Mar28’15: UTSW’s Dr.AdamYopp Oral-Pres. Ph2 Liver Data at SSO’15/Houston
Mar25-28 2015: “Society of Surgical Oncology's 68th Annual Cancer Symposium (SSO 2015)”, Houston http://events.jspargo.com/SSO15/public/enter.aspx …12/10/14/PR: “• Data from a Phase I/II IST that evaluated bavituximab in combination with sorafenib in patients with advanced hepatocellular carcinoma (Liver cancer) has been accepted for poster presentation at the 2015 Gastrointestinal Cancers Symposium to be held Jan15-17, 2015 in San Francisco, California [ http://tinyurl.com/q5dyruw ]and for an oral presentation at the Society of Surgical Oncology's 68th Annual Cancer Symposium to be held Mar25-28, 2015 in Houston.” Schedule: http://djgcreate.com/ssocalendar2/public/ - - - - - - - - - - - - - - Mar28 2015 12:45-2:15pm: Hepatobiliary Parallel Session/Gastrointestinal Track #GBCC-310 ”A Phase II Study of Bavituximab & Sorafenib in Advanced Hepatocellular Carcinoma (HCC)” Presenter: Adam C. Yopp (MD, Assist.Prof.Surgery, UTSW/Dallas, PI, Bavi+Sorafenib Liver ISThttp://clinicaltrials.gov/ct2/show/NCT01264705 ) …Authors: Adam Yopp*, H. Zhu, J. Mansour, A. Singal, Y. Arriaga, S. Beg, UTSW-MC/Dallas ABSTRACT: BACKGROUND: Bavituximab is a first-in-class immunomodulator targeting phosphatidylserine (PS), a membrane lipid externalized on tumor and endothelial cells. Preclinical and phase I studies demonstrated that sorafenib upregulates PS externalization and can be given safely with bavituximab. We thus evaluated the safety and clinical activity of bavituximab + sorafenib in HCC. METHODS: Patients with locally advanced or metastatic HCC deemed ineligible for curative therapy with no previous systemic treament, ECOG score = 2, Child Pugh score A or B7 received bavituximab, 3 mg/kg IV weekly, and sorafenib, 400 mg PO BID until disease progression or intolerable toxicity. 38 patients were accrued providing a power of 80% and 2-sided significance level of 10% to show an 8.2mo. time to progression compared to historical control, 5.5mos. Secondary endpoints included safety and tolerability, 4-mo. PFS, OS, and response rates. Correlative studies using tissue from pre- and post-treatment tumor biopsies included IHC analysis of regulatory, cytotoxic, and helper T cells in addition to macrophage infiltrates. RESULTS: 38 patients were accrued, 7 still on treatment. Patient characteristics: median age: 60.5 years, male 74%, HCV: 79%, Black: 47%/Hispanic: 29%/White: 21%, previous treatment 37%, and metastases: 24%. Median follow-up is currently 6.1 months with current median TTP of 6.8 months (95% CI 3,10). Four month PFS is 76% and there are no partial or complete responses. Treatment related adverse events were observed in 53% of patients, one grade 3 (GI bleed), four grade 2 (DVT, anorexia, diarrhea, and infusion reaction). Most common grade 1 events were diarrhea (18%), fatigue (16%), and anorexia (16%). Six patients had tissue analyzed pre- and post-treatment, 2 of 6 demonstrated increase tumor infiltration of CD4+, CD8+, and macrophages with a corresponding decrease in Tregs. CONCLUSIONS: Bavituximab & sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, combination therapy demonstrated an improvement in TTP and PFS at 4 months. Combination therapy increases immune tumor infiltrates. ID: 86
