46 results on '"Kirk S. Culotta"'
Search Results
2. Supplemental Figure 1 from An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
- Author
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Joseph A. Ludwig, James E. O'Dorisio, Kirk S. Culotta, Dannette K. Doolittle, Adrianna S. Buford, Rebecca L. Maywald, Ramani A. Aiyer, Vandhana Ramamoorthy, Brian A. Menegaz, and Salah-Eddine Lamhamedi-Cherradi
- Abstract
Supplemental Figure 1. Gene expression changes between sensitive and YK-resistant ES cell lines
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- 2023
3. Supplemental Figure 3 from An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
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Joseph A. Ludwig, James E. O'Dorisio, Kirk S. Culotta, Dannette K. Doolittle, Adrianna S. Buford, Rebecca L. Maywald, Ramani A. Aiyer, Vandhana Ramamoorthy, Brian A. Menegaz, and Salah-Eddine Lamhamedi-Cherradi
- Abstract
Supplemental Figure 3. The YK-resistant clone (TC71#3)displayed cross resistance to imatinib
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- 2023
4. Supplemental Materials and Methods from An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
- Author
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Joseph A. Ludwig, James E. O'Dorisio, Kirk S. Culotta, Dannette K. Doolittle, Adrianna S. Buford, Rebecca L. Maywald, Ramani A. Aiyer, Vandhana Ramamoorthy, Brian A. Menegaz, and Salah-Eddine Lamhamedi-Cherradi
- Abstract
Supplemental Materials and Methods. Gene expression profiling and analysis
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- 2023
5. Supplemental Figure 4 from An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
- Author
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Joseph A. Ludwig, James E. O'Dorisio, Kirk S. Culotta, Dannette K. Doolittle, Adrianna S. Buford, Rebecca L. Maywald, Ramani A. Aiyer, Vandhana Ramamoorthy, Brian A. Menegaz, and Salah-Eddine Lamhamedi-Cherradi
- Abstract
Supplemental Figure 4. Proteomic analysis of sensitive and resistant ES cell lines to YK-4-279
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- 2023
6. Supplemental Figure 2 from An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
- Author
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Joseph A. Ludwig, James E. O'Dorisio, Kirk S. Culotta, Dannette K. Doolittle, Adrianna S. Buford, Rebecca L. Maywald, Ramani A. Aiyer, Vandhana Ramamoorthy, Brian A. Menegaz, and Salah-Eddine Lamhamedi-Cherradi
- Abstract
Supplemental Figure 2. Nuclear, cytoplasmic and total RHA levels are identical between sensitive and YK-Resistant ES cell lines.
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- 2023
7. Perspective on this Article from Phase II Randomized, Placebo-Controlled Trial of Green Tea Extract in Patients with High-Risk Oral Premalignant Lesions
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Vassiliki Papadimitrakopoulou, Waun K. Hong, Yuko M. Sagesaka, Ann Gillenwater, Li Mao, Kirk S. Culotta, Ignacio Wistuba, Adel K. El-Naggar, J. Jack Lee, Xi-ming Tang, Jack Martin, Diane Liu, and Anne S. Tsao
- Abstract
Perspective on this Article from Phase II Randomized, Placebo-Controlled Trial of Green Tea Extract in Patients with High-Risk Oral Premalignant Lesions
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- 2023
8. Supplementary Materials and Methods from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
- Author
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Kevin B. Kim, Patrick Hwu, Roland L. Bassett, John J. Wright, Janet E. Dancey, Wenbin Liu, Sanjay Gupta, Chaan S. Ng, Wanleng Deng, Sha Huang, Quanyun Xu, Timothy L. Madden, Kirk S. Culotta, Victor G. Prieto, Alexander J. Lazar, Wen-Jen Hwu, Agop Y. Bedikian, Nicholas E. Papadopoulos, Patricia S. Fox, and Michael A. Davies
- Abstract
PDF file - 43K
- Published
- 2023
9. Supplementary Figure 1 from A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
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Marina Konopleva, Deborah Thomas, Linda J. Bendall, Jan Burger, Susan O'Brien, Elias Jabbour, Keith A. Baggerly, Wenbin Liu, Lianchun Xiao, Rebecca Garris, Mary Ann Richie, Hongbo Lu, Zhihong Zeng, Kirk S. Culotta, Jordan Basnett, Jitesh D. Kawedia, Michael E. Rytting, Jorge Cortes, Farhad Ravandi, Hagop Kantarjian, Yanis Boumber, and Naval Daver
- Abstract
Supplementary Figure 1.Baseline 4EBP1 and outcomes.
