المؤلفون: Subbiah IM; Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Falchook GS; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kaseb AO; Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hess KR; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tsimberidou AM; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Fu S; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Subbiah V; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hong DS; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Naing A; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Piha-Paul SA; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Akmal O; Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Janku F; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kurzrock R; Moores Cancer Center, University of California San Diego, San Diego, CA, USA.

المصدر: Oncotarget [Oncotarget] 2015 Sep 29; Vol. 6 (29), pp. 28453-62.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural

بيانات الدورية: Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: Print Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: MEDLINE

مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Biomarkers, Tumor/*antagonists & inhibitors , Carcinoma, Hepatocellular/*drug therapy , Liver Neoplasms/*drug therapy, Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; Child ; Clinical Trials, Phase I as Topic ; Disease-Free Survival ; Female ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Male ; Middle Aged ; Molecular Targeted Therapy/methods ; Multivariate Analysis ; Mutation ; Outcome Assessment, Health Care/methods ; Outcome Assessment, Health Care/statistics & numerical data ; Prognosis ; Young Adult

مستخلص: Purpose: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies.
Methods: We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004.
Results: Thirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013).
Conclusions: In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.

المؤلفون: Subbiah V; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States. Electronic address: vsubbiah@mdanderson.org., Berry J; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Roxas M; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Guha-Thakurta N; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Subbiah IM; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Ali SM; Foundation Medicine, Boston, MA, United States., McMahon C; Foundation Medicine, Boston, MA, United States., Miller V; Foundation Medicine, Boston, MA, United States., Cascone T; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Pai S; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Tang Z; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States., Heymach JV; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.

المصدر: Lung cancer (Amsterdam, Netherlands) [Lung Cancer] 2015 Jul; Vol. 89 (1), pp. 76-9. Date of Electronic Publication: 2015 Apr 22.

نوع المنشور: Case Reports; Journal Article; Research Support, N.I.H., Extramural

بيانات الدورية: Publisher: Elsevier Scientific Publishers Country of Publication: Ireland NLM ID: 8800805 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8332 (Electronic) Linking ISSN: 01695002 NLM ISO Abbreviation: Lung Cancer Subsets: MEDLINE

مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Brain Neoplasms/*drug therapy , Carcinoma, Non-Small-Cell Lung/*drug therapy , Lung Neoplasms/*drug therapy , Oncogene Proteins, Fusion/*genetics, Aged ; Blood-Brain Barrier ; Brain Neoplasms/genetics ; Brain Neoplasms/secondary ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/secondary ; Everolimus/administration & dosage ; Female ; Gene Amplification ; Gene Rearrangement ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Magnetic Resonance Imaging ; Neuroimaging ; Piperidines/administration & dosage ; Proto-Oncogene Proteins c-akt/genetics ; Quinazolines/administration & dosage

مستخلص: In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.
Competing Interests: SMA, CM and VAM are employees of and have equity interest in Foundation Medicine.
(Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

المؤلفون: Subbiah IM; Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Blackmon SH; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Surgery, The Methodist Hospital and Weill Cornell College of Medicine, Houston, Texas., Correa AM; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kee B; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Vaporciyan AA; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Swisher SG; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Eng C; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

المصدر: Oncotarget [Oncotarget] 2014 Aug 30; Vol. 5 (16), pp. 6584-93.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: Print Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: MEDLINE

مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*administration & dosage , Colorectal Neoplasms/*drug therapy , Colorectal Neoplasms/*surgery , Lung Neoplasms/*drug therapy , Lung Neoplasms/*surgery , Metastasectomy/*methods, Camptothecin/administration & dosage ; Camptothecin/analogs & derivatives ; Capecitabine ; Chemotherapy, Adjuvant ; Colorectal Neoplasms/pathology ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Female ; Fluorouracil/administration & dosage ; Fluorouracil/analogs & derivatives ; Humans ; Irinotecan ; Lung Neoplasms/secondary ; Male ; Middle Aged ; Neoadjuvant Therapy ; Organoplatinum Compounds/administration & dosage ; Oxaliplatin ; Preoperative Care/methods ; Prospective Studies ; Survival Rate