= = = = = = = = = = = = = = = = = = = = = H. 1st Investigator-Sponsored (IST) Ph.I/II Trial (Bavi+Sorafenib vs. Liver Cancer/HCC, open-label, n=9+38=47) ...Note: Sorafenib = Onyx/Bayer's Nexavar - see http://www.nexavar.com Protocol: http://clinicaltrials.gov/ct2/show/NCT01264705 UTSW: http://tinyurl.com/mwdc2ql (5 sites: 3/UTSW, Parkland-Hosp, Dallas/VA, PI=Dr. Adam Yopp) ...1-16-15 ASCO Gastro-Symposium: Ph.2 data/n=38 (Adam Yopp), “These clinical outcomes of TTP=6.7/DCR=58%/PFS=4mo are quite encouraging…”http://tinyurl.com/m9uz9mo …11-8-14: SITC'14 Ph.2 Correlative Studies data (biopsies B4/After) on 6pts, incl. KOL Dimitry Gabrilovich’s comments: http://tinyurl.com/pchzr6h ...9-9-14 Enrollment complete. http://tinyurl.com/ktrfswj (ph2=38 Ph1=9) ...4-4-12 AACR'12: Dr. Adam Yopp, "promising safety profile to-date" http://tinyurl.com/7yrwqm7 (see #5591) ...Feb'12-Sep'14 10+ times: CEO Steve King hints of future ex-US partner-driven Bavi+Sorafenib/LIVER trial in Asia-Pacific: http://tinyurl.com/nkaxtcc ......Articles & Data describe Liver Cancer challenges in Asian populations: http://tinyurl.com/7z7o8j9 & http://tinyurl.com/7z99cy4 ...12-1-10: PPHM's 1st IST (Liver Cancer) initiated at UTSW, ~56 patients - http://tinyurl.com/3xd3e6c …Per S.King, 5-18-10/R&R, "We've had a lot of interest in running clinical trials with the compound from investigators who have either had prior experience with the drug or would like to study the drug in various settings. Potential IST indications include all the major solid tumor types. Of particular interest is Liver Cancer, in which we have a natural tie-in with our HCV program, Ovarian Cancer and Pancreatic Cancer, also very nicely supported by the prior data."
1-16-15/PPHM: ”Positive HCC Data are the Kickoff for IST Data Driven 2015” PPHM announced presentation of data from the Phase II IST of bavituximab with sorafenib in HCC at GI ASCO. These are promising data, particularly given the patient population and we believe they open the door to future randomized studies in HCC patients using bavituximab in combination with sorafenib as well as with anti-PD-1 inhibitors. Reiterate Buy.
EVENT PPHM announced data from the Phase II single-center, single-arm, open-label IST of bavituximab with sorafenib in 38 HCC patients at GI ASCO. The data showed that time to progression (primary endpoint) was 6.7 mos, disease control rate was 58% (22/38), 4-mo. PFS was 62%, DSS was 8.7 mos and median OS was 6.2 mos. Two patients (5%) achieved PR and 20 (53%) achieved SD. The drug combination was well tolerated and there were no autoimmune AEs reported.
IMPACT We're impressed with the continued positive data coming out of this HCC study. Despite this being an open-label, single-arm study, these positive data are impressive given that these are heavily pre-treated patients with poor prognosis. Translational data from tumor biopsies of 6 patients from this study at SITC 2014 showed increased tumor infiltration of CD8+ T cells and induction of PD-1 expression in the tumor following treatment, giving additional support for combination study with anti-PD-1 inhibitors. These correlated with longer time on study and longer time to progression. With these promising data, we believe the door is open to future randomized studies in HCC patients using bavituximab in combination with sorafenib as well as with anti-PD-1 inhibitors. The pivotal Phase III SUNRISE study continues to enroll patients at over 150 global centers and we look forward to a data-driven 2015 with catalysts from multiple ISTs in NSCLC, breast cancer, melanoma, rectal adenocarcinoma and additional data from the Phase II IST in HCC. We believe that data from the Phase Ib of bavituximab with ipilimumab in melanoma will garner interest and increase visibility. This study, set to enroll up to 24 patients, should provide further support for combination of bavituximab with checkpoint inhibitors. We believe these ISTs will not only increase visibility for PPHM but also expand bavituximab's potential treatment profile.