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- 2023
10. Supplementary Figure Legends 1-2 from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
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Kevin B. Kim, Patrick Hwu, Roland L. Bassett, John J. Wright, Janet E. Dancey, Wenbin Liu, Sanjay Gupta, Chaan S. Ng, Wanleng Deng, Sha Huang, Quanyun Xu, Timothy L. Madden, Kirk S. Culotta, Victor G. Prieto, Alexander J. Lazar, Wen-Jen Hwu, Agop Y. Bedikian, Nicholas E. Papadopoulos, Patricia S. Fox, and Michael A. Davies
- Abstract
PDF file - 85K
- Published
- 2023
11. Data from A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
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Marina Konopleva, Deborah Thomas, Linda J. Bendall, Jan Burger, Susan O'Brien, Elias Jabbour, Keith A. Baggerly, Wenbin Liu, Lianchun Xiao, Rebecca Garris, Mary Ann Richie, Hongbo Lu, Zhihong Zeng, Kirk S. Culotta, Jordan Basnett, Jitesh D. Kawedia, Michael E. Rytting, Jorge Cortes, Farhad Ravandi, Hagop Kantarjian, Yanis Boumber, and Naval Daver
- Abstract
Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD.Results: The median age of patients was 25 years (range, 11–64) and median number of prior treatments was 2 (range, 1–7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders.Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. Clin Cancer Res; 21(12); 2704–14. ©2015 AACR.
- Published
- 2023
12. Supplementary Figure 2 from A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
- Author
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Marina Konopleva, Deborah Thomas, Linda J. Bendall, Jan Burger, Susan O'Brien, Elias Jabbour, Keith A. Baggerly, Wenbin Liu, Lianchun Xiao, Rebecca Garris, Mary Ann Richie, Hongbo Lu, Zhihong Zeng, Kirk S. Culotta, Jordan Basnett, Jitesh D. Kawedia, Michael E. Rytting, Jorge Cortes, Farhad Ravandi, Hagop Kantarjian, Yanis Boumber, and Naval Daver
- Abstract
Supplementary Figure 2. OS and EFS by salvage status.
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- 2023
13. Supplementary Figure 2 from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
- Author
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Kevin B. Kim, Patrick Hwu, Roland L. Bassett, John J. Wright, Janet E. Dancey, Wenbin Liu, Sanjay Gupta, Chaan S. Ng, Wanleng Deng, Sha Huang, Quanyun Xu, Timothy L. Madden, Kirk S. Culotta, Victor G. Prieto, Alexander J. Lazar, Wen-Jen Hwu, Agop Y. Bedikian, Nicholas E. Papadopoulos, Patricia S. Fox, and Michael A. Davies
- Abstract
PDF file - 70K
- Published
- 2023
14. Data from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
- Author
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Kevin B. Kim, Patrick Hwu, Roland L. Bassett, John J. Wright, Janet E. Dancey, Wenbin Liu, Sanjay Gupta, Chaan S. Ng, Wanleng Deng, Sha Huang, Quanyun Xu, Timothy L. Madden, Kirk S. Culotta, Victor G. Prieto, Alexander J. Lazar, Wen-Jen Hwu, Agop Y. Bedikian, Nicholas E. Papadopoulos, Patricia S. Fox, and Michael A. Davies
- Abstract
Purpose: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.Patients and Methods: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.Results: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.Conclusions: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK. Clin Cancer Res; 18(4); 1120–8. ©2012 AACR.
