Publications by authors named "Amir Mortazavi"

52 Publications

A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

Cancer Chemother Pharmacol 2021 Jan 25. Epub 2021 Jan 25.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, USA.

Purpose: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity.

Methods: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD.

Results: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached).

Conclusion: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors.

Trial Registration: NCT01129193, registered 5/24/2010.
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http://dx.doi.org/10.1007/s00280-020-04229-3DOI Listing
January 2021

Risk Factors for Emergency Room and Hospital Care Among Patients With Solid Tumors on Immune Checkpoint Inhibitor Therapy.

Am J Clin Oncol 2021 Mar;44(3):114-120

Tisch Cancer Institute, Division of Hematology/Oncology.

Objectives: Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown.

Methods: We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment.

Results: Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003).

Conclusions: Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.
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http://dx.doi.org/10.1097/COC.0000000000000793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902456PMC
March 2021

Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer.

Clin Cancer Res 2021 Mar 1;27(5):1391-1398. Epub 2020 Dec 1.

NCI, Bethesda, Maryland.

Purpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.

Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.

Results: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline ( = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months; < 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS ( = 0.045). PD-L1 CTCs on-therapy were associated with worse OS ( < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category.

Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1 CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925349PMC
March 2021

Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies.

Cancer 2020 Nov 20. Epub 2020 Nov 20.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616).

Methods: Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1).

Results: Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related.

Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing.

Lay Summary: Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.
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http://dx.doi.org/10.1002/cncr.33328DOI Listing
November 2020

Alterations of DNA damage response genes correlate with response and overall survival in anti-PD-1/PD-L1-treated advanced urothelial cancer.

Cancer Med 2020 Dec 23;9(24):9365-9372. Epub 2020 Oct 23.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.

DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti-PD-1/PD-L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti-PD-1/PD-L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum-based chemotherapy. DDR alterations (including ATM) were associated with a non-significantly higher ORR to PD-1/PD-L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non-significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20-1.38, p = 0.19). ATM alterations were associated with a non-significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65-19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD-1/PD-L1 blockade versus 24% ORR in patients with <3 DDR alterations. In summary, DDR alterations were associated with non-significantly higher ORR and longer OS for patients with advanced UC receiving anti-PD-1/PD-L1 agents. ATM alterations were associated with shorter OS.
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http://dx.doi.org/10.1002/cam4.3552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774722PMC
December 2020

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.

J Clin Oncol 2020 11 11;38(31):3672-3684. Epub 2020 Sep 11.

Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, and the Comprehensive Cancer Center, Columbus, OH.

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances.

Patients And Methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).

Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.

Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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http://dx.doi.org/10.1200/JCO.20.01652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605393PMC
November 2020

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

J Natl Compr Canc Netw 2020 09;18(9):1160-1170

National Comprehensive Cancer Network.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.
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http://dx.doi.org/10.6004/jnccn.2020.0043DOI Listing
September 2020

A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer.

Cancer 2020 Oct 5;126(20):4485-4497. Epub 2020 Aug 5.

Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.

Background: Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation.

Methods: The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells.

Results: Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment.

Conclusions: Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration.
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http://dx.doi.org/10.1002/cncr.33067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590121PMC
October 2020

Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.

Oncologist 2020 08 13;25(8):680-688. Epub 2020 May 13.

Penn State Cancer Institute, Hershey, Pennsylvania, USA.

Background: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear.

Materials And Methods: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI.

Results: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003).

Conclusions: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression.

Implications For Practice: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.
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http://dx.doi.org/10.1634/theoncologist.2019-0851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418353PMC
August 2020

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer.

J Clin Oncol 2020 06 9;38(16):1797-1806. Epub 2020 Apr 9.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA.

Purpose: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons.

Patients And Methods: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS).

Results: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank = .04; maximum efficiency robust test = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.

Conclusion: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.
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http://dx.doi.org/10.1200/JCO.19.03091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983PMC
June 2020

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study.

J Immunother Cancer 2020 03;8(1)

Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.

Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.

Results: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).

Conclusions: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.
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http://dx.doi.org/10.1136/jitc-2020-000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174076PMC
March 2020

Co-occurrence of multiple endocrine neoplasia type 4 and spinal neurofibromatosis: a case report.

Fam Cancer 2020 04;19(2):189-192

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, A440 Starling-Loving Hall, 320 W 10th Ave, Columbus, OH, 43210, USA.