ACTION We reiterate our Buy rating and $5 target. With Peregrine being a pivotal stage company, we view the risk/reward profile as favorable, and we believe visibility from the broadening bavituximab profile and partnering potential should drive the stock in 2015.
= = = = = = = = = = = = = = = = = = = = = H. 1st Investigator-Sponsored (IST) Ph.I/II Trial (Bavi+Sorafenib vs. Liver Cancer/HCC, open-label, n=9+38=47) ...Note: Sorafenib = Onyx/Bayer's Nexavar - see http://www.nexavar.com Protocol: http://clinicaltrials.gov/ct2/show/NCT01264705 UTSW: http://tinyurl.com/mwdc2ql (5 sites: 3/UTSW, Parkland-Hosp, Dallas/VA, PI=Dr. Adam Yopp) ...1-16-15 ASCO Gastro-Symposium: Ph.2 data/n=38 (Adam Yopp), “These clinical outcomes of TTP=6.7/DCR=58%/PFS=4mo are quite encouraging…”http://tinyurl.com/m9uz9mo …11-8-14: SITC'14 Ph.2 Correlative Studies data (biopsies B4/After) on 6pts, incl. KOL Dimitry Gabrilovich’s comments: http://tinyurl.com/pchzr6h ...9-9-14 Enrollment complete. http://tinyurl.com/ktrfswj (ph2=38 Ph1=9) ...4-4-12 AACR'12: Dr. Adam Yopp, "promising safety profile to-date" http://tinyurl.com/7yrwqm7 (see #5591) ...Feb'12-Sep'14 10+ times: CEO Steve King hints of future ex-US partner-driven Bavi+Sorafenib/LIVER trial in Asia-Pacific: http://tinyurl.com/nkaxtcc ......Articles & Data describe Liver Cancer challenges in Asian populations: http://tinyurl.com/7z7o8j9 & http://tinyurl.com/7z99cy4 ...12-1-10: PPHM's 1st IST (Liver Cancer) initiated at UTSW, ~56 patients - http://tinyurl.com/3xd3e6c …Per S.King, 5-18-10/R&R, "We've had a lot of interest in running clinical trials with the compound from investigators who have either had prior experience with the drug or would like to study the drug in various settings. Potential IST indications include all the major solid tumor types. Of particular interest is Liver Cancer, in which we have a natural tie-in with our HCV program, Ovarian Cancer and Pancreatic Cancer, also very nicely supported by the prior data."
- - - - - - - - - - - - - - - - KNOWN UPCOMING…
Jan15-17: Gastrointestinal Cancers Symposium (ASCO/ASTRO/SSO), SanFran - PR+Poster: http://tinyurl.com/m9uz9mo …Jan16 12-2pm/poster: Adam C. Yopp/Poster (MD/UTSW/Dallas): Ph.2 Data from Bavi+Sorafenib Liver IST
Jan29-30: GTC’s 7th Immunotherapeutics & Immunomonitoring Conf., SanDiego http://tinyurl.com/lqnb3ou (GTC = Global Technolology Community http://www.gtcbio.com ) …Jan30 2:25-2:50pm, Dr. Bruce Freimark (PPHM’s Dir/PreClin.Res) speaks in session=“Combinatorial Immunotherapies”: "Blockade of PS Enhances the Anti-tumor Activity of Targeted Therapy & Immune Checkpoint Inhibitors by Reducing Immunosuppressive Inflammatory Cells in the Tumor Microenvironment”
Feb8-13: Keystone Tumor Immunology Conf., Banff, Alberta http://tinyurl.com/mwkzoxz …Feb9 Dr. Bruce Freimark [Dir./Pre-Clin.Res.Oncology], “Antibody-Mediated Blockade of PS Enhances the Anti-Tumor Activity of Immune Checkpoint Inhibitors by Affecting Myeloid Derived Suppressor Cells (MDSC) and Lymphocyte Populations in the Tumor Microenvironment”
Mar25-28 2015: Society of Surgical Oncology's 68th Annual Cancer Symposium (SSO 2015), Houston http://tinyurl.com/q667hua …Mar28 12:45pm/Oral-Pres: Adam C. Yopp (MD/UTSW/Dallas), Ph.2 Data) from Bavi+Sorafenib Liver IST, ”A Phase II Study of Bavituximab & Sorafenib in Advanced Hepatocellular Carcinoma (HCC)”
1-30-15: Extensive-Analysis by MLV/GeorgeZavoico of Bavi+Sorafenib LIVER IST/Ph2-data presented 1-16-15 at the ASCO Gastrointestinal Cancers Symposium in SanFran…