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- 2023
15. Supplementary Figure 1 from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
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Kevin B. Kim, Patrick Hwu, Roland L. Bassett, John J. Wright, Janet E. Dancey, Wenbin Liu, Sanjay Gupta, Chaan S. Ng, Wanleng Deng, Sha Huang, Quanyun Xu, Timothy L. Madden, Kirk S. Culotta, Victor G. Prieto, Alexander J. Lazar, Wen-Jen Hwu, Agop Y. Bedikian, Nicholas E. Papadopoulos, Patricia S. Fox, and Michael A. Davies
- Abstract
PDF file - 126K
- Published
- 2023
16. Supplementary Table 2 from Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
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Kevin B. Kim, Patrick Hwu, Roland L. Bassett, John J. Wright, Janet E. Dancey, Wenbin Liu, Sanjay Gupta, Chaan S. Ng, Wanleng Deng, Sha Huang, Quanyun Xu, Timothy L. Madden, Kirk S. Culotta, Victor G. Prieto, Alexander J. Lazar, Wen-Jen Hwu, Agop Y. Bedikian, Nicholas E. Papadopoulos, Patricia S. Fox, and Michael A. Davies
- Abstract
PDF file - 70K
- Published
- 2023
17. Supplementary material and methods, Tables 1-3 from A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
- Author
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Marina Konopleva, Deborah Thomas, Linda J. Bendall, Jan Burger, Susan O'Brien, Elias Jabbour, Keith A. Baggerly, Wenbin Liu, Lianchun Xiao, Rebecca Garris, Mary Ann Richie, Hongbo Lu, Zhihong Zeng, Kirk S. Culotta, Jordan Basnett, Jitesh D. Kawedia, Michael E. Rytting, Jorge Cortes, Farhad Ravandi, Hagop Kantarjian, Yanis Boumber, and Naval Daver
- Abstract
Supplementary material and methods, Tables 1-3. Supplementary table 1. Changes in the expression of proteins and their phosphorylated forms with everolimus treatment analyzed by RPPA; Supplementary table 2. Results of binomial analysis showing direction of changes in the expression of proteins and their phosphorylated forms, analyzed by RPPA, for individual patients; Supplementary Table 3. Major everolimus pharmacokinetic parameters in cycles 1 and 2a.
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- 2023
18. Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases
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Fu Siqing, Yan Ping Zhang, Filip Janku, Razelle Kurzrock, Kirk S. Culotta, Ming Mo Hou, David S. Hong, Gerald S. Falchook, Aung Naing, and Alan L. Myers
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Paclitaxel ,Pharmacology toxicology ,Pharmacology ,Toxicology ,03 medical and health sciences ,0302 clinical medicine ,Hepatic arterial infusion ,Pharmacokinetics ,Albumin bound paclitaxel ,Albumins ,Hepatic extraction ,Humans ,Infusions, Intra-Arterial ,Medicine ,Pharmacology (medical) ,In patient ,Aged ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Liver Neoplasms ,Middle Aged ,Antineoplastic Agents, Phytogenic ,Treatment Outcome ,030104 developmental biology ,Oncology ,Area Under Curve ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Cancer patients with predominantly hepatic metastases have poor outcomes and limited options. Hepatic arterial infusion (HAI) of a therapeutic agent may be an appropriate option for producing increased drug concentrations at the tumor sites while reducing systemic adverse effects in normal tissues.Patients with predominantly hepatic metastases (n = 48) were placed in 6 groups according to nanoparticle albumin-bound paclitaxel (nab-paclitaxel) dose level using a 3 + 3 design plus dose expansion for responsive tumor types. We evaluated the toxicity, antitumor activity, and pharmacokinetics of nab-paclitaxel delivered via HAI.Thirty-eight and ten patients underwent HAI over 1 and 4 h, respectively, at doses of up to 300 mg/m(2). The treatment was safe and exhibited antitumor activity. Pharmacokinetic analyses revealed that HAI of nab-paclitaxel over 4 h resulted in markedly lower peak drug concentrations (C max) and longer times to peak concentration (T max) than that over 1 h. The self-control pharmacokinetic studies showed that HAI of nab-paclitaxel led to much lower C max and areas under the curve (AUC), compared with intravenous infusion.HAI of nab-paclitaxel at up to 300 mg/m(2) over 4 h was well tolerated. Pharmacokinetic evaluation of C max, T max, and AUC implied that 4-h HAI enhanced hepatic extraction of nab-paclitaxel. Further preclinical and clinical studies are required to develop reliable methods of evaluation of hepatic extraction (clinicaltrials.gov registration number NCT00732836, first registered on August 8, 2008, and last updated on October 27, 2014).
