Afshin Dowlati

Case Western Reserve University School of Medicine, Cleveland, Ohio, United States

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Publications (121)794.19 Total impact

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    ABSTRACT: There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2014; 9(9):1316-1323. · 4.55 Impact Factor
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    ABSTRACT: Purpose: Deregulation of STAT3 activation is a hallmark of many cancer cells and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling. Experimental design: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth and viability in cultured mesothelioma cells. Results: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (p = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 down regulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein which interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth. Conclusion: These results suggest that PIAS3 protein expression impacts survival in mesothelioma patients and that PIAS3 activation could become a therapeutic strategy.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 08/2014;
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    ABSTRACT: Erlotinib is a tyrosine kinase inhibitor approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest since many tumors express wild-type (wt) epidermal growth factor receptor (EGFR) or develop a second-site EGFR mutation. To test drug combinations that could improve the efficacy of erlotinib, we combined erlotinib with quinacrine, which inhibits the FACT (facilitates chromatin transcription) complex that is required for NF-kappaB transcriptional activity. In A549 (wtEGFR), H1975 (EGFR-L858R/T790M) and H1993 (MET amplification) NSCLC cells, this drug combination was highly synergistic, as quantified by Chou-Talalay combination indices, and slowed xenograft tumor growth. At a sub-IC50 but more clinically attainable concentration of erlotinib, quinacrine, alone or in combination with erlotinib, significantly inhibited colony formation and induced cell cycle arrest and apoptosis. Quinacrine decreased the level of active FACT subunit SSRP1 and suppressed NF-kappaB-dependent luciferase activity. Knockdown of SSRP1 decreased cell growth and sensitized cells to erlotinib. Moreover, transcriptomic profiling showed that quinacrine or combination treatment significantly affected cell cycle-related genes that contain binding sites for transcription factors that regulate SSRP1 target genes. As potential biomarkers of drug combination efficacy, we identified genes that were more strongly suppressed by the combination than by either single treatment, and whose increased expression predicted poorer survival in lung adenocarcinoma patients. This preclinical study shows that quinacrine overcomes erlotinib resistance by inhibiting FACT and cell cycle progression, and supports a clinical trial testing erlotinib alone versus this combination in advanced NSCLC.
    Molecular Cancer Therapeutics 07/2014; · 5.60 Impact Factor
  • Afshin Dowlati, Gary Wildey
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2014; 9(6):750-1. · 4.55 Impact Factor
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    ABSTRACT: Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients. Patients with metastatic solid tumors received sunitinib (37.5 mg/day 4 weeks on/2 weeks off) and bevacizumab (5 mg/kg intravenously every 2 weeks). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays. Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 weeks of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold. Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development.
    Cancer biology & therapy 05/2014; 15(8). · 3.29 Impact Factor
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    ABSTRACT: Background:We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.Methods:Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.Results:Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).Conclusions:Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.British Journal of Cancer advance online publication, 6 May 2014; doi:10.1038/bjc.2014.233 www.bjcancer.com.
    British Journal of Cancer 05/2014; · 5.08 Impact Factor
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    ABSTRACT: Background/Purpose This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). Methods Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. Results Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. Conclusion Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.
    Investigational New Drugs 03/2014; · 3.50 Impact Factor
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    ABSTRACT: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir. Cancer 2013. © 2013 American Cancer Society.
    Cancer 01/2014; · 5.20 Impact Factor
