I want to test the clinical hypothesis that angiogenesis is an important target in bladder cancer. One of the clinical trials I am currently running is a phase II study of TRC105 in patients with advanced/metastatic urothelial carcinoma. The median survival of patients with metastatic disease that has progressed after first line chemotherapy is 6 to 9 months. There is no FDA-approved drug for this setting and no standard conventional chemotherapy agent(s) have demonstrated a survival benefit in this patient population. This highlights the need for the development of novel therapies for these patients.Multiple lines of evidence support targeting angiogenesis in bladder cancer. Microvessel density, a histological measure of angiogenesis, has been correlated with stage, recurrence, and survival. Several reports have described increased expression of vascular endothelial growth factor (VEGF), a mediator of angiogenesis, in the tissue, serum, and urine of patients with bladder cancer and correlated these markers with stage and prognosis. Inhibitors of angiogenesis have shown activity in preclinical models of bladder cancer. A functional autocrine loop involving VEGF/VEGFR2 may be important in the pathogenesis of some bladder cancers. In a recent non-clinical study, 6 of 13 bladder tumor cell lines examined expressed VEGFR2 (Flk-1). Further analysis of the T24 bladder tumor cell line revealed a functional autocrine loop involving VEGF and VEGFR2. TRC105 is a genetically engineered human/murine chimeric monoclonal antibody, that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition and apoptosis. TRC105 is directed against human CD105 (endoglin), an angiogenic membrane protein that is highly expressed on proliferating vasculature in solid tumors including bladder tumors. Inhibitors of angiogenesis either alone or in combination with chemotherapy have demonstrated antitumor efficacy in patients with metastatic bladder cancer. This is a Phase II study of TRC105 in patients with metastatic urothelial carcinoma that have progressed despite treatment with prior cytotoxic chemotherapy. The primary objective of the study will be to determine the activity of TRC105 as determined by Response Evaluation Criteria in Solid Tumors (RECIST). TRC105 will be administered at a dose of 15mg/kg intravenously every two weeks, on days 1 and 15 of each 28 day cycle. Patients may continue on study as long as they are tolerating therapy and are free of disease progression. This trial is currently under review by the NCI Medical Oncology Branch (MOB) office of protocol administration. A second trial I am developing is a phase I study of gemcitabine, carboplatin and lenalidomide (GCL) as first line therapy for the treatment of patients with advanced/metastatic urothelial carcinoma. Cisplatin-based combination chemotherapy is considered the standard of care for patients with metastatic bladder cancer. However greater than 40% of patients are ineligible for such treatment based on renal function or disease/functional status. This has led many oncologists to utilize non-cisplatin-based therapy such as gemcitabine plus carboplatin in patients with advanced bladder cancer. This alternative combination is well tolerated with a comparable response rate of 36-58% compared to the response rate of gemcitabine and cisplatin of 45-64%. This regimen has become a community standard for patients with advanced bladder cancer in polls of community oncologists, carboplatin-based therapy is utilized in approximately 66% of patients with advanced/metastatic bladder cancer. Lenalidomide has both immunomodulatory and anti-angiogenic properties. The anti-angiogenic activity of lenalidomide is mediated through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation. In addition, lenalidomide has a variety of immunomodulatory effects, including stimulation of T cell proliferation, and production of IL-2, IL-10 and IFN-gamma, inhibition of IL-1 beta and IL-6 and modulation of IL-12 production. The drug has gained interest in solid tumors because of its anti-angiogenic properties, anti-neoplastic properties and favorable toxicity profile. Preliminary evaluation of an ongoing study in metastatic prostate cancer patients has demonstrated significant activity of lenalidomide in combination with bevacizumab and docetaxel with the first 14 patients enrolled having a 100% PSA response (decline greater than or equal to 50%) for patients receiving at leats 2 cycles. Lenalidomide which target different angiogenic factors, and has immunomodulation properties in combination with an active chemotherapy regimen of gemcitabine and carboplatin is a promising regimen in patient with metastatic bladder cancer who are in great need for better therapies. This is a single-stage Phase II study for patients with metastatic bladder cancer who are ineligible for cisplatin therapy. Gemcitabine 1000 mg/m2 will be administered intravenously on day 1 and 8 and carboplatin AUC 4.5 on day 1 with treatment re-cycled every 21 days. Lenalidomide will be administered at 10 mg orally once daily day 1 through 14 every 21 days. This trial is currently under review by the NCI MOB office of protocol administration. I will be the principle investigator of these two trials.A secondary objective is to test alternative imaging modalities for restaging and assessing response to treatment in bladder cancer. I have established collaboration with the Molecular Imaging Program within the Center for Cancer Research at the NCI and am currently the lead investigator in a pilot study of F-18 sodium fluoride PET/CT for metastatic burden quantification in prostate cancer. I plan to conduct a prospective study of FDG PET/CT to evaluate treatment response in patients with advance bladder cancer. Advancing the treatments available for patients with bladder cancer with a focus on anti-angiogenic targeted agents is my primary goal. Along the way, I want to get many other scientist and clinicians at the NCI interested in learning more about the biology of bladder cancer. It is my hope that these efforts will help advance our understanding of the mechanisms of tumor development and find much needed novel therapies for the treatment of this aggressive and deadly malignancy.
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