Showing papers by "Saby George published in 2017"

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870).

Abstract: Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival.Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (CI), 22%-53%], the median progression-free survival was 13.8 months (95% CI, 6.0-18.8), and the median overall survival was 65.3 months (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P = 0.03).Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199-208. ©2017 AACR.

Clinical Correlates of Benefit From Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer

Abstract: BACKGROUND: We sought to identify potential clinical variables associated with outcomes after radium-223 therapy in routine practice. METHODS: Consecutive non-trial mCRPC patients who received ≥1 dose of radium dichloride-223 at four academic and one community urology-specific cancer centers from May 2013 to June 2014 were retrospectively identified. Association of baseline and on-therapy clinical variables with number of radium doses received and clinical outcomes including overall survival were analyzed using chi-square statistics, cox proportional hazards, and Kaplan–Meier methods. Bone Scan Index (BSI) was derived from available bone scans using EXINI software. RESULTS: One hundred and forty-five patients were included. Radium-223 was administered for six cycles in 74 patients (51%). One-year survival in this heavily pre-treated population was 64% (95%CI: 54–73%). In univariate and multivariate analysis, survival was highly associated with receiving all six doses of Radium-223. Receipt of six doses was associated with ECOG PS of 0–1, lower baseline PSA & pain level, no prior abiraterone/enzalutamide, <5 BSI value, and normal alkaline phosphatase. In patients who reported baseline pain (n = 72), pain declined in 51% after one dose and increased in 7%. PSA declined ≥50% in 16% (18/110). Alkaline phosphatase declined ≥25% in 48% (33/69) and ≥50% in 16/69 patients. BSI declined in 17 (68%) of the 25 patients who had bone scan available at treatment follow-up. Grade ≥3 neutropenia, anemia, and thrombocytopenia occurred in 4% (n = 114), 4% (n = 125), and 5% (n = 123), respectively. CONCLUSIONS: Patients earlier in their disease course with <5 BSI, low pain score, and good ECOG performance status are optimal candidates for radium-223. Radium-223 therapy is well tolerated with most patients reporting declines in pain scores and BSI. Prostate 77:479–488, 2017. (Less)

Selenomethionine and methyl selenocysteine: multiple-dose pharmacokinetics in selenium-replete men.

Abstract: // James R. Marshall 1 , Raymond F. Burk 2 , Rochelle Payne Ondracek 1 , Kristina E. Hill 2 , Marjorie Perloff 3 , Warren Davis 1 , Roberto Pili 4 , Saby George 1 , Raymond Bergan 5 1 Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 2 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, C2104 Medical Center North, Nashville, TN 37232, USA 3 National Cancer Institute, Bethesda, MD 20892, USA 4 Department of Medicine, Indiana University School of Medicine, R3 C516, Indianapolis, IN 46202, USA 5 Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97239, USA Correspondence to: James R. Marshall, email: james.marshall@roswellpark.org Keywords: selenium, selenomethionine, methyl selenocysteine, chemoprevention, pharmacokinetics Received: December 01, 2016 Accepted: February 06, 2017 Published: February 17, 2017 ABSTRACT According to the Nutritional Prevention of Cancer (NPC) trial, a selenized yeast supplement containing selenium, 200 mcg/day, decreased the incidence of total cancer, cancers of the prostate, colon and lung, and cancer mortality. The active agent in the selenized yeast supplement was assumed to be selenomethionine (SEMET), although the supplement had not been well speciated. The SELECT study, largely motivated by the NPC trial, enrolling nearly 40 times as many subjects, showed unequivocally that selenium 200 mcg/day, with selenium in the form of SEMET, does not protect selenium-replete men against prostate or other major cancer. The agent tested by SELECT, pure SEMET, could have been different from the selenized yeast tested in NPC. One of the selenium forms suspected of having chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine (MSC). This study, with 29 selenium-replete patients enrolled in a randomized, double-blind trial, compared the multiple-dose toxicity, pharmacokinetics and pharmacodynamics of MSC and SEMET. Patients were on trial for 84 days. No toxicity was observed. Although SEMET supplementation increased blood selenium concentration more than MSC did, neither form had a more than minimal impact on the two major selenoproteins: selenoprotein P(SEPP1) and glutathione peroxidase(GPX).

Second-line systemic therapy in metastatic renal-cell carcinoma: A review.

Abstract: Treatment in metastatic renal-cell carcinoma (mRCC) has evolved tremendously in the last decade. The development of newer targeted agents, like vascular endothelial growth factor inhibitors and immunotherapy have changed the treatment paradigm in mRCC patients. Axitinib and everolimus have been used extensively in patients who progressed on prior antiangiogenic therapy. The newer agents including nivolumab, cabozantinib, and lenvatinib in combination with everolimus have all demonstrated overall survival benefit over everolimus. However, with multiple treatment options, optimal choice and sequencing becomes challenging. This article provides an overview of different therapeutic options available as second-line treatment in patients with mRCC along with future directions.

