Dr Curiel/Viral Genetics' P-IND Clears FDA To Commence Clinical Trials (ovarian cancer/Sorafenib) in Humans - MarketWatch

Viral Genetics' P-IND Clears FDA To Commence Clinical Trials in Humans - MarketWatch

Viral Genetics' P-IND Clears FDA To Commence Clinical Trials in Humans 

Set to Begin First Ovarian Cancer Study Test Site for Metabolic Disruption Technology (MDT) Combination Therapy

 

SAN MARINO, Calif., May 21, 2012 (BUSINESS WIRE) -- A physician-initiated Investigational New Drug (P-IND) application submitted to the FDA in late April, 2012, has cleared the FDA's screening process with the requirement for a regular IND application being waived, resulting in the company being able to begin the first of at least two proposed clinical trial sites to investigate a potential oncology treatment developed from Viral Genetics' (pinksheets:VRAL) Metabolic Disruption Technology (MDT), which is licensed exclusively to the Company. The P-IND -- part of a larger, coordinated research effort -- was submitted by the first test site at the Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, which includes patient enrollment at Scott and White Hospital (S&W) in Temple, Texas. Additional test sites may also be added in the future.

Enrollment and treatment of patients is expected to commence upon completion of internal hospital Institutional Review Boards (IRBs), which are already underway. The UT Health Science Center portion of the study will commence when all approvals are finalized.

This clinical trial -- a milestone in the Company's transition from preclinical to clinical-stage -- will be the first for the intellectual property developed by Dr. M. Karen Newell Rogers, Viral Genetics' Chief Scientist and licensed exclusively by the Company. It will examine the safety and efficacy of one of Viral Genetics licensed MDT compounds in combination with an existing cancer drug, sorafenib (marketed as Nexavar(TM)) in the treatment of patients resistant or otherwise unsuitable for standard treatments for stage III or IV ovarian cancer and related carcinomas.

The Primary Investigator on the trial is Tyler Curiel, M.D., MPH, a medical oncologist affiliated with the CTRC at the UT Health Science Center. Dr. Curiel is leading this study as he investigates the efficacy of combining two compounds in a cancer treatment that is hoped to cause the starvation of tumor cells and enhanced anti-tumor immunity, leading to the reduction of tumor size and reduced disease progression.....

abstract: Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

Objective: The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy.

Methods: This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC.

Results: Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation.

Conclusions: Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

abstract: RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors (vemurafenib/sorafenib/secondary malignancies)

"Purpose 

RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation.

Methods
Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165)........."

open access: Development and validation of a prediction index for hand-foot skin reaction in cancer patients receiving sorafenib

Background: This study describes a repeated measures prediction index to identify patients at high risk of ≥ grade 2 hand-foot skin reaction (HFSR) before each week of sorafenib therapy.

Results: Pretreatment white blood cell count, female gender, good performance status, presence of lung and liver metastases and number of affected organs were predictors for ≥ grade 2 HFSR.

Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

Conclusion:

Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.

Expert Review - slides: Renal Cell Carcinoma Biology and the Rationale for VEGF (sorafenib, sunitinib, erlotinib, avastin, interleukins, etc)

Note: if you are unable to access this slide presentation it is because you need to register on the site (free); it may be of interest to those with clear cell ovarian cancer; the largest % of renal cancers are of the clear cell subtype (a known ~75%) ------------------------------------------------------------------------------------------------------- MODULE 1: Renal Cell Carcinoma Biology and Rationale for VEGF Expert review with Lee Lokey, MD, and Brian I. Rini, MD, focusing on renal cell carcinoma
Discussant:	Brian I. Rini, MD—Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, United States
Interviewed by:	Lee Lokey, MD—prIME Oncology, Atlanta, Georgia, United States

abstract: Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial — JCO

Conclusion: Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.