1-30-15 MLV Peregrine Company Update: ”Phase II Liver Cancer Trial of Bavituximab + Sorafenib Meets Primary Endpoint of mTTP” (George B. Zavoico) https://mlv.bluematrix.com/sellside/EmailDocViewer?encrypt=3a98541b-c0bb-457b-a3ed-81855ce5ceb7&mime=pdf PAGE 1 of 11 (see remainder below): We note that a non-randomized, single-arm Phase II trial of bavituximab in combination with sorafenib (Nexavar®) for the treatment of advanced hepatocellular carcinoma (HCC) met its primary endpoint of prolonging the median time to radiologic progression (mTTP) compared to historical data. The combination was also safe and well-tolerated. However, the improved mTTP did not translate into an improvement in median overall survival (mOS), a secondary endpoint, most likely due to the small size of the trial (n=38) and early deaths unrelated to disease progression. We believe that the prolongation of mTTP is a signal of efficacy that supports our view that bavituximab is an active drug. We conclude that further evaluation is warranted in a larger, randomized trial. We maintain our BUY rating and $3.50 price target for Peregrine Pharmaceuticals, Inc.
• Results. As reported at the ASCO-Gastrointestinal Cancers symposium on January 16, a mTTP of 6.7 months was reported for the bavituximab/sorafenib combination. This is a 1.2 to 3.9-month improvement over a range of 2.8 to 5.5 months for sorafenib alone reported in four prior Phase III trials. The median disease specific survival (mDSS), a secondary endpoint, was 8.7 months. These promising results were confounded by a median overall survival (mOS), another secondary endpoint, of 6.2 months, which is outside the 6.5 to 10.7- month range reported in prior trials for sorafenib alone.
• Protocol and Demographics. This investigator-sponsored, open label Phase I/II trial (ClinicalTrials.gov<http://clinicaltrials.gov/>; identifier: NCT01264705) enrolled patients with advanced HCC not eligible for resection or transplantation who were at least four weeks removed from prior locoregional therapies. Patients with metastatic disease were allowed. Notably, patients in this trial were more seriously ill than in prior trials of sorafenib alone based on the proportion of patients with Child-Pugh A score, ECOG performance status 0, and macrovascular invasion (MVI). However, fewer patients in this trial presented with extrahepatic spread (metastases) than in prior trials.
• Medical History. HCC is a heterogeneous disease, complicated and exacerbated by comorbidities such as hepatitis B or C (HBV or HCV) infection, alcohol abuse, underlying cirrhosis, and/or nonalcoholic steatohepatitis (NASH). Response to therapy can vary, depending on severity of disease, comorbidities, and medical history. Patients in different geographic regions are also known to have different prognoses. This heterogeneity underscores the necessity of conducting large enough randomized trials with well defined eligibility criteria to properly compare different therapeutic regimens.
• Summary. Since the adverse event profile of the bavituximab/sorafenib combination was not markedly different than with sorafenib alone, we conclude that this combination is as safe and well tolerated as sorafenib. While we would have liked to see a longer mOS with the combination, we are nevertheless encouraged by the improved mTTP for this difficult to treat patient population for which sorafenib is the only approved therapy. We think the results of this trial justify a larger and more rigorously designed and randomized Phase IIb trial to determine if the combination is superior to sorafenib alone in this indication.