Multiple Endocrine Neoplasia (MEN) type 4 is a rare genetic condition that results from variants of the CDKN1B gene and predisposes individuals to develop endocrine tumors. Spinal neurofibromatosis (SNF) is an uncommon subtype of neurofibromatosis type 1 (NF1) characterized by bilateral neurofibromas of all spinal roots. Here we report a case of the co-occurrence of these syndromes, which has not yet been described in the literature. A male in his 60s presented with Gleason 5 + 4 localized prostate adenocarcinoma treated with radical prostatectomy. Two years later, he developed liver and bone metastasis consistent with trans-differentiation into small cell carcinoma. He developed hypercalcemia due to primary hyperparathyroidism from a parathyroid adenoma treated surgically. His family history was significant for a first-degree relative with a clinical diagnosis of NF1 and several second-degree relatives with multiple café-au-lait macules. Spine MRI showed multiple bilateral neurofibromas. Germline genetic testing showed a pathogenic variant in the CDKN1B gene, a variant in the NF1 gene, and a normal MEN1 gene. In this rare case of MEN4 and SNF, the patient was asymptomatic for much of his life. In addition to parathyroid adenoma and spinal neurofibromas, he had prostate adenocarcinoma with trans-differentiation into metastatic small cell cancer. Whether this diagnosis was coincidental or related to an emerging phenotype remains to be elucidated.
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http://dx.doi.org/10.1007/s10689-019-00152-6DOI Listing
April 2020

Comparative effectiveness of surgery versus external beam radiation with/without brachytherapy in high-risk localized prostate cancer.

Cancer Med 2020 01 7;9(1):27-34. Epub 2019 Nov 7.

Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Background: It remains controversial if radical prostatectomy or definitive radiation therapy produces equivalent outcomes in high-risk localized prostate cancer.

Methods: We queried The Surveillance, Epidemiology, and End Results (SEER) database for those who received upfront surgery or who were recommended for surgery but instead received radiation. Inverse probability of treatment weighing was used to adjust for covariate imbalance and the weighted Cox proportional hazards model was used to estimate the effects of treatment groups on survival. A meta-analysis was performed to pool estimates from published studies.

Results: Among eligible 62 533 patients, 59 540 had upfront surgery and 2993 patients had upfront radiotherapy. EBRT + BT was associated with a superior cancer-specific survival (CSS) compared with surgery or EBRT alone (HR, 0.55, 95% CI, 0.3-1.0; HR, 0.49, 95% CI, 0.24-0.98, respectively), whereas EBRT was associated with an inferior overall survival (OS) compared with surgery (HR, 1.46, 95% CI, 1.16-1.8). Radiotherapy (EBRT ± BT) was inferior to surgery by OS (HR, 1.63, 95% CI, 1.13-2.34) in patients ≤ 65 years, and was superior to surgery by CSS in patients > 65 years (HR, 0.69, 95% CI, 0.49-0.97). The meta-analysis showed consistent results.

Conclusion: EBRT + BT was associated with a significantly better prostate CSS compared with surgery or EBRT. EBRT alone was inferior to surgery by OS.
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http://dx.doi.org/10.1002/cam4.2605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943084PMC
January 2020

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020.

J Natl Compr Canc Netw 2019 11;17(11):1278-1285

National Comprehensive Cancer Network.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.
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http://dx.doi.org/10.6004/jnccn.2019.0054DOI Listing
November 2019

Periodically rotated overlapping parallel lines with enhanced reconstruction acquisition to improve motion-induced artifacts in bladder cancer imaging: Initial findings.

Medicine (Baltimore) 2019 Oct;98(42):e17075

Wright Center of Innovation in Biomedical Imaging, Department of Radiology.

Motion-induced artifacts have been a major drawback in bladder cancer imaging. This study is to evaluate the clinical utility of periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) acquisition in improving motion-induced artifacts in T2-weighted (T2W) magnetic resonance imaging (MRI) of bladder cancer at 3T.Sixteen patient MRI exams were included. Using a Likert scale, 2 radiologists independently scored T2W data without and with PROPELLER in terms of artifact severity and tumor visualization. Statistical analysis was done to assess the image quality improvement by PROPELLER and inter-observer variability.Without PROPELLER, the median scores of artifact severity and tumor visualization were 1.5 and 1.5 for reviewer 1, and 2.0 and 2.0 for reviewer 2. With PROPELLER, the scores increased to 3 and 3.5 for reviewer 1, and 3.5 and 3.5 for reviewer 2. Despite the inter-observer variability (κ scores < 0.2), both reviewers found significant improvement in artifacts and visualization (all P < .001).PROPELLER acquisition significantly improved the image quality of T2W-MRI. These initial findings indicate that this technique should be utilized in clinical MRI of the bladder.
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http://dx.doi.org/10.1097/MD.0000000000017075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824794PMC
October 2019

F-Sodium fluoride PET/CT predicts overall survival in patients with advanced genitourinary malignancies treated with cabozantinib and nivolumab with or without ipilimumab.

