Vicus Therapeutics, announced the initiation of a phase II trial evaluating VT-122, a novel investigational combination of etodolac and propranolol, and Nexavar (sorafenib) tablets, as a potential new treatment option for patients with advanced liver cancer (hepatocellular carcinoma), systemic inflammation and cachexia.
The randomized, open label, multi-centre phase II study will evaluate whether VT-122 in combination with Nexavar increases "Clinical Benefit Response," which is a composite measurement of pain, performance status, and lean body mass, as compared to Nexavar alone. The secondary efficacy endpoints of this study are cancer and cachexia specific symptoms, duration of Nexavar therapy and overall survival.
The study will be conducted under Vicus US IND and is expected to enroll 80 patients with advanced liver cancer, systemic inflammation and cachexia at multiple sites in the United States. Enrollment into this study is expected to be completed by the end of 2011.
Vicus Therapeutics, LLC, Bayer HealthCare Pharmaceuticals, Inc. and Onyx Pharmaceuticals, Inc. have entered into an agreement pursuant to which Bayer and Onyx have agreed to support the study. The terms of the agreement are confidential.
The most common trajectory of the cancer patient is local progression, development of metastases, cancer-induced systemic inflammation and the associated symptom cluster of the anorexia-cachexia syndrome. The anorexia-cachexia symptom cluster includes cachexia (anorexia, weight loss and muscle wasting), fatigue, weakness, pain, dyspnea, nausea, malaise, anxiety, depression and poor performance status. This symptom cluster is further associated with poor tolerance, adherence and response to anti-cancer therapy, disease progression and reduced life expectancy.
Hepatocellular carcinoma is the most common form of liver cancer and is responsible for about 90 per cent of the primary malignant liver tumours in adults. Liver cancer is the sixth most common cancer in the world and the third leading cause of cancer-related deaths globally.
VT-122 is a novel investigational combination of etodolac and propranolol that targets pathways associated with cancer-induced systemic inflammation, a suspected cause of cancer cachexia.1,2 VT-122 has demonstrated the ability to increase lean body mass (muscle) and lower other markers of systemic inflammation in a phase II trial of patients with advanced lung cancer.
Preclinical and clinical studies show that propranolol and etodolac, when used individually, attenuate systemic inflammation, hyper-metabolism, and weight loss. Furthermore, non-clinical studies show that this combination acts synergistically to attenuate systemic inflammation, activate cellular immunity, reduce metastasis, and increase animal survival.
Nexavar is approved in the US for the treatment of patients with unresectable liver cancer and for the treatment of patients with advanced kidney cancer. Nexavar inhibits both the tumour cell and tumour vasculature. In preclinical studies, Nexavar has been shown to inhibit members of two classes of kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) - two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.
Nexavar in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. Nexavar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential are advised to avoid becoming pregnant and Female patients should also be advised against breast-feeding while receiving Nexavar.
Cardiac ischemia and/or myocardial infarction may occur. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischemia and/or myocardial infarction. Gastrointestinal perforation was an uncommon adverse reaction and has been reported in less than 1% of patients taking Nexavar.
Uncommon but serious adverse reactions including keratoacanthomas/squamous cell cancer of the skin and Stevens - Johnson syndrome have been reported in clinical trials. An increased risk of bleeding may occur following Nexavar administration. If bleeding necessitates medical intervention, consider discontinuation of Nexavar. Hypertension may occur early in the course of treatment. Monitor blood pressure weekly during the first 6 weeks and periodically thereafter and treat, as required.
Hand-foot skin reaction and rash are common and management may include topical therapies for symptomatic relief. In cases of any severe or persistent adverse reactions, temporary treatment interruption, dose modification, or permanent discontinuation of Nexavar should be considered. Temporary interruption of Nexavar therapy is recommended in patients undergoing major surgical procedures.
Elevations in serum lipase and reductions in serum phosphate of unknown etiology have been associated with Nexavar. Caution is recommended when administering Nexavar with compounds that are metabolized/eliminated predominantly by the UGT1A9 pathway, UGT1A1 pathway (eg, irinotecan), doxorubicin, docetaxel, fluorouracil, and substrates of CYP2B6 and CYP2C8, and CYP3A4 inducers. Concomitant use of carboplatin and paclitaxel with sorafenib resulted in an increase in paclitaxel exposure and an increase in Nexavar exposure. Patients taking concomitant warfarin should be monitored regularly for changes in prothrombin time, INR, or clinical bleeding episodes. Nexavar exposure decreases when co-administered with oral neomycin. Effects of other antibiotics on Nexavar pharmacokinetics have not been studied
Most common adverse reactions reported for Nexavar-treated patients vs placebo-treated patients in unresectable HCC, respectively, were: diarrhoea (55% vs 25%), fatigue (46% vs 45%), abdominal pain (31% vs 26%), weight loss (30% vs 10%), anorexia (29% vs 18%), nausea (24% vs 20%), and hand-foot skin reaction (21% vs 3%). Grade 3/4 adverse reactions were 45% vs 32%.
Most common adverse reactions reported for Nexavar-treated patients vs placebo-treated patients in advanced RCC, respectively, were: diarrhea (43% vs 13%), rash/desquamation (40% vs 16%), fatigue (37% vs 28%), hand-foot skin reaction (30% vs 7%), alopecia (27% vs 3%),and nausea (23% vs 19%). Grade 3/4 adverse reactions were 38% vs 28%.
Vicus Therapeutics is a biopharmaceutical company dedicated to bringing breakthrough therapies to patients with cancer. Vicus lead investigational therapy, VT-122, is a combination of etodolac and propranolol. VT-122 showed positive results in a phase II clinical trial of lung cancer patients and is currently being evaluated in a phase II clinical trial of liver cancer patients receiving Nexavar (sorafenib).