- Published
- 2015
19. Physical and chemical stability of proflavine contrast agent solutions for early detection of oral cancer
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Yan Ping Zhang, Alan L. Myers, Rebecca Richards-Kortum, Kirk S. Culotta, Jitesh D. Kawedia, Ann M. Gillenwater, and Mark A. Kramer
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Pathology ,medicine.medical_specialty ,Drug Storage ,Contrast Media ,Early detection ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Optical imaging ,Drug Stability ,Refrigeration ,medicine ,Pharmacology (medical) ,Ablative surgery ,030212 general & internal medicine ,Proflavine ,business.industry ,Sterile water ,Cancer ,PROFLAVINE HEMISULFATE ,medicine.disease ,Pharmaceutical Solutions ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Mouth Neoplasms ,Chemical stability ,business ,Biomedical engineering - Abstract
Background and purpose Proflavine hemisulfate solution is a fluorescence contrast agent to visualize cell nuclei using high-resolution optical imaging devices such as the high-resolution microendoscope. These devices provide real-time imaging to distinguish between normal versus neoplastic tissue. These images could be helpful for early screening of oral cancer and its precursors and to determine accurate margins of malignant tissue for ablative surgery. Extemporaneous preparation of proflavine solution for these diagnostic procedures requires preparation in batches and long-term storage to improve compounding efficiency in the pharmacy. However, there is a paucity of long-term stability data for proflavine contrast solutions. Methods The physical and chemical stability of 0.01% (10 mg/100 ml) proflavine hemisulfate solutions prepared in sterile water was determined following storage at refrigeration (4–8℃) and room temperature (23℃). Concentrations of proflavine were measured at predetermined time points up to 12 months using a validated stability-indicating high-performance liquid chromatography method. Results Proflavine solutions stored under refrigeration were physically and chemically stable for at least 12 months with concentrations ranging from 95% to 105% compared to initial concentration. However, in solutions stored at room temperature increased turbidity and particulates were observed in some of the tested vials at 9 months and 12 months with peak particle count reaching 17-fold increase compared to baseline. Solutions stored at room temperature were chemically stable up to six months (94–105%). Conclusion Proflavine solutions at concentration of 0.01% were chemically and physically stable for at least 12 months under refrigeration. The solution was chemically stable for six months when stored at room temperature. We recommend long-term storage of proflavine solutions under refrigeration prior to diagnostic procedure.
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- 2014
20. Dual inhibition of the vascular endothelial growth factor pathway: A phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors
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Gerald Steven Falchook, Luis H. Camacho, Goldy C. George, David S. Hong, Siqing Fu, Wen Liu, Kirk S. Culotta, Aung Naing, Kenna Lynn Anderes, Sarina Anne Piha-Paul, Jennifer J. Wheler, Susan Percy Ivy, Stacy Moulder, Suhendan Ekmekcioglu, Razelle Kurzrock, Yuejin Wen, Apostolia Maria Tsimberidou, Ignacio Garrido-Laguna, and Darren W. Davis
- Subjects
Cancer Research ,medicine.medical_specialty ,Bevacizumab ,business.industry ,Area under the curve ,Cancer ,medicine.disease ,Gastroenterology ,Inflammatory breast cancer ,Surgery ,Cediranib ,Vascular endothelial growth factor ,chemistry.chemical_compound ,Oncology ,Pharmacokinetics ,chemistry ,Tumor progression ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
BACKGROUND The current study was conducted to evaluate the safety and biological activity of dual inhibition of the vascular endothelial growth factor (VEGF) pathway with combined bevacizumab and cediranib (a VEGF receptor tyrosine kinase inhibitor). METHODS This was a 3 + 3 dose escalation study in patients with advanced solid tumors. Cediranib was given orally daily for 21 days and bevacizumab intravenously every 2 weeks. Pharmacokinetics and correlates (nitric oxide synthase, nitrate oxide, and circulating tumor cells) were assessed. RESULTS Fifty-one patients were treated. Dose-limiting toxicities (DLTs) (grade 3-4; graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events [version 3.0]) observed included 1 patient with chest pain, 1 patient with fatigue, 2 patients with thrombocytopenia, 3 patients with hypertension (1 with intracranial hemorrhage), and 1 patient with grade 5 hemoptysis. Moreover, 2 patients presented with grade 3 intracranial bleeding beyond the DLT window. Dose level 2 (cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks) was selected as the recommended phase 2 dose (RP2D); 17 patients were treated at dose level 2 with 1 DLT and no intracranial bleeding or severe hypertension reported. Pharmacokinetics of cediranib at dose level 3 demonstrated a 46% to 77% increase in area under the curve (0-24 hours) on cycle 1 day 1 compared with historical controls. Four patients attained partial remissions: inflammatory breast cancer (-54%), basal cell carcinoma (-33%), alveolar soft part sarcoma (-33%), and synovial sarcoma (-32%). Patients with a lower circulating tumor cell count (