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    ABSTRACT: Objectives Sorafenib is a multi-tyrosine kinase inhibitor of Raf kinase, VEGFR, and PDGFR. Angiogenesis is important for growth and progression of SCLC. This trial was conducted to evaluate whether the combination of cisplatin and etoposide plus concurrent and sequential sorafenib could prolong survival in patients with previously untreated SCLC. Methods Previously untreated patients with extensive stage SCLC were treated with cisplatin and etoposide days 1, 2, 3 for four cycles, concurrent with sorafenib 200 mg orally bid starting day 1 cycle 1. Patients with no disease progression after four cycles continued sorafenib 400 mg orally bid as maintenance for maximum of 12 months. The primary endpoint was 1 year survival with response rate and safety as secondary endpoints. Results A total of 18 patients were enrolled with 17 evaluable patients. One patient had a complete response, seven patients had a partial response (overall response rate of 47 %) and one patient had stable disease. Overall median survival was 7.4 months and 1 year survival was 25 %. The most common treatment-related adverse events included fatigue, anorexia, rash, diarrhea, neutropenia and weight loss. Grade 5 GI bleeding, pulmonary hemorrhage and neutropenia occurred in one pt (6 %) each. Accrual was halted on the basis of safety profile as well as preliminary efficacy data. Conclusions The combination of platinum based chemotherapy and sorafenib has significant toxicity at current dose levels and is associated with disappointing efficacy data.
    Investigational New Drugs 01/2014; · 3.50 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored. Through examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS). There was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%. There is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time.
    Clinical Lung Cancer 12/2013; · 2.04 Impact Factor
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    ABSTRACT: Many challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions. The National Cancer Institute (NCI) and the ASCO (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature. Few rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations. A combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided.
    Journal of Oncology Practice 10/2013;
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    ABSTRACT: Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. Single-agent dasatinib does not have clinical activity in metastatic PDAC.
    The Oncologist 09/2013; · 4.10 Impact Factor
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    ABSTRACT: Protein inhibitor of activated STAT3 (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In the present study we sought to determine if PIAS3 inhibits cell growth in non-small cell lung cancer (NSCLC) cell lines by inducing apoptosis. Our results demonstrate that over-expression of PIAS3 promotes mitochondrial depolarization, leading to cytochrome c release, caspase 9 and 3 activation and PARP cleavage. This intrinsic pathway activation was associated with decreased Bcl-xL expression and increased Noxa expression and was independent of p53 status. Furthermore, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to discover STAT3-independent mediators of PIAS3-induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 over-expression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes was uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy as well as its potential to synergize with Bcl-2 targeted inhibitors. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2013; · 6.20 Impact Factor
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    ABSTRACT: Heat shock protein 27 (Hsp27) is a chaperone protein and its expression is increased in response to various stress stimuli including anti-cancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization, but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anti-cancer drug development.
    Journal of Medicinal Chemistry 06/2013; · 5.61 Impact Factor
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    ABSTRACT: PURPOSE: Pazopanib is a potent, multi-targeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics (PK). The objective of this study was to establish the maximum tolerated dose (MTD) and PK profile of pazopanib in patients with varying degrees of hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. RESULTS: Ninety eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and AUC(0-24) in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower MTD in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. CONCLUSIONS: In patients with mild liver dysfunction, pazopanib is well tolerated at the FDA-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.
    Clinical Cancer Research 05/2013; · 7.84 Impact Factor
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    ABSTRACT: OBJECTIVE: Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. METHODS: We conducted a phase II study evaluating 3x weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1x weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage IB2-IVB cervical (n = 22) or stage II-IV vaginal (n = 3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography (PET/CT) and clinical examination. RESULTS: 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. CONCLUSIONS: The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
    Gynecologic Oncology 04/2013; · 3.93 Impact Factor
