-tumoral macrophages, epithelial-to-mesenchymal transition (EMT) and metastasis in a variety of cancer models.
Altiratinib inhibited MET kinase for more than 24 hours after a single 10 mg/kg dose in a gastric cancer xenograft model leading to significant inhibition of tumor growth.
Altiratinib blocked bevacizumab-induced evasive vascularization and EMT in an aggressive, invasive glioblastoma model.
Altiratinib inhibited primary tumor growth and showed additive activity with paclitaxel; in addition, it reduced TIE2-expressing macrophages in the tumor stroma and significantly reduced lung metastases in a metastatic breast cancer model.
Altiratinib exhibited a long off-rate from kinases (greater than 24 hours from TIE2 and TRKA) in a variety of cell-based assays, based on its binding mode.
Altiratinib inhibited microvessel density and tumor growth in a xenograft model where both TIE2 and VEGFR2 kinases contribute to vessel growth.
Altiratinib compared favorably with other multi-targeted MET inhibitors, and had additional activity in inhibiting oncogenic MET mutants found in papillary renal cell carcinoma (PRCC), while other MET inhibitors have not been shown to inhibit activated MET mutants.

On November 20, 2014 OncoSec Medical reported that it has entered into a Sponsored Research Agreement (SRA) with the University of Washington to evaluate the immunologic mechanisms of intratumoral DNA IL-12 electroporation (Press release OncoSec Medical, NOV 20, 2014, View Source [SID:1234500996]).

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Dr. I. Nicholas Crispe, MBBS, PhD, a professor in the Department of Immunology at the University of Washington and an expert in liver immunology and tolerance, will serve as the principal investigator. Using a novel liver cell isolation approach, Dr. Crispe has demonstrated that different types of liver cells have the capacity to present antigens, which likely contributes to hepatic immunosuppressive mechanisms. In this SRA, Dr. Crispe will apply these techniques to the B16 melanoma tumor model to not only better understand the systemic mechanisms of intratumoral DNA IL-12 electroporation (ImmunoPulse), but also to potentially identify other molecular targets that might combine with IL-12 to enhance immune response.

Dr. Robert H. Pierce, Chief Scientific Officer of OncoSec Medical, said, "We are excited to embark on this project with Dr. Crispe, who has tremendous expertise in mechanisms of immune tolerance. We believe he will bring fresh insights into tumor immuno-biology from his extensive knowledge of mechanisms of pathogen-induced immuno-subversion."

Dr. Crispe said, "We are focusing on taking the insights we have learned from studies of the basic biology of immune tolerance, and translating them directly to a model of human cancer. Although our initial target is malignant melanoma, we believe it is likely that data from these studies will be directly applicable to other cancers."

Interleukin-12 (IL-12) is a potent inflammatory cytokine that regulates multiple aspects of the immune system; in particular, it initiates both innate and adaptive immune responses. IL-12 is a key driver of the cascade of biological events that ultimately lead to T-cell-specific killing of cancer cells. Moreover, cytokines and chemokines induced by this pathway also increase the recruitment of inflammatory T-cells into tumors.

ImmunoPulse is a proprietary investigational electroporation device that delivers plasmid IL-12 DNA directly into tumors. By locally delivering and expressing IL-12, ImmunoPulse has shown in clinical studies to elicit anti-tumor immune activity, which has led not only to local tumor regression, but also to systemic anti-tumor regression, while mitigating toxicities typically observed with systemic administration of IL-12. Preliminary interim data from OncoSec’s ongoing Phase II study in melanoma provide evidence that local delivery of IL-12 by electroporation increases the production of cytokines such as IFN-γ, resulting in increased expression of genes related to the processes required for cytotoxic CD8+ T cells to recognize and kill cancer cells.

On November 19, 2014 Sunesis Pharmaceuticals reported the online publication of results from the Company’s Phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) in the November 7, 2014 Ahead of Print issue of Haematologica (Press release Sunesis, NOV 19, 2014, View Source;p=RssLanding&cat=news&id=1991012 [SID:1234500984]). The article, titled "A Phase 1b/2 study of combination vosaroxin and cytarabine in patients with relapsed or refractory acute myeloid leukemia," is available online at View Source

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"Acute myeloid leukemia is a complex, genetically heterogeneous cancer for which there has been no advancement in drug treatment in over 40 years," stated Dr. Jeffrey Lancet, Senior Member and Professor of Oncologic Sciences at the H. Lee Moffitt Cancer Center, Tampa, Florida and lead author of the publication. "In this study, we see that vosaroxin, in combination with cytarabine, is active and well tolerated. These results were mirrored in the Phase 3 VALOR trial, which demonstrated clinically meaningful outcomes supported by encouraging response rates and a manageable safety profile.

The Phase 1b/2 study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed or refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m2 on days 1, 4) were given in combination with cytarabine on 1 of 2 schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m2 per day on days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m2 per day on days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. The maximum tolerated dose for schedule A was vosaroxin 80 mg/m2 (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis); the maximum tolerated dose was not reached for schedule B (recommended phase 2 dose: 90 mg/m2).

The median age in the study was 60 years, and patients had received as many as 6 prior cycles of therapy. Furthermore, most patients (89%) had intermediate or unfavorable cytogenetic risk status. The most common treatment-emergent nonhematologic adverse events of any grade were diarrhea, hypokalemia, nausea, and stomatitis. In the efficacy population, (all first relapsed or primary refractory patients treated with vosaroxin 80-90 mg/m2; n=69), the complete remission (CR) and combined CR rates (CR or CR with incomplete blood count recovery) were 25% and 28%, respectively. Thirty-day all-cause mortality was 2.5% among all patients treated at 80-90 mg/m2. Based upon these results, the phase 3 VALOR trial of vosaroxin plus cytarabine was initiated in patients with first relapsed or refractory acute myeloid leukemia.