Impact of suboptimal neoadjuvant chemotherapy on peri‐operative outcomes and survival after robot‐assisted radical cystectomy: a multicentre multinational study

Abstract: Objectives To evaluate the effect of suboptimal dosing on the outcomes of patients who received neoadjuvant chemotherapy (NAC) and robot-assisted radical cystectomy (RARC). Patients and Methods We retrospectively reviewed 336 consecutive patients with urothelial carcinoma of the bladder who were treated with NAC and RARC at three academic institutions. Outcomes were compared between 3 groups: patients who received optimal NAC; patients who received suboptimal NAC; and those who did not receive NAC. To adjust for potential baseline differences between the three groups, propensity-score-based matching was performed. The suboptimal dose group was defined as those who received fewer than three cycles of cisplatin-based chemotherapy, received decreased dosage, or one's not treated with cisplatin. Primary outcomes analyzed were recurrence-free survival (RFS) and overall survival (OS). Secondary outcomes were perioperative complications and readmissions after RARC. Results Within the cohort after propensity-score matching, 69 patients received optimal dose NAC, 41 received suboptimal NAC and 69 did not receive NAC. Complication rates and readmission rates between the 3 groups did not differ significantly. On multivariable analysis, suboptimal dosing and no NAC were independent predictors of worse RFS (HR: 2.5, 95%CI: 1.2-5.7, p=0.01 and HR 2.4, 95%CI 1.28-5.16, p=0.01) and worse OS (HR 4.5, 95%CI 1.6-15.0, p<0.01 and HR 4.9, 95%CI 1.9-15.6, p<0.01) in patients who received NAC and RARC. Failure to achieve pathological complete response (ypT0N0) was also an independent predictor of worse RFS (HR 6.6, 95%CI 1.3-20.9, p=0.02) and OS (HR 4.9, 95%CI: 1.8-15.3, p=0.02). Conclusion Optimal NAC resulted in a better RFS and OS when compared to suboptimal or no NAC. Suboptimal and no NAC were associated with worse OS and RFS. These findings will allow for improved patient counseling and treatment selection. This article is protected by copyright. All rights reserved.

Is RECIST-defined progression free-survival a meaningful endpoint in the era of immunotherapy?

Abstract: 488Background: Progression-free survival (PFS) is often used as a primary endpoint in oncology clinical trials as a surrogate for overall survival. Traditionally, the Response Evaluation Criteria in Solid Tumors (RECIST) have defined disease progression as a significant increase in the size of tumor lesions and the development of new lesions. However, some patients starting immunotherapy have shown initial increased size of tumor lesions followed by tumor regression, due to the unique mechanism of action of immunotherapies. This initial “pseudo-progression” could be classified inaccurately as disease progression, as evidenced by benefit from the treatment beyond progression approach (JAMA Oncol 2016). The phase III CheckMate 025 trial of nivolumab versus everolimus in patients with advanced renal cell carcinoma allowed treatment beyond progression if there was investigator-assessed clinical benefit and tolerability. The purpose of our study was to test if treatment duration for an immunotherapy was differ...

First-line vascular endothelial growth factor inhibitors for advanced renal cell carcinoma and the impact of new agents entering the treatment paradigm.

Abstract: Clinical trials assessing the safety and efficacy of new therapies versus standard of care (SOC) for advanced RCC (aRCC), which includes locally advanced and metastatic RCC (mRCC), are ongoing. The current first-line standards of care for the treatment of aRCC with clear cell histology are the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib[1,2]. This article is protected by copyright. All rights reserved.

Bone scan index at baseline as a tool for predicting hematologic toxicity in metastatic castration-resistant prostate cancer patients eligible for radium-223 treatment.

Abstract: e16513Background: The prognosis of castration-resistant prostate cancer with skeletal metastasis (CRPCSM) is poor. The ALSYMPCA trial led to the approval of radium-223 (Ra223) in such patients. Fac...

Selenomethionine and methyl selenocysteine: multiple-dose pharmacokinetics in selenium-replete men

Abstract: // James R. Marshall 1 , Raymond F. Burk 2 , Rochelle Payne Ondracek 1 , Kristina E. Hill 2 , Marjorie Perloff 3 , Warren Davis 1 , Roberto Pili 4 , Saby George 1 , Raymond Bergan 5 1 Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 2 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, C2104 Medical Center North, Nashville, TN 37232, USA 3 National Cancer Institute, Bethesda, MD 20892, USA 4 Department of Medicine, Indiana University School of Medicine, R3 C516, Indianapolis, IN 46202, USA 5 Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97239, USA Correspondence to: James R. Marshall, email: james.marshall@roswellpark.org Keywords: selenium, selenomethionine, methyl selenocysteine, chemoprevention, pharmacokinetics Received: December 01, 2016 Accepted: February 06, 2017 Published: February 17, 2017 ABSTRACT According to the Nutritional Prevention of Cancer (NPC) trial, a selenized yeast supplement containing selenium, 200 mcg/day, decreased the incidence of total cancer, cancers of the prostate, colon and lung, and cancer mortality. The active agent in the selenized yeast supplement was assumed to be selenomethionine (SEMET), although the supplement had not been well speciated. The SELECT study, largely motivated by the NPC trial, enrolling nearly 40 times as many subjects, showed unequivocally that selenium 200 mcg/day, with selenium in the form of SEMET, does not protect selenium-replete men against prostate or other major cancer. The agent tested by SELECT, pure SEMET, could have been different from the selenized yeast tested in NPC. One of the selenium forms suspected of having chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine (MSC). This study, with 29 selenium-replete patients enrolled in a randomized, double-blind trial, compared the multiple-dose toxicity, pharmacokinetics and pharmacodynamics of MSC and SEMET. Patients were on trial for 84 days. No toxicity was observed. Although SEMET supplementation increased blood selenium concentration more than MSC did, neither form had a more than minimal impact on the two major selenoproteins: selenoprotein P(SEPP1) and glutathione peroxidase(GPX).