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    ABSTRACT: Introduction This study aimed to assess the safety and tolerability of the multitargeted tyrosine kinase inhibitor, vandetanib (V), in combination with two chemotherapeutic agents, oxaliplatin (O) and docetaxel (D) in advanced gastroesophageal (GE) cancer. Methods This was a Phase I study (NCT00732745) with a standard 3 + 3 dose escalation design. The primary aim was to determine the optimal dose of the combination of vandetanib and OD chemotherapy. Results Initial treatment for the first cohort consisted of oxaliplatin at 100 mg/m2 on day 1, docetaxel at 35 mg/m2 on days 1 and 8 and vandetanib 100 mg PO daily of 21-day treatment cycles. As dose limiting toxicity (DLT) was reached in 2 out of 3 patients in cohort 1 (one grade 3 and one grade 4 diarrhea with dehydration), 6 patients were treated then at dose level -1 (O 80 mg/m2 on day 1, D 30 mg/m2 on days 1 and 8, V 100 mg PO daily days 1-21) in which no further DLTs were observed. This dose was established as maximum tolerated dose and is the recommended phase 2 dose. 8 out of 9 enrolled patients had adenocarcinoma. At dose level 1, 1 of the 3 patients had a documented partial response and 2 patients had stable disease. At dose level -1, 1 of 6 patients achieved a complete response, 2 of 6 patients had stable disease, and 3 of 6 patients had progressive disease. Conclusions Vandetanib added to oxaliplatin and docetaxel showed manageable toxicity and limited activity in advanced GE cancer.
    Investigational New Drugs 04/2013; · 3.50 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is a disease for which little recent therapeutic advance has been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore the use of surrogate endpoints in SCLC has not been explored. Through examining SCLC trials published in the Journal of Clinical Oncology (8,471 patients from 66 trials between 1983-2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary endpoints for all trials and sought to discover surrogate endpoint for overall survival (OS). There were increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% of trials in 2006-2010 [p=0.001]) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010 [p=0.005]). 72.2% of trials published in 1986-1996 failed to report a primary endpoint whereas only 5.56% of trials in 2006-2010 failed to do so (p=0.004). Of phase II trials, primary endpoint was identified as RR in 65%, OS in 25%, and PFS in 10%. There is a strong correlation between RR and both PFS (p=0.013) and OS (p=0.012) in extensive-stage disease (ED). RR (p=0.029) exhibits a negative trend over time with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for LD (p=0.036) and ED (p=0.058). We found no change in overall survival (p=0.383) over time.
    Clinical Lung Cancer 01/2013; · 2.04 Impact Factor
  • Ernest C Borden, Afshin Dowlati
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    ABSTRACT: As cancer therapy progresses through the development of molecularly targeted drugs, the focus of Phase I trials needs to shift towards investigating end points that could guide more effective trial design, dosing and choice of tumour setting for Phase II studies.
    dressNature Reviews Drug Discovery 11/2012; 11(12):889-90. · 33.08 Impact Factor
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    ABSTRACT: Background: Anaplastic Thyroid Cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogeneis mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor which acts on raf-1 serine/threonine kinase. In preclinical mouse models sorafenib inhibits growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with anaplastic thyroid carcinoma who had failed up to two previous therapies. Methods: The primary endpoint of the trial was RECIST-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. Results: Two of 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months respectively. For the patients with stable disease the median duration was 4 months (range 3-11 months). The overall median PFS was 1.9 months with a median and 1-year survival of 3.9 months and 20% respectively. Toxicity was manageable and as previously described for sorafenib including hypertension and skin rash. Conclusion: Sorafenib has activity in ATC but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.
    Thyroid: official journal of the American Thyroid Association 10/2012; · 2.60 Impact Factor

Publication Stats

5k Citations
794.19 Total Impact Points

Institutions

  • 2001–2014
    • Case Western Reserve University School of Medicine
      • Department of Medicine
      Cleveland, Ohio, United States
  • 1998–2014
    • Case Western Reserve University
      • • Division of Hematology and Oncology
      • • School of Medicine
      • • Department of Radiology (University Hospitals Case Medical Center)
      • • Department of Medicine (University Hospitals Case Medical Center)
      Cleveland, Ohio, United States
  • 2008–2009
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2007
    • US Oncology
      The Woodlands, Texas, United States
  • 2002
    • University of Nairobi
      • College of Health Sciences
      Nairobi, Nairobi Province, Kenya
  • 1995–1999
    • University of Liège
      • • Department of Internal Medicine
      • • Department of Pneumology
      Luik, Walloon Region, Belgium