Eur J Nucl Med Mol Imaging 2020 01 14;47(1):178-184. Epub 2019 Sep 14.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: We evaluated the prognostic value of F-sodium fluoride (NaF) PET/CT in patients with urological malignancies treated with cabozantinib and nivolumab with or without ipilimumab.

Methods: We prospectively recruited patients with advanced urological malignancies into a phase I trial of cabozantinib plus nivolumab with or without ipilimumab. NaF PET/CT scans were performed pre- and 8 weeks post-treatment. We measured the total volume of fluoride avid bone (FTV) using a standardized uptake value (SUV) threshold of 10. We used Kaplan-Meier analysis to predict the overall survival (OS) of patients in terms of SUVmax, FTV, total lesion fluoride (TLF) uptake at baseline and 8 weeks post-treatment, and percent change in FTV and TLF.

Result: Of 111 patients who underwent NaF PET/CT, 30 had bone metastases at baseline. Four of the 30 patients survived for the duration of the study period. OS ranged from 0.23 to 34 months (m) (median 6.0 m). The baseline FTV of all 30 patients ranged from 9.6 to 1570 ml (median 439 ml). The FTV 8 weeks post-treatment was 56-6296 ml (median 448 ml) from 19 available patients. Patients with higher TLF at baseline had shorter OS than patients with lower TLF (3.4 vs 14 m; p = 0.022). Patients with higher SUVmax at follow-up had shorter OS than patients with lower SUVmax (5.6 vs 24 m; p = 0.010). However, FTV and TLF 8 weeks post-treatment did not show a significant difference between groups (5.6 vs 17 m; p = 0.49), and the percent changes in FTV (12 vs 14 m; p = 0.49) and TLF (5.6 vs 17 m; p = 0.54) also were not significant.

Conclusion: Higher TLF at baseline and higher SUVmax at follow-up NaF PET/CT corresponded with shorter survival in patients with bone metastases from urological malignancies who underwent treatment. NaF PET/CT may be a useful predictor of OS in this population.
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http://dx.doi.org/10.1007/s00259-019-04483-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885023PMC
January 2020

Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study.

Lancet Oncol 2019 10 16;20(10):1386-1394. Epub 2019 Aug 16.

Department of Hematology and Medical Oncology, Cleveland Clinic-Taussig Cancer Institute, Cleveland, OH, USA.

Background: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor.

Methods: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811.

Findings: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2).

Interpretation: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting.

Funding: Pfizer.
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http://dx.doi.org/10.1016/S1470-2045(19)30513-3DOI Listing
October 2019

Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653).

J Clin Oncol 2019 10 7;37(29):2682-2688. Epub 2019 Aug 7.

University of California, Davis, Davis, CA.

Purpose: Patients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population.

Methods: Patients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m intravenously followed by eribulin 1.4 mg/m, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%.

Results: Between June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each).

Conclusion: Gemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.
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http://dx.doi.org/10.1200/JCO.19.00861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006847PMC
October 2019

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study.

Lancet Oncol 2019 04 28;20(4):581-590. Epub 2019 Feb 28.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.

Methods: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.

Findings: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.

Interpretation: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(18)30907-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849381PMC
April 2019

Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors.

Clin Cancer Res 2019 06 25;25(12):3495-3507. Epub 2019 Feb 25.

Arthur G. James Cancer Hospital/Comprehensive Cancer Center, Columbus, Ohio.

Purpose: This first-in-human phase I study (NCT01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines.

Patients And Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a "promiscuous T-cell epitope." Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.

Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.

Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159438PMC
June 2019

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes.

Cancer 2019 02 20;125(4):533-540. Epub 2018 Dec 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

Background: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.

Methods: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.

Results: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [C ] after TIW dosing of 0.2 ng/mL/mg).

Conclusions: To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.
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http://dx.doi.org/10.1002/cncr.31817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590473PMC
February 2019

Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma.

Clin Genitourin Cancer 2018 12 29;16(6):437-444.e6. Epub 2018 Jul 29.