- Published
- 2014
21. Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma
- Author
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Wen-Jen Hwu, Timothy L. Madden, Roland L. Bassett, Sanjay Gupta, Patrick Hwu, Michael A. Davies, Victor G. Prieto, Wenbin Liu, John J. Wright, Kirk S. Culotta, Nicholas E. Papadopoulos, Chaan S. Ng, Kevin B. Kim, Patricia S. Fox, Wanleng Deng, Sha Huang, Agop Y. Bedikian, Janet Dancey, Quanyun Xu, and Alexander J. Lazar
- Subjects
Adult ,Male ,Niacinamide ,Proto-Oncogene Proteins B-raf ,Sorafenib ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,Pyridines ,Phases of clinical research ,Article ,Young Adult ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm Metastasis ,Melanoma ,Aged ,Neoplasm Staging ,Sirolimus ,business.industry ,Phenylurea Compounds ,Benzenesulfonates ,Cancer ,Middle Aged ,medicine.disease ,Survival Analysis ,Temsirolimus ,Surgery ,Treatment Outcome ,Response Evaluation Criteria in Solid Tumors ,Mutation ,Toxicity ,Female ,business ,medicine.drug - Abstract
Purpose: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma. Patients and Methods: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins. Results: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK. Conclusions: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK. Clin Cancer Res; 18(4); 1120–8. ©2012 AACR.
- Published
- 2012
22. Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma
- Author
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Heather D, Brooks, Bonnie S, Glisson, B Nebiyou, Bekele, Faye M, Johnson, Lawrence E, Ginsberg, Adel, El-Naggar, Kirk S, Culotta, Naoko, Takebe, John, Wright, Hai T, Tran, and Vassiliki A, Papadimitrakopoulou
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Dasatinib ,Phases of clinical research ,Antineoplastic Agents ,Disease-Free Survival ,Article ,Internal medicine ,medicine ,Carcinoma ,Humans ,Neoplasm Metastasis ,Child ,Protein Kinase Inhibitors ,business.industry ,Head and neck cancer ,Cancer ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,Surgery ,Thiazoles ,Pyrimidines ,Tolerability ,Head and Neck Neoplasms ,Toxicity ,Carcinoma, Squamous Cell ,Cytokines ,Female ,business ,medicine.drug - Abstract
BACKGROUND: Treatment options for patients with advanced head and neck squamous cell carcinoma (HNSCC) are scarce. This phase 2 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and efficacy of dasatinib in this setting. METHODS: Patients with recurrent and/or metastatic HNSCC after platinum-based therapy were treated with dasatinib either orally or via percutaneous feeding gastrostomy (PFG). Primary endpoints were 12-week progression-free survival (PFS) and objective response rate with a 2-stage design and early withdrawal if the 12-week PFS rate was ≤20% and no patients had an objective response (OR). Forty-nine serum cytokines and angiogenic factors (CAFs) were analyzed from treated patients. RESULTS: Of the 15 patients enrolled, 12 were evaluable for response, and all patients were evaluable for toxicity. No OR was observed and 2 patients (16.7%) had stable disease (SD) at 8 weeks. The median treatment duration was 59 days, the median time to disease progression was 3.9 weeks, and the median survival was 26 weeks. One patient required a dose reduction, 3 patients required dose interruptions, and 4 patients were hospitalized for toxicity. Dasatinib inhibited c-Src both when administered orally and via PFG. Greater mean drug exposure, decreased half-life, and greater maximum concentration were observed in patients receiving dasatinib via PFG. Eleven baseline CAFs were associated with treatment outcome and 1 CAF, macrophage migration inhibitory factor, was found to be differentially modulated in correlation with SD versus disease progression. CONCLUSIONS: Single-agent dasatinib failed to demonstrate significant activity in patients with advanced HNSCC, despite c-Src inhibition. The toxicity profile was consistent with that reported in other solid tumors, and the drug can be given via PFG tube. Cancer 2011. © 2010 American Cancer Society.