Sorafenib in Combination With Gemcitabine in Recurrent Epithelial Ovarian Cancer: A Study of the Princess Margaret Hospital Phase II Consortium

Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada; †Juravinski Cancer Centre, McMaster University,Hamilton, Ontario, Canada; ‡Fox Chase Cancer Center, Philadelphia, PA; and §National Cancer Institute, Bethesda, MD.

Abstract

OBJECTIVES: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC.

CONCLUSION: This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.

abstract: Sorafenib efficacy in ovarian clear cell carcinoma revealed by transcriptome profiling. - in research- Cancer Science

JCO: Lettter: Risk of Arterial Thrombosis Not Increased by Sorafenib or Sunitinib

Note: analyzing the research including a reference to Avastin

Abstract/full acess: Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib

Background: Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.

METHODS
Patients and treatment
The analyses were performed on genomic DNA from 178 patients (143 males and 35 females) with solid tumors who received sorafenib (VEGFR2 inhibitor) and/or bevacizumab (anti-VEGF) with or without other agents....cont'd (excerpt from pdf file)

Conclusions: This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.

Cardiovascular Safety of VEGF-Targeting Therapies: Current Evidence and Handling Strategies -- Girardi et al., 10.1634/theoncologist.2009-0235 -- The Oncologist

Abstract
Treatment with the angiogenesis inhibitors bevacizumab, sunitinib, and sorafenib as single agents or in combination with conventional chemotherapy is becoming a cornerstone of modern anticancer therapy. However, the potential toxicity of these drugs, mainly to the cardiovascular system, is still being investigated. Patient assessment at baseline, of crucial importance in candidates for treatment, involves the evaluation of risk factors and screening for past or present cardiovascular disease. Strict monitoring of treatment-related adverse effects must be conducted in order to allow the early detection of cardiovascular toxicities and their prompt medication. In the present paper, the most frequent cardiovascular toxicities and their underlying mechanisms are investigated, with a view to providing indications for effective patient management.

Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer

Note: this would have been a phase 1 trial Results
Four patients were enrolled. After preoperative treatment and cytoreductive surgery, all patients were excluded from protocol due to severe toxicities. Three patients had life threatening events (cardiac output failure, myocardial infarction, anastomotic leak); two patients had primary progressive disease. The study was terminated on the basis of the recommendation of an independent data safety monitoring board.
Conclusion
The addition of sorafenib to carboplatin/paclitaxel chemotherapy was not feasible within this neoadjuvant regimen in primary advanced ovarian cancer. Although the occurrence of serious adverse events might have emerged at random, a detrimental effect of preoperative study medication could not be denied. Further evaluations of sorafenib in ovarian cancer are warranted.

Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer.

RESULTS: .....Four patients were enrolled. After preoperative treatment and cytoreductive surgery, all patients were excluded from protocol due to severe toxicities. Three patients had life threatening events (cardiac output failure, myocardial infarction, anastomotic leak); two patients had primary progressive disease.
CONCLUSION: The addition of sorafenib to carboplatin/paclitaxel chemotherapy was not feasible within this neoadjuvant regimen in primary advanced ovarian cancer. Although the occurrence of serious adverse events might have emerged at random, a detrimental effect of preoperative study medication could not be denied. Further evaluations of sorafenib in ovarian cancer are warranted.

repost: Combination therapy: intermittent Sorafenib with (Avastin) bevacizumab yields activity and decreased toxicity.

Toxicity of sorafenib: clinical and molecular aspects; Expert Opinion on Drug Safety - abstract

Take home message: Although not life-threatening, toxicity of sorafenib can severely impact the physical, psychological and social well-being of patients. The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist, cardiologist and dermatologist

abstract: Association of Skeletal Muscle Wasting With Treatment With Sorafenib

Note: this study is not specific to ovarian cancer but may be of interest for those deciding on Sorafenib:

abstract: Safety and efficacy results of the advanced renal cell carcinoma Sorafenib expanded access program in North America

Note: while this is not specific to ovarian cancer knowing the side effects which patients experienced may be helpful