مستخلص: Background: The benefit of preoperative chemotherapy prior to pulmonary metastasectomy for patients with colorectal carcinoma (CRC) is unknown. Here, we identify outcomes of preoperative chemotherapy in patients with resected primary CRC who then underwent pulmonary metastasectomy.
Methods: We queried a prospective database to identify treatment characteristics. Multivariate analyses identified predictors of overall survival (OS) and progression-free survival (PFS).
Results: 229 patients underwent lung metastasectomy, of whom 115 proceeded to surgery without chemotherapy while 114 received preoperative regimen based on oxaliplatin (32%), irinotecan (46%), capecitabine (16%), or other (6%). Median PFS in preoperative chemotherapy vs. surgery alone arms were comparable (p=0.004). Patients on oxaliplatin-based therapy had an improved OS vs. an irinotecan, capecitabine, or alternate regimen (p=.019). On multivariate analysis, the irinotecan subset had a worse OS (HR 1.846; 95% CI 1.070, 3.185) vs. surgery alone arm (p=0.028). The OS of an oxaliplatin-based regimen vs. no chemotherapy was inconclusive (HR 0.57; 95% CI 0.237 to 1.389, p=0.218). Multivariate analysis demonstrated a worse PFS and OS for the male gender and an incomplete resection (R2).
Conclusion: Prospective trials on specific preoperative regimens and criteria for patient selection may identify a role for preoperative chemotherapy prior to a curative pulmonary metastasectomy.

المؤلفون: Tsimberidou AM; Phase I Program, Department of Investigational Cancer Therapeutics, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. atsimber@mdanderson.org, Leick MB, Lim J, Fu S, Wheler J, Piha-Paul SA, Hong D, Falchook GS, Naing A, Subbiah IM, Fortier A, Avritscher R, Kurzrock R

المصدر: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2013 Feb; Vol. 71 (2), pp. 389-97. Date of Electronic Publication: 2012 Nov 11.

نوع المنشور: Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE

مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Liver Neoplasms/*drug therapy , Liver Neoplasms/*secondary , Organoplatinum Compounds/*administration & dosage , Organoplatinum Compounds/*therapeutic use, Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Female ; Hepatic Artery ; Humans ; Infusions, Intra-Arterial ; Liver Neoplasms/mortality ; Male ; Middle Aged ; Organoplatinum Compounds/adverse effects ; Oxaliplatin

مستخلص: Background: Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients.
Patients and Methods: Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab. Patients were divided into two treatment arms according to KRAS mutational status and physician choice. A "3 + 3" design was used.
Results: Among 76 patients (median age 61 years; 34 women; median number of prior therapies 4), the most common cancer was colorectal (CRC) (n = 58). Overall, the only dose-limiting toxicity was Grade 3 diarrhea (n = 2). The most common treatment-related toxicities were hypertension (n = 40), nausea (n = 29), fatigue (n = 28), and transaminitis (n = 26). Of 76 patients, one (1 %) had a complete response (CR), 12 (16 %) had a partial response (PR), and 12 (16 %) had SD for ≥ 6 months (total CR/PR/SD ≥ 6 months 25/76 = 33 %). In CRC (n = 58), total CR/PR/SD ≥ 6 months was 31 % (n = 18). Both patients with pancreatic neuroendocrine tumors achieved a PR (24+ months) and a CR (6+ months). Time to treatment failure (TTF) on the current regimen was 3.5 versus 2.8 months on patients' prior systemic treatment (p = 0.37).
Conclusions: HAI oxaliplatin combination therapy with 5-fluorouracil, leucovorin, bevacizumab, and/or cetuximab was well tolerated and had antitumor activity in selected heavily pretreated patients with predominant liver disease.