- Published
- 2010
23. A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
- Author
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Jitesh D. Kawedia, Mary Ann Richie, Zhihong Zeng, Jordan Basnett, Marina Konopleva, Farhad Ravandi, Linda J. Bendall, Elias Jabbour, Michael Rytting, Yanis Boumber, Deborah A. Thomas, Naval Daver, Kirk S. Culotta, Wenbin Liu, Susan O'Brien, Rebecca Garris, Hagop M. Kantarjian, Jorge E. Cortes, Keith A. Baggerly, Hongbo Lu, Lianchun Xiao, and Jan A. Burger
- Subjects
Male ,Cancer Research ,Neoplasm, Residual ,medicine.medical_treatment ,Gastroenterology ,Dexamethasone ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Child ,Cancer ,Pediatric ,TOR Serine-Threonine Kinases ,Area under the curve ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Treatment Outcome ,Oncology ,Vincristine ,Residual ,6.1 Pharmaceuticals ,Female ,Drug Monitoring ,medicine.drug ,Signal Transduction ,Adult ,medicine.medical_specialty ,Cyclophosphamide ,Adolescent ,Childhood Leukemia ,Pediatric Cancer ,Oncology and Carcinogenesis ,Article ,Young Adult ,Rare Diseases ,Refractory ,Clinical Research ,Internal medicine ,Mucositis ,Humans ,Oncology & Carcinogenesis ,Protein Kinase Inhibitors ,Chemotherapy ,Everolimus ,business.industry ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Survival Analysis ,Surgery ,Doxorubicin ,Neoplasm ,business ,Biomarkers - Abstract
Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. Results: The median age of patients was 25 years (range, 11–64) and median number of prior treatments was 2 (range, 1–7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. Clin Cancer Res; 21(12); 2704–14. ©2015 AACR.
- Published
- 2015
24. l-Arginine modulates CD3ζ expression and T cell function in activated human T lymphocytes
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Augusto C. Ochoa, Joanna DeSalvo, Hae-Joon Park, Juan B. Ochoa, Jovanny Zabaleta, Claudia Hernandez, Arnold H. Zea, Paulo C. Rodriguez, and Kirk S. Culotta
- Subjects
CD3 Complex ,T-Lymphocytes ,media_common.quotation_subject ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,Apoptosis ,Biology ,Arginine ,Lymphocyte Activation ,medicine ,Humans ,Cytotoxic T cell ,RNA, Messenger ,IL-2 receptor ,Phosphorylation ,Internalization ,Antigen-presenting cell ,Cells, Cultured ,Cell Proliferation ,media_common ,T-cell receptor ,CD28 ,Natural killer T cell ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Cytokines ,Tyrosine ,Calcium - Abstract
Engagement of the T cell receptor (TCR) by antigen or anti-CD3 antibody results in a cycle of internalization and re-expression of the CD3zeta. Following internalization, CD3zeta is degraded and replaced by newly synthesized CD3zeta on the cell surface. Here, we provide evidence that availability of the amino acid L-arginine modulates the cycle of internalization and re-expression of CD3zeta and cause T cell dysfunction. T cells stimulated and cultured in presence of L-arginine, undergo the normal cycle of internalization and re-expression of CD3zeta. In contrast, T cells stimulated and cultured in absence of L-arginine, present a sustained down-regulation of CD3zeta preventing the normal expression of the TCR, exhibit a decreased proliferation, and a significantly diminished production of IFNgamma, IL5, and IL10, but not IL2. The replenishment of L-arginine recovers the expression of CD3zeta. The decreased expression of CD3zeta is not caused by a decreased CD3zeta mRNA, an increased CD3zeta degradation or T cell apoptosis.