"The results published in Haematologica online were the foundation for the VALOR trial, among the largest studies ever conducted in the relapsed or refractory AML setting," said Adam Craig, Chief Medical Officer of Sunesis. "Based on the outcome of VALOR, we plan to submit a Marketing Authorization Application for vosaroxin and look forward to discussing the data with the U.S. Food and Drug Administration. We also look forward to building upon these and other data for vosaroxin in AML through investigator-sponsored studies."

On November 19, 2014 BIND Therapeutics reported positive results from its ongoing Phase 2 study of BIND-014 in non-small cell lung cancer (NSCLC), demonstrating it has met the primary objective in the once every three weeks (Q3W) arm as measured by overall response rate (ORR) (Press release BIND Therapeutics, NOV 19, 2014, View Source [SID:1234500985]). The data demonstrate that BIND-014 is well-tolerated with clinically meaningful anti-tumor activity at a lower dose than conventional docetaxel in patients with advanced or metastatic NSCLC. BIND-014 also demonstrates promising anti-tumor activity in patients with tumors expressing KRAS mutations (mutated Kirsten ras oncogene homolog). KRAS mutations in NSCLC are generally associated with poor response to currently available drug therapy regimens, including docetaxel. An additional signal was observed in patients with squamous cell carcinomas, a major NSCLC subtype poorly served by existing available therapies. These data were presented at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

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"We believe the activity and tolerability of BIND-014 demonstrated in this study suggest meaningful differentiation from the historical docetaxel experience, in both the broader NSCLC patient population and in two important groups of patients with high unmet medical need," said Hagop Youssoufian, M.D., M.Sc., Chief Medical Officer, BIND Therapeutics. "Furthermore, as the first product candidate from our Medicinal Nanoengineering platform to enter the clinic, we believe that the increased efficacy and reduced toxicity at a lower dose compared to historical docetaxel experience suggests that Accurins are successful in targeting the therapeutic payload to the tumor. Based on these positive results, we plan to conduct additional global, multicenter Phase 2 studies to confirm and expand the dataset on BIND-014 and to define an expeditious regulatory path for BIND-014."

The Q3W dosing arm of the open label, multicenter, Phase 2 study enrolled 40 patients with advanced metastatic NSCLC who were treated with 60 mg/m2 of BIND-014 on Day 1 of a 21-day cycle and achieved the following preliminary results:

Five patients (13%, N=40) achieved a partial response with a median duration of response of 5.2 months and median progression free survival (PFS) of 2.7 months. There was one unconfirmed partial response that was not included in the analysis per RECIST v1.1.
Nine patients were enrolled with a confirmed KRAS mutation and two of those nine experienced an objective response (22%); median PFS in patients with KRAS mutant tumors was 2.7 months.
In patients with squamous cell carcinoma (n=9) there were no confirmed objective responses; however, median PFS in patients with squamous cell carcinoma was 2.8 months. Prolonged ( > 4 cycles) disease control was also noted in six of nine (66%) patients with squamous histology.
Preliminary median overall survival was 6.2 months for all patients treated, 9.6 months in patients with KRAS mutant tumors and 11.1 months in patients with squamous cell carcinoma.
Twenty-one of 40 patients received four or more cycles of therapy, attesting to the tolerability of BIND-014. Consistent with previous results, neutropenia, anemia, neuropathy, and alopecia, commonly observed with docetaxel, were significantly reduced with BIND-014.

"Data from this open label study suggest the potential for BIND-014 superiority over docetaxel in the treatment of NSCLC patients," said Ronald B. Natale, M.D., Medical Director of the Clinical Lung Cancer Program at the Women’s Guild Lung Institute and investigator for the Phase 2 trial of BIND-014 in NSCLC. "Furthermore, BIND-014 demonstrated intriguing activity in patients with KRAS mutated lung cancers, a group of patients who have historically been unresponsive to standard treatment with docetaxel. This initial experience with BIND-014 provides a glimpse into a new way to selectively target NSCLC tumors, an area of cancer with high unmet need."

BIND plans to initiate global, multicenter Phase 2 studies of BIND-014 in patients with KRAS mutant NSCLC and in patients with NSCLC of squamous histology who have progressed on prior therapy. These studies aim to assess overall survival and additional endpoints to position BIND-014 for subsequent registration studies.

Based on the promising results of the Q3W arm presented today and the more patient-friendly once every three week dosing schedule, combined with the absence of a confirmed partial response in the first 22 patients enrolled on the Q1W schedule, the company will not continue enrollment on the weekly dosing schedule.

Data from the Phase 2 study will be included in a presentation by BIND CEO Scott Minick at the Stifel Nicolaus Weisel Healthcare Conference in New York at 8:35 a.m. EST today. Interested parties may access a live webcast of the presentation by visiting the BIND Therapeutics website at www.bindtherapeutics.com. The webcast will be archived on the BIND Therapeutics website following the event for one week.

On November 18, 2014 Teva Pharmaceutical Industries reported the commercial availability of a liquid formulation of TREANDA (bendamustine HCI) Injection (Press release Teva, NOV 18, 2014, View Source;p=RssLanding&cat=news&id=1990616 [SID:1234500981]). This new liquid formulation removes the step of reconstituting lyophilized powder with sterile water prior to adding the required dose of medicine to the infusion bag and administering to a patient. By eliminating the need for reconstitution, preparation time for healthcare professionals is reduced.

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"TREANDA continues to play a valuable role in the treatment of patients with CLL or indolent B-cell NHL that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen," said Paul Rittman, Vice President and General Manager, Teva Oncology. "With the new liquid formulation of TREANDA, we are not only building on the legacy of this important product, but also furthering Teva’s commitment to continuously improving our medicines."