MLV/George B. Zavoico - init. 2-8-10 Buy/PT=$10, CURR: Buy/$3.50 http://www.mlvco.com
Pgs 12-14: Disclosures & MLV Corp. Info.
= = = = = = = = = = = = = = = = = = = = = = = = = = = H. 1st Investigator-Sponsored (IST) Ph.I/II Trial (Bavi+Sorafenib vs. Liver Cancer/HCC, open-label, n=9+38=47) ...Note: Sorafenib = Onyx/Bayer's Nexavar - see http://www.nexavar.com Protocol: http://clinicaltrials.gov/ct2/show/NCT01264705 UTSW: http://tinyurl.com/mwdc2ql (5 sites: 3/UTSW, Parkland-Hosp, Dallas/VA, PI=Dr. Adam Yopp) ...1-16-15 ASCO Gastro-Symposium: Ph.2 data/n=38 (Adam Yopp), “These clinical outcomes of TTP=6.7/DCR=58%/PFS=4mo are quite encouraging…”http://tinyurl.com/m9uz9mo …11-8-14: SITC'14 Ph.2 Correlative Studies data (biopsies B4/After) on 6pts, incl. KOL Dimitry Gabrilovich’s comments: http://tinyurl.com/pchzr6h ...9-9-14 Enrollment complete. http://tinyurl.com/ktrfswj (ph2=38 Ph1=9) ...4-4-12 AACR'12: Dr. Adam Yopp, "promising safety profile to-date" http://tinyurl.com/7yrwqm7 (see #5591) ...Feb'12-Sep'14 10+ times: CEO Steve King hints of future ex-US partner-driven Bavi+Sorafenib/LIVER trial in Asia-Pacific: http://tinyurl.com/nkaxtcc ......Articles & Data describe Liver Cancer challenges in Asian populations: http://tinyurl.com/7z7o8j9 & http://tinyurl.com/7z99cy4 ...12-1-10: PPHM's 1st IST (Liver Cancer) initiated at UTSW, ~56 patients - http://tinyurl.com/3xd3e6c …Per S.King, 5-18-10/R&R, "We've had a lot of interest in running clinical trials with the compound from investigators who have either had prior experience with the drug or would like to study the drug in various settings. Potential IST indications include all the major solid tumor types. Of particular interest is Liver Cancer, in which we have a natural tie-in with our HCV program, Ovarian Cancer and Pancreatic Cancer, also very nicely supported by the prior data."
= = = = = = = = = = = = = = = = = = 1-16-14/PR: Bavi+Sorafenib LIVER IST Ph2-data at ASCO Gastrointestinal Cancers Symposium in SanFran. Dr. Adam Yopp (UTSW), "These clinical outcomes of TTP, DCR, and 4-mo. PFS are quite encouraging, especially in this heavily pretreated patient cohort with very poor prognosis due to their unfavorable disease biology including a high rate of macrovascular invasion. I was also pleased to see an extended tail in the survival curve that is typical of emerging immunotherapies for cancer…”.
1-16-15: Phase II Clinical Data of Peregrine Pharmaceuticals' Bavituximab in Combination With Sorafenib Presented at ASCO Gastrointestinal Cancers Symposium • Positive Trends in Time to Progression, Disease Control Rates and 4-Month Progression-Free Survival Endpoints Were Reported in a Patient Population With Poor Prognosis • Survival Curves Showed Patients With Prolonged Survival Consistent With Those Seen in Other Immunotherapy Studies in Different Indications • Overall Data From Trial Support Bavituximab's Immunostimulatory Mechanism-of-Action • http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=891707
TUSTIN 1/16/15: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) (NASDAQ: PPHMP), today announced the presentation of clinical data related to the company's immuno-oncology development program and its lead investigational immunotherapy drug candidate bavituximab at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. This conference is being held January 15-17, 2015 at the Moscone West Convention Center in San Francisco, California.
The clinical presentation titled: "A Phase II Study of Bavituximab and Sorafenib in Advanced Hepatocellular Carcinoma (HCC)" will be presented this afternoon by Adam Yopp, M.D., assistant professor of surgery at the University of Texas Southwestern Medical Center Dallas, Texas.