- Published
- 2004
25. <scp>l</scp>-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes
- Author
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Joanna DeSalvo, David G. Quiceno, Jovanny Zabaleta, Augusto C. Ochoa, Kirk S. Culotta, Arnold H. Zea, Juan B. Ochoa, and Paulo C. Rodriguez
- Subjects
CD3 Complex ,T-Lymphocytes ,T cell ,Immunology ,Down-Regulation ,Arginine ,Jurkat cells ,Nitric oxide ,Jurkat Cells ,Mice ,chemistry.chemical_compound ,Extracellular ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Cationic Amino Acid Transporter 2 ,Cells, Cultured ,Interleukin-13 ,Arginase ,biology ,Cell growth ,Macrophage Activation ,Coculture Techniques ,Up-Regulation ,Cell biology ,Mice, Inbred C57BL ,Nitric oxide synthase ,medicine.anatomical_structure ,chemistry ,Macrophages, Peritoneal ,biology.protein ,Female ,Interleukin-4 ,Extracellular Space ,Cell Division - Abstract
l-Arginine plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by inducible nitric oxide synthase to produce nitric oxide, important in the cytotoxic mechanisms, and by arginase I (ASE I) and arginase II (ASE II) to synthesize l-ornithine and urea, the first being the precursor for the production of polyamines needed for cell proliferation. l-Arginine availability can modulate T cell function. Human T cells stimulated and cultured in the absence of l-arginine lose the expression of the TCR ζ-chain (CD3ζ) and have an impaired proliferation and a decreased cytokine production. The aim of this work was to test whether activated macrophages could modulate extracellular levels of l-arginine and alter T cell function, and to determine which metabolic pathway was responsible for this event. The results show that macrophages stimulated with IL-4 + IL-13 up-regulate ASE I and cationic amino acid transporter 2B, causing a rapid reduction of extracellular levels of l-arginine and inducing decreased expression of CD3ζ and diminished proliferation in normal T lymphocytes. Competitive inhibitors of ASE I or the addition of excess l-arginine lead to the re-expression of CD3ζ and recovery of T cell proliferation. In contrast, inducible nitric oxide synthase or ASE II failed to significantly reduce the extracellular levels of l-arginine and modulate CD3ζ expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regulation of CD3ζ in cancer and chronic infectious diseases.
- Published
- 2003
26. Regulation of T Cell Receptor CD3ζ Chain Expression byl-Arginine
- Author
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Augusto C. Ochoa, Paulo C. Rodriguez, Arnold H. Zea, Juan B. Ochoa, Jovanny Zabaleta, and Kirk S. Culotta
- Subjects
DNA, Complementary ,Time Factors ,CD3 Complex ,Transcription, Genetic ,T cell ,Receptors, Antigen, T-Cell ,Down-Regulation ,Apoptosis ,Biology ,Arginine ,Transfection ,Biochemistry ,Jurkat cells ,Jurkat Cells ,medicine ,Animals ,Humans ,Cytotoxic T cell ,RNA, Messenger ,IL-2 receptor ,Cycloheximide ,Receptor ,Molecular Biology ,Cell Nucleus ,Protein Synthesis Inhibitors ,Macrophages ,T-cell receptor ,CD28 ,Cell Biology ,Blotting, Northern ,Flow Cytometry ,Molecular biology ,medicine.anatomical_structure ,COS Cells ,Dactinomycin ,Hepatocytes ,Signal transduction - Abstract
L-Arg plays a central role in the normal function of several organ systems including the immune system. L-Arg can be depleted by arginase I produced by macrophages and hepatocytes in several disease states such as trauma and sepsis and following liver transplantation. The decrease in L-Arg levels induces a profound decrease in T cell function through mechanisms that have remained unclear. The data presented here demonstrate that Jurkat T cells cultured in medium without L-Arg (L-Arg-free RPMI) have a rapid decrease in the expression of the T cell antigen receptor zeta chain (CD3zeta), the principal signal transduction element in this receptor, and a decrease in T cell proliferation. This phenomenon is completely reversed by the replenishment of L-Arg but not other amino acids. These changes are not caused by cell apoptosis; instead, the diminished expression of CD3zeta protein is paralleled by a decrease in CD3zeta mRNA. This change in CD3zeta mRNA expression is not caused by a decrease in the transcription rate but rather by a significantly shorter CD3zeta mRNA half-life. This mechanism is sensitive to cycloheximide. Therefore, the regulation of L-Arg concentration in the microenvironment could represent an important mechanism to modulate the expression of CD3zeta and the T cell receptor and consequently of T cell function.