المؤلفون: Subbiah IM; Department of Investigational Cancer Therapeutics. isubbiah@mdanderson.org, Subbiah V, Tsimberidou AM, Naing A, Kaseb AO, Javle M, Fu S, Hong DS, Piha-Paul S, Wheler JJ, Hess KR, Janku F, Falchook GS, Wolff RA, Kurzrock R

المصدر: Oncotarget [Oncotarget] 2013 Jan; Vol. 4 (1), pp. 156-65.

نوع المنشور: Clinical Trial, Phase I; Journal Article

بيانات الدورية: Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: Print Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: MEDLINE

مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Bile Duct Neoplasms/*drug therapy , Bile Ducts, Intrahepatic/*drug effects , Cholangiocarcinoma/*drug therapy , Gallbladder Neoplasms/*drug therapy, Adult ; Aged ; Analysis of Variance ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Arteriovenous Fistula/chemically induced ; Bile Duct Neoplasms/pathology ; Bile Ducts, Intrahepatic/pathology ; Cholangiocarcinoma/pathology ; Disease-Free Survival ; Female ; Gallbladder Neoplasms/pathology ; Gastrointestinal Hemorrhage/chemically induced ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Organoplatinum Compounds/administration & dosage ; Organoplatinum Compounds/adverse effects ; Oxaliplatin ; Treatment Outcome

مستخلص: Purpose: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. methods: Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies.
Results: Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, >3 metastatic sites, elevated alanine aminotransferase (ALT) (>56IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD >6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK.
Conclusions: The PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients.

المؤلفون: Tsimberidou AM; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. atsimber@mdanderson.org, Fu S, Subbiah IM, Naing A, Hong DS, Wen S, Fortier AH, Lim J, Kurzrock R

المصدر: Hepato-gastroenterology [Hepatogastroenterology] 2012 Jun; Vol. 59 (116), pp. 960-4.

نوع المنشور: Clinical Trial, Phase I; Journal Article

بيانات الدورية: Publisher: Thieme Country of Publication: Greece NLM ID: 8007849 Publication Model: Print Cited Medium: Print ISSN: 0172-6390 (Print) Linking ISSN: 01726390 NLM ISO Abbreviation: Hepatogastroenterology Subsets: MEDLINE

مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*administration & dosage , Peritoneal Neoplasms/*drug therapy, Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Bevacizumab ; Female ; Humans ; Infusions, Intravenous ; Injections, Intraperitoneal ; Male ; Middle Aged ; Organoplatinum Compounds/administration & dosage ; Organoplatinum Compounds/adverse effects ; Oxaliplatin ; Paclitaxel/administration & dosage ; Paclitaxel/adverse effects ; Peritoneal Neoplasms/mortality

مستخلص: Background/aims: We conducted a phase I trial of IP oxaliplatin and paclitaxel with IV paclitaxel and bevacizumab in patients with peritoneal carcinomatosis.
Methodology: Patients received IV bevacizumab (2.5mg/kg) over 1 hour (day 1), then IV paclitaxel (110 mg/m2) 24-hr-infusion (day 1) and IP oxaliplatin (25-40 mg/m2) (day 2), and IP paclitaxel (30-60 mg/m2) (day 8 from cycle 2 onwards). A '3+3' design was used.
Results: Nineteen patients were treated (median age 60 years; 10 women, 9 men; median number of prior therapies 3). Primary tumors were colorectal (n=9), signet ring carcinoma (n=2), gastric (n=2), ovarian (n=2) and others (n=4). The maximum tolerated doses (MTD) of IP oxaliplatin and IP paclitaxel were 25mg/m2 and 60 mg/ m2, respectively. Nine (47%) patients reported no toxicities >grade 2. Two patients receiving IP oxaliplatin 40 mg/m2 and IP paclitaxel 60 mg/m2 had dose limiting toxicities (DLT) of grade 3 diarrhea/dehydration and febrile neutropenia. Toxicities included abdominal pain (n=14), nausea (n=10) and constipation (n=7). Of 12 patients restaged at 2 months, 7 (58%) had stable disease (SD) including 2 (17%) who had SD for >4 months.
Conclusions: IP paclitaxel and IP oxaliplatin can be given safely at 60 mg/m2 and 25mg/m2, respectively.