On April 7, 2016 TapImmune, Inc. (TPIV), a clinical-stage immuno-oncology company specializing in the development of innovative peptide and gene-based immunotherapeutics and vaccines for the treatment of cancer & metastatic disease, reported it has successfully completed formulation development, scale-up, GMP (Good Manufacturing Practice) manufacturing, and the release of TPIV 200, its multi-epitope folate receptor peptide vaccine for breast and ovarian cancer (Press release, TapImmune, APR 7, 2016, View Source [SID:1234510571]). The manufactured product contains five peptide antigens freeze dried in a single vial, ready for injection after reconstitution and addition of granulocyte-macrophage colony-stimulating factor (GM-CSF). TPIV 200 doses are now available for the upcoming Phase II clinical trials in both triple negative breast cancer and ovarian cancer.

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The initiation of Phase II clinical trials for TPIV 200 is the result of a successful Phase I study in ovarian and breast cancer which demonstrated that the vaccine was safe, well-tolerated, and generated a robust and lasting folate receptor alpha-specific T-cell response for most patients.

TapImmune has announced its plans to initiate, in 2016, several clinical trials with TPIV 200 vaccine including: a) a 280 patient Phase II trial in triple-negative breast cancer funded by a grant from the U.S Department of Defense (DOD) to the Mayo Clinic; b) a combination trial with a checkpoint inhibitor in ovarian cancer; and, c) at least two additional trials funded and administered by TapImmune.

"The successful release of our folate receptor vaccine represents an important milestone in the progression of TapImmune product pipeline and its technologies. The improved process achieved a formulation that may be reliably manufactured, is easy to prepare and administer to the patient at bed-side, while also being cost-competitive," stated Dr. Glynn Wilson, Chairman and CEO of TapImmune. "The experience we gained in completing this work is being directly applied to our formulation work for a second product in our pipeline, the HER2/Neu T-cell vaccine. Our objective is to file an investigational new drug (IND) application with the U.S. Food and Drug Administration for HER2/Neu vaccine trials in the next 12 months."

"The release of this first GMP batch of vaccine product will supply the first Tapimmune sponsored Phase II trial in breast cancer, for which at least six clinical sites are currently being screened and initiated, and also the Mayo Clinic sponsored Phase II study funded by the DOD," commented Patrick Yeramian, MD, Chief Medical Officer of TapImmune.

On April 7, 2016 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported the acceptance of an abstract for an oral plenary session presentation relating to its Phase 1 clinical development program for entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK, at the 2016 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in New Orleans, Louisiana (Press release, Ignyta, APR 7, 2016, View Source [SID:1234510530]). The company also announced the acceptance of three other abstracts for poster presentations at the meeting, relating to entrectinib, the company’s RXDX-107 product candidate, and a novel diagnostic statistical method to assess RNA expression.

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"We are honored that the Scientific Program Committee has selected our entrectinib Phase 1 data update abstract for an oral presentation, as well as three additional abstracts for poster presentations," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "We look forward to sharing data from each of these abstracts in this prestigious forum, and to discussing the data and our future plans with key scientific and clinical experts."

Details of the presentations are as follows:

Oral presentation:

Date/time: Sunday, April 17, 2016, 5:12 PM – 5:30 PM, Central time
Title:
Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements – updated phase 1 results. (Abstract number CT007)
Presenter: Alexander Drilon, M.D., Memorial Sloan Kettering Cancer Center

Poster presentations:

Date/time: Monday, April 18, 2016, 1:00 PM – 5:00 PM, Central time
Title:
Entrectinib is effective against the gatekeeper and other emerging resistance mutations in NTRK-, ROS1- and ALK- rearranged cancers. (Abstract number 2136)

Date/time: Wednesday, April 20, 2016, 8:00 AM – 12:00 PM, Central time
Title:
RXDX-107 exhibits multiple mechanisms of intracellular delivery and results in extensive drug-induced interstrand crosslinks in solid tumor preclinical models. (Abstract number 4780)

Date/time: Wednesday, April 20, 2016, 8:00 AM – 12:00 PM, Central time
Title:
A novel, statistical-based method to determine RNA expression by next-generation sequencing in clinical FFPE samples. (Abstract number 5274)

Several angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway have been approved for cancer treatment. However, VEGF inhibitors alone were shown to promote tumor invasion and metastasis by increasing intratumoral hypoxia in some preclinical and clinical studies. Emerging reports suggest that Delta-like ligand 4 (Dll4) is a promising target of angiogenesis inhibition to augment the effects of VEGF inhibitors. To evaluate the effects of simultaneous blockade against VEGF and Dll4, we developed a bispecific antibody, HD105, targeting VEGF and Dll4. The HD105 bispecific antibody, which is composed of an anti-VEGF antibody (bevacizumab-similar) backbone C-terminally linked with a Dll4-targeting single-chain variable fragment, showed potent binding affinities against VEGF (KD: 1.3 nM) and Dll4 (KD: 30 nM). In addition, the HD105 bispecific antibody competitively inhibited the binding of ligands to their receptors, i.e., VEGF to VEGFR2 (EC50: 2.84 ± 0.41 nM) and Dll4 to Notch1 (EC50: 1.14 ± 0.06 nM). Using in vitro cell-based assays, we found that HD105 effectively blocked both the VEGF/VEGFR2 and Dll4/Notch1 signaling pathways in endothelial cells, resulting in a conspicuous inhibition of endothelial cell proliferation and sprouting. HD105 also suppressed Dll4-induced Notch1-dependent activation of the luciferase gene. In vivo xenograft studies demonstrated that HD105 more efficiently inhibited the tumor progression of human A549 lung and SCH gastric cancers than an anti-VEGF antibody or anti-Dll4 antibody alone. In conclusion, HD105 may be a novel therapeutic bispecific antibody for cancer treatment.