Department of Medicine, Rutgers Cancer Institute of New Jersey, NJ. Electronic address:

Background: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma.

Patients And Methods: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete).

Results: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths.

Conclusion: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.
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http://dx.doi.org/10.1016/j.clgc.2018.07.021DOI Listing
December 2018

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Invest New Drugs 2018 10 7;36(5):919-926. Epub 2018 Aug 7.

Taussig Cancer Institute, 9500 Euclid Ave, Cleveland, OH, 44195-0001, USA.

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.
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http://dx.doi.org/10.1007/s10637-018-0630-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153554PMC
October 2018

Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention.

Mol Nutr Food Res 2018 09 29;62(18):e1800079. Epub 2018 Aug 29.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210.

Bladder cancer is a significant health burden due to its high prevalence, risk of mortality, morbidity, and high cost of medical care. Epidemiologic evidence suggests that diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Phytochemicals in cruciferous vegetables, such as glucosinolates, which are enzymatically hydrolyzed to bioactive isothiocyanates, are possible mediators of an anticancer effect. In vitro studies have shown inhibition of bladder cancer cell lines, cell cycle arrest, and induction of apoptosis by these isothiocyanates, in particular sulforaphane and erucin. Although not yet completely understood, many mechanisms of anticancer activity at the steps of cancer initiation, promotion, and progression have been attributed to these isothiocyanates. They target multiple pathways including the adaptive stress response, phase I/II enzyme modulation, pro-growth, pro-survival, pro-inflammatory signaling, angiogenesis, and even epigenetic modulation. Multiple in vivo studies have shown the bioavailability of isothiocyanates and their antitumoral effects. Although human studies are limited, they support oral bioavailability with reasonable plasma and urine concentrations achieved. Overall, both cell and animal studies support a potential role for isothiocyanates in bladder cancer prevention and treatment. Future studies are necessary to examine clinically relevant outcomes and define guidelines on ameliorating the bladder cancer burden.
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http://dx.doi.org/10.1002/mnfr.201800079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196731PMC
September 2018

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with Alterations.

Cancer Discov 2018 07 30;8(7):812-821. Epub 2018 May 30.

Memorial Sloan Kettering Cancer Center, New York, New York.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of alterations. Patients ( = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. BJG398 is active in patients with alterations in , resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716598PMC
July 2018

Effects of a Group-Mediated Exercise and Dietary Intervention in the Treatment of Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Results From the IDEA-P Trial.

Ann Behav Med 2018 04;52(5):412-428

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Although androgen-deprivation therapy (ADT) is the foundation of treatment for prostate cancer, the physiological impacts of ADT result in functional decline and enhanced risk of chronic disease and metabolic syndrome.

Purpose: The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is a single-blind, randomized, pilot trial comparing the effects of a group-mediated, cognitive-behavioral (GMCB) exercise and dietary intervention (EX+D) with those of a standard-of-care (SC) control during the treatment of prostate cancer patients undergoing ADT.

Methods: A total of 32 prostate cancer patients (M age = 66.28, SD = 7.79) undergoing ADT were randomly assigned to the 12-week EX+D intervention (n = 16) or control (n = 16). The primary outcome in IDEA-P was change in mobility performance with secondary outcomes including body composition and muscular strength. Blinded assessment of outcomes were obtained at baseline and at 2- and 3-month follow-ups.

Results: Favorable adherence and retention rates were observed, and no serious intervention-related adverse events were documented. Intent-to-treat ANCOVA controlling for baseline value and ADT duration demonstrated that EX+D resulted in significantly greater improvements in mobility performance (p < .02), muscular strength (p < .01), body fat percentage (p < .05), and fat mass (p < .03) at 3-month follow-up, relative to control.

Conclusion: Findings from the IDEA-P trial suggest that a GMCB-based EX+D intervention resulted in significant, clinically meaningful improvements in mobility performance, muscular strength, and body composition, relative to controls. Collectively, these results suggest that the EX+D was a safe and well-tolerated intervention for prostate cancer patients on ADT. The utility of implementing this approach in the treatment of prostate cancer patients on ADT should be evaluated in future large-scale efficacy trials.

Clinical Trial Information: NCT02050906.
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http://dx.doi.org/10.1093/abm/kax002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361261PMC
April 2018

A Potential Role for Adjuvant Chemotherapy and Radiotherapy for Patients With High-Risk Bladder Cancer Treated With Cystectomy in the United States.

JAMA Surg 2018 01 17;153(1):e174592. Epub 2018 Jan 17.