In this single-center, single-arm, open-label investigator-sponsored trial (IST), 38 patients with advanced HCC received bavituximab (3mg/kg) weekly and sorafenib (400 mg) twice daily until disease progression or toxicity. Data show that the combination of bavituximab and sorafenib is associated with an improved time to progression (TTP) of 6.7 months, a disease specific survival (DSS) of 8.7 months, a disease control rate (DCR) of 58% (22 out of 38 patients) and a 4-month progression-free survival (PFS) of 62%. Two patients (5%) achieved a partial response according to Response Evaluation Criteria In Solid Tumors (RECIST). The secondary endpoint of median overall survival (OS) was 6.2 months. The combination of bavituximab and sorafenib was well-tolerated in patients with advanced HCC with no indications of autoimmune adverse events that have been seen with other checkpoint immunotherapies.
"These clinical outcomes of time to progression, disease control rate and 4-month progression-free survival are quite encouraging, especially in this heavily pretreated patient cohort with very poor prognosis due to their unfavorable disease biology including a high rate of macrovascular invasion," said Dr. Yopp. "I was also pleased to see an extended tail in the survival curve that is typical of emerging immunotherapies for cancer. The positive data from this study should be considered as rationale for future randomized trials to further evaluate the potential of bavituximab in liver cancer."
"These data, along with recently reported translational data from this study, continue to build the knowledge base for the bavituximab clinical program and, in particular, highlight the potential immunotherapeutic synergies of bavituximab and sorafenib. We agree with Dr. Yopp that these data warrant further clinical evaluation of this combination in later stage clinical trials," said Joseph Shan, VP of Clinical & Regulatory for Peregrine. "We continue to build value in the bavituximab program across multiple programs including the execution of the SUNRISE Phase III trial in second-line, non-small cell lung cancer and from data generated from this and other investigator-sponsored trials as well as other ongoing clinical trials. We look forward to new clinical collaborations with the goal of further exploring the utility of bavituximab in combination with other immuno-oncology drugs."
Liver IST Clinical Translation Data Recently presented translational data of 6 patients from this trial show that half of the patients evaluated had an increase in tumor fighting immune cells following one cycle of bavituximab treatment, similar to what has been shown for PS-targeting antibodies in multiple preclinical cancer models. In addition, the increase in immune response was associated with patients that remained on study treatment for longer time periods, suggesting the possibility of a clinically meaningful anti-tumor immune response. Three of the six patients evaluated had increased infiltration of activated tumor-fighting T-cells (CD8) into the tumor microenvironment which correlated with a prolonged time to disease progression. In addition, these responding patients initially expressed lower levels of PD-1 positive cells, an established marker of T-cell activation and disease outcome, prior to the initiation of therapy that was followed by a measurable rise post bavituximab treatment.
About the Phase II Trial In this Phase II non-randomized, open-label trial, 38 patients with advanced HCC received bavituximab weekly and sorafenib (400 mg) twice daily, until disease progression or toxicity. The primary endpoint of this trial is radiologic time to progression with imaging occurring at 6 week intervals. Secondary endpoints of this trial include overall survival (OS), progression free survival (PFS), safety and response rates. In order to leverage recent understandings surrounding the immune-stimulatory mechanism of action of bavituximab, several additional components have been installed into this portion of the trial. These include plasma and serum collection and tissue biopsies for evaluating changes in immune response following bavituximab treatment to assess whether combination therapy reactivates tumor immunity by changing the tumor microenvironment from immunosuppressive to immunoreactive by changing the tumor infiltrating cell composition or inducing T-cell response to tumor antigens. More information on this trial can be found at ClinicalTrials.gov using the Identifier NCT01264705. [ https://clinicaltrials.gov/ct2/show/NCT01264705 ]
ABOUT PEREGRINE PHARMACEUTICALS, INC. Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a pipeline of novel drug candidates in clinical trials for the treatment and diagnosis of cancer. The company's lead immunotherapy candidate, bavituximab is in Phase III development for the treatment of second-line non-small lung cancer (the "SUNRISE trial") along with several investigator-sponsored trials evaluating other treatment combinations and additional oncology indications. The company is also advancing a molecular imaging agent, 124I-PGN650, in an exploratory clinical trial for the imaging of multiple solid tumor types. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com . Safe Harbor *snip* Contact: Christopher Keenan, Peregrine Pharmaceuticals, Inc., 800-987-8256, info@peregrineinc.com
Nice post CJ. Everyone take their time and read this post again and pay close attention. I like the paragraph with Joe Shan quotes agreeing with Adam Yopp.