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SAR405838 is a potent and specific MDM2 inhibitor currently being evaluated in Phase I clinical trials for the treatment of human cancer. Using the SJSA-1 osteosarcoma cell line which harbors an amplified MDM2 gene and wild-type p53, we have investigated the acquired resistance mechanisms both in vitro and in vivo to SAR405838. Treatment of SJSA-1 cells with SAR405838 in vitro leads to dose-dependent cell growth inhibition, cell cycle arrest and robust apoptosis. However, prolonged treatment of SJSA-1 cells in vitro with SAR405838 results in profound acquired resistance to the drug. Analysis of in vitro-derived resistant cell lines showed that p53 is mutated in the DNA binding domain and can no longer be activated by SAR405838. Treatment of the parental SJSA-1 xenograft tumors with SAR405838 in mice yields rapid tumor regression but the tumors eventually regrow. Culturing the regrown tumors established a number of sublines, which showed only modest (3-5 times) loss of sensitivity to SAR405838 in vitro. Sequencing of the p53 showed that it retains its wild-type status in these in vivo sublines, with the exception of one subline, which harbors a single heterozygous C176F p53 mutation. Using xenograft models of two in vivo derived sublines, which has either wild-type p53 or p53 containing a single heterozygous C176F mutation, we showed that while SAR405838 effectively achieves partial tumor regression in these models, it no longer induces complete tumor regression and tumors resume growth once the treatment is stopped. Harvesting and culturing tumors obtained from a prolonged treatment with SAR405838 in mice established additional in vivo sublines, which all contain a single heterozygous C176F mutation with no additional p53 mutation detected. Interestingly, SAR405838 can still effectively activate p53 in all sublines containing a single heterozygous C176F mutation, with a moderately reduced potency as compared to that in the parental cell line. Consistently, SAR405838 is 3-5 times less effective in all the in vivo derived sublines containing a single heterozygous C176F p53 mutation than in the SJSA-1 parental cell line in assays of cell growth and apoptosis. Computational modeling suggested that a p53 tetramer containing two wild-type p53 molecules and two C176F mutated molecules can maintain the structural stability and interactions with DNA by formation of additional hydrophobic and cation-π interactions which compensate for the loss of sulphur-zinc coordination. Our data thus show that SJSA-1 tumor cells acquire very different levels of resistance in vitro and in vivo to the MDM2 inhibitor SAR405838. Our present study may have a significant implication for the investigation of resistant mechanisms for other classes of anticancer drugs.

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The treatment of chronic myeloid leukemia (CML) has improved considerably since the introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2001 and the approval of second-generation TKIs (dasatinib and nilotinib) beginning in 2006.The objective of this study was to explore treatment patterns of TKI therapy (adherence, duration, and switching) among patients with CML in the United States, following the availability of second-generation TKIs.
This study used US health plan claims data from January 1, 2007, through December 31, 2011. Patients were required to be aged ≥18 years, have a prescription fill for a TKI, and a diagnosis of CML. Duration of TKI use was determined based on a gap in TKI coverage of ≥180 consecutive days after TKI initiation or switch to another TKI within the 180-day window. To account for censoring due to disenrollment from the health plan or end of the study period, median treatment duration was projected by using the Kaplan-Meier estimator.
We identified 695 patients who started TKI treatment and had a CML diagnosis during the study time frame. The mean age of patients was 55 years, and 58% of patients were male. The most common first-line TKI was imatinib (82%), with dasatinib and nilotinib use equally distributed (9%). Among the 148 (21.3%) patients who initiated a second-line TKI, the majority had switched from imatinib to dasatinib or nilotinib (86%). The median duration of first-line TKI use was 39.8 months and second-line TKI use was 22.4 months. Median duration of treatment for first-line (P = 0.4342) and second-line (P = 0.1792) treatment did not differ significantly according to TKI. Mean adherence (ie, proportion of days covered) during the first line of therapy was 0.90.
For the US patients studied, we found that imatinib was used more frequently than other TKIs in the first-line setting, but there was an increased use of second-generation TKIs in the first-line setting over time (9% in 2008 vs 43% in 2011 were nilotinib or dasatinib users). Only about one fifth of patients switched to a second-line TKI during the period of data collection.
Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

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