Department of Urology, The Ohio State University, Columbus.

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http://dx.doi.org/10.1001/jamasurg.2017.4592DOI Listing
January 2018

Quantitative Assessment of Heterogeneity in Bladder Tumor MRI Diffusivity: Can Response be Predicted Prior to Neoadjuvant Chemotherapy?

Bladder Cancer 2017 Oct 27;3(4):237-244. Epub 2017 Oct 27.

Department of Radiology, Wright Center of Innovation in Biomedical Imaging, The Ohio State University, Columbus, OH, USA.

Background: It is a critical unmet need to predict chemosensitivity in muscle-invasive bladder cancer patients who receive neoadjuvant chemotherapy (NAC). Quantification of tumor heterogeneity has been shown to be useful in the assessment of therapeutic response. Apparent diffusion coefficient (ADC) is derived from diffusion weighted MRI (DWI) to quantify the water diffusivity which characterizes micro-cellularity in tumor tissues.

Objective: The aim of this study is to assess if a quantitative measurement of ADC heterogeneity in bladder tumors can be a predictor of therapeutic response to NAC.

Materials And Methods: Twenty patients with pT2 bladder cancer have been included in this study. Patient MRI was performed on a 3T system with DWI prior to NAC. Regions of interest (ROIs) were placed over the whole tumor volume on ADC maps to acquire a data matrix of voxel-wise ADC values for each patient. We performed histogram analysis on each ADC data matrix to calculate uniformity (U) and entropy (E). These quantities were subsequently correlated with the patient's response to chemotherapy. Statistical significance was found with  < 0.05.

Results: Fifteen patients were categorized as responders, and five as non-responders. The data showed that tumors of responders were significantly higher in U ( = 0.01) and lower in E ( < 0.01) than non-responders. This finding indicates that resistant tumors were more heterogeneous in their spatial distribution of ADC values. While this difference in ADC heterogeneity was not always visually recognizable, it could be quantified by the data analytics.

Conclusions: This study demonstrates that the quantitative readout of tumor heterogeneity in micro-cellularity is associated with the patient's defined response to chemotherapy. Quantification of tumor ADC heterogeneity may provide useful information to enable the prediction of chemotherapeutic response prior to the treatment to improve patient outcomes.
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http://dx.doi.org/10.3233/BLC-170110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676757PMC
October 2017

Analytic validation and real-time clinical application of an amplicon-based targeted gene panel for advanced cancer.

Oncotarget 2017 Sep 1;8(44):75822-75833. Epub 2017 Sep 1.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Multiplex somatic testing has emerged as a strategy to test patients with advanced cancer. We demonstrate our analytic validation approach for a gene hotspot panel and real-time prospective clinical application for any cancer type. The TruSight Tumor 26 assay amplifies 85 somatic hotspot regions across 26 genes. Using cell line and tumor mixes, we observed that 100% of the 14,715 targeted bases had at least 1000x raw coverage. We determined the sensitivity (100%, 95% CI: 96-100%), positive predictive value (100%, 95% CI: 96-100%), reproducibility (100% concordance), and limit of detection (3% variant allele frequency at 1000x read depth) of this assay to detect single nucleotide variants and small insertions and deletions. Next, we applied the assay prospectively in a clinical tumor sequencing study to evaluate 174 patients with metastatic or advanced cancer, including frozen tumors, formalin-fixed tumors, and enriched peripheral blood mononuclear cells in hematologic cancers. We reported one or more somatic mutations in 89 (53%) of the sequenced tumors (167 passing quality filters). Forty-three of these patients (26%) had mutations that would enable eligibility for targeted therapies. This study demonstrates the validity and feasibility of applying TruSight Tumor 26 for pan-cancer testing using multiple specimen types.
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http://dx.doi.org/10.18632/oncotarget.20616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652665PMC
September 2017

A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas.

Leuk Lymphoma 2017 Oct 7;58(10):2310-2318. Epub 2017 Mar 7.

f Division of Hematology, Department of Internal Medicine , The Ohio State University , Columbus , OH , USA.

Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively. Treatment was associated with reduction of serum CD44, a transmembrane glycoprotein associated with steroid and immunomodulatory drug resistance in MM. Our findings indicate that AR-42 is safe and that further investigation of AR-42 in combination regimens for the treatment of patients with lymphoma and MM is warranted.

Trial Registration: http://clinicaltrials.gov/ct2/show/NCT01129193.
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http://dx.doi.org/10.1080/10428194.2017.1298751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489371PMC
October 2017