2-4-16 Annals of Surgical Oncology: Bavi+Sorafenib vs. Liver Cancer/HCC - murine xenograft tests and Ph.1 human data from Dr. Yopp's UTSW IST trial...
2-4-16: “Antibody-Mediated Blockade of Phosphatidylserine Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinomas Xenografts” Annals of Surgical Oncology - Translational Research & Biomarkers (pp 1-9) Xiaoyun Cheng, Li Li, Philip E. Thorpe, Adam C. Yopp, Rolf A. Brekken, Xianming Huang http://link.springer.com/article/10.1245%2Fs10434-016-5107-5 ABSTRACT - Background Currently, the only FDA-approved systemic therapy for hepatocellular carcinoma (HCC) is the multi-receptor tyrosine kinase inhibitor, sorafenib, which provides only modest clinical benefit. We recently showed that treatment with a phosphatidylserine (PS) targeting agent suppresses tumor growth by targeting tumor vasculature & reactivating antitumor immunity. METHODS We tested the hypothesis that sorafenib increases PS exposure on tumor vasculature, thereby enhancing the antitumor efficacy of PS targeting. We evaluated the efficacy of combining a PS targeting agent (2aG4) with sorafenib in murine xenograft models of human HCC. RESULTS Our results demonstrate that combination of 2aG4 & sorafenib had a superior therapeutic effect over single agent therapy. Mechanistic studies showed that sorafenib significantly increased PS exposure on tumor vasculature; the percentage of PS-positive vessels increased from 19 to 52, 23 to 68, and 30 to 55 % in PLC/PRF/5, C3A, and Huh7 tumors, respectively. Combination therapy significantly decreased tumor microvessel density and the level of M2 macrophages, while increasing the apoptotic index of tumor endothelial cells and the frequency of M1 macrophages. Furthermore, we report the findings of a Phase I clinical study of bavituximab, a chimeric version of 2aG4, combined with sorafenib in HCC patients. The Phase I results demonstrate the appropriate dose of bavituximab to be given with sorafenib in future clinical trials. CONCLUSIONS Overall, these results strongly support the combination of bavituximab with sorafenib as a promising systemic therapeutic strategy for the treatment for advanced HCC patients. -------- Xiaoyun Cheng & Li Li have contributed equally to this work. Rolf Brekken & Xianming Huang are consultants to, have equity interest in, and have a sponsored research agreement with Peregrine Pharmaceuticals Inc.
2-4-16/Annals.Surg.Onco.(Brekken/Thorpe/Yopp/Xianming) article: Murine xenograft & Ph.1/human data http://tinyurl.com/gtk2qg8 ...”Bavi+sorafenib combo had a superior therapeutic effect over single agent therapy.”
12-1-10: PPHM's 1st IST (Liver Cancer) initiated at UTSW, ~56 patients - http://tinyurl.com/3xd3e6c …Per S.King, 5-18-10/R&R, "We've had a lot of interest in running clinical trials with the compound from investigators who have either had prior experience with the drug or would like to study the drug in various settings. Potential IST indications include all the major solid tumor types. Of particular interest is Liver Cancer, in which we have a natural tie-in with our HCV program, Ovarian Cancer and Pancreatic Cancer, also very nicely supported by the prior data.”
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