Citations

Abstract Purpose: Surrogate biomarkers are lacking for predicting or monitoring response to anti-angiogenesis therapies. We investigated whether circulating biomarkers (CBMs) of angiogenesis (i.e., bFGF, SDF-1α, HGF, sKIT, Ang-2, and PlGF) correlated with treatment efficacy in a pooled analysis of metastatic colorectal cancer (mCRC) and recurrent glioblastoma multiforme (rGBM) patients (pts) treated with bevacizumab/sorafenib (BEV/SOR). Experimental procedures: Peripheral blood samples were obtained for CBM analyses from pts enrolled in the North Central Cancer Treatment Group (NCCTG) phase II studies N054C (mCRC, n=75, Grothey, ASCO 2010) and N0776 (rGBM, n=54, Galanis, ASCO 2010). Blood collection time points were: baseline (BL), cycle 1 day 3 (C1D3), prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and after the pt went off study. Plasma CBM levels were determined by commercially-available ELISAs (R&D Systems) and performed according to manufacturer's instructions. For each CBM, a linear regression model that adjusted for study was used to evaluate the correlation with either progression-free survival (PFS) success/failure or progression within 14 days of the last blood draw for the following measures: absolute BL levels, log2 BL levels; C1D3 log2-fold change (FC) from BL, prior to cycle 2 log2-FC from BL, last draw log2-FC from BL, and last draw log2-FC from prior draw. Results summary: There appears to be no significant difference in the PFS or overall survival (OS) between the pts on these two studies; therefore, we pooled the patients from both studies for a combined analyses. We found no difference in absolute or log2 levels for any of the CBMs during the course of BEV/SOR treatment. In these pooled analyses, we found increased absolute and increased log2 BL SDF-1α levels were significantly correlated with PFS success (p=0.023 and p=0.02, respectively). After correcting for multiple comparisons (method of Benjamini & Hochberg) the p-values <0.05 had a false-discovery-rate of 41.4%. None of the other CBM measures were significantly correlated with either PFS success/failure or progression within 14 days of the last blood draw (all p>0.10). Conclusions: This study provides preliminary evidence that SDF-1α may be a useful CBM for determining treatment efficacy in these pts treated with BEV/SOR. Further prospective validation of SDF-1α for predicting pt progression with this treatment combination in advanced disease (e.g., mCRC and rGBM) appears warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5562. doi:1538-7445.AM2012-5562

Abstract Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. This Phase I study evaluated the safety and tolerability of combined therapy with the mTOR inhibitor RAD001, RT and TMZ. Methods: All patients received weekly oral RAD001, starting 1 week prior to RT/TMZ and continuing until progression, with a break from therapy between RT/TMZ and adjuvant TMZ. RAD001 was dose escalated in cohorts of 6 patients. In addition to RAD001, all pts received standard treatment with RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily × 5 every 28 days). DLTs were defined during therapy with RAD001 combined with TMZ/RT. Results: A total of 18 patients were enrolled. Combined RAD001/RT/TMZ was well tolerated at all dose levels with 1 of 6 patients with a DLT at each dose level. DLTs were Grade 3 fatigue (RAD001 25 mg/week), Grade 4 hematologic toxicity (RAD001 50 mg/week), and Grade 4 liver function elevation (RAD001 70 mg/week). With adverse event information available for all 18 patients, no grade 5 events were seen. Nine grade 4 events (thrombosis, fatigue, anemia, neutropenia, thrombocytopenia, leukopenia, SGPT (ALT), SGOT (AST), bilirubin elevation) were seen in 3 patients. On the basis of these results, the recommended Phase II dose currently being tested is RAD001 70 mg/week in combination with standard RT/TMZ and adjuvant TMZ. FDG PET scans were also obtained prior to the first dose of RAD001 and within 24 hours of the second dose of RAD001, prior to starting RT or TMZ, and changes in maximum standard uptake values (SUV) were compared between scans for each patient. Two patients at 25 mg RAD001/week had a 21% and 24% change in SUV, and 2 patients receiving 70 mg/week had a change in SUV uptake of −33% and −16%. Additional follow-up will be required to evaluate whether these SUV changes are associated with outcome. Conclusions: RAD001 in combination with RT/TMZ and adjuvant TMZ was well tolerated, and the imaging results support continued evaluation of PET imaging as an early predictor of response to therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C56.

Abstract Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (103–109 TCID50). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54–277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3–38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients. Cancer Res; 70(3); 875–82

Abstract Purpose: Preexisting antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its antitumor potency. In contrast to “naked” viruses, cell-associated viruses are protected from antibody neutralization. Hence, we hypothesized that measles virotherapy of ovarian cancer in measles-immune mice might be superior if MV-infected mesenchymal stem cell (MSC) carriers are used. Experimental Design: Antimeasles antibodies titers in ovarian cancer patients were determined. The protection of MV by MSC from antimeasles antibodies, the in vivo biodistribution profiles, and tumor infiltration capability of MSC were determined. Measles-naïve or immune tumor–bearing mice were treated with naked virus or MSC-associated virus and mice survivals were compared. Results: MSC transferred MV infection to target cells via cell-to-cell heterofusion and induced syncytia formation in the presence of high titers of antimeasles antibody, at levels that completely inactivated naked virus. Athymic mice bearing i.p. human SKOV3ip.1 ovarian tumor xenografts passively immunized with measles-immune human serum were treated with saline, naked MV, or MV-infected MSC. Bioluminescent and fluorescent imaging data indicated that i.p. administered MSC localized to peritoneal tumors, infiltrated into the tumor parenchyma, and transferred virus infection to tumors in measles naïve and passively immunized mice. Survival of the measles-immune mice was significantly enhanced by treatment with MV-infected MSC. In contrast, survivals of passively immunized mice were not prolonged by treatment with naked virus or uninfected MSC. Conclusions: MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients. (Clin Cancer Res 2009;15(23):7246–55)