- Published
- 2002
27. An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma
- Author
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Vandhana Ramamoorthy, Kirk S. Culotta, Ramani Aiyer, Rebecca L. Maywald, Joseph A. Ludwig, Adrianna S. Buford, Dannette K. Doolittle, Brian A. Menegaz, James E. O'dorisio, and Salah Eddine Lamhamedi-Cherradi
- Subjects
Male ,Proteomics ,Cancer Research ,Indoles ,Cell Survival ,Blotting, Western ,Administration, Oral ,Drug resistance ,Mice, SCID ,Sarcoma, Ewing ,Pharmacology ,chemistry.chemical_compound ,Cyclin D1 ,Enzastaurin ,Mice, Inbred NOD ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Tissue Distribution ,Transcription factor ,Cell Proliferation ,Mice, Knockout ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Imatinib ,medicine.disease ,Fusion protein ,Survival Analysis ,Xenograft Model Antitumor Assays ,Tumor Burden ,Treatment Outcome ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,FLI1 ,Area Under Curve ,Sarcoma ,business ,medicine.drug ,Interleukin Receptor Common gamma Subunit - Abstract
Ewing sarcoma is a transcription factor–mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279–mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. Mol Cancer Ther; 14(7); 1591–604. ©2015 AACR.
- Published
- 2014
28. Dual inhibition of the vascular endothelial growth factor pathway: a phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors
- Author
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David S, Hong, Ignacio, Garrido-Laguna, Suhendan, Ekmekcioglu, Gerald S, Falchook, Aung, Naing, Jennifer J, Wheler, Siqing, Fu, Stacy L, Moulder, Sarina, Piha-Paul, Apostolia M, Tsimberidou, YueJin, Wen, Kirk S, Culotta, Kenna, Anderes, Darren W, Davis, Wen, Liu, Goldy C, George, Luis H, Camacho, Susan, Percy Ivy, and Razelle, Kurzrock
- Subjects
Adult ,Male ,Vascular Endothelial Growth Factor A ,Sarcoma ,Kaplan-Meier Estimate ,Middle Aged ,Antibodies, Monoclonal, Humanized ,Neoplastic Cells, Circulating ,Drug Administration Schedule ,Bevacizumab ,Treatment Outcome ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Hypertension ,Quinazolines ,Humans ,Female ,Aged ,Cerebral Hemorrhage ,Signal Transduction - Abstract
The current study was conducted to evaluate the safety and biological activity of dual inhibition of the vascular endothelial growth factor (VEGF) pathway with combined bevacizumab and cediranib (a VEGF receptor tyrosine kinase inhibitor).This was a 3 + 3 dose escalation study in patients with advanced solid tumors. Cediranib was given orally daily for 21 days and bevacizumab intravenously every 2 weeks. Pharmacokinetics and correlates (nitric oxide synthase, nitrate oxide, and circulating tumor cells) were assessed.Fifty-one patients were treated. Dose-limiting toxicities (DLTs) (grade 3-4; graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events [version 3.0]) observed included 1 patient with chest pain, 1 patient with fatigue, 2 patients with thrombocytopenia, 3 patients with hypertension (1 with intracranial hemorrhage), and 1 patient with grade 5 hemoptysis. Moreover, 2 patients presented with grade 3 intracranial bleeding beyond the DLT window. Dose level 2 (cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks) was selected as the recommended phase 2 dose (RP2D); 17 patients were treated at dose level 2 with 1 DLT and no intracranial bleeding or severe hypertension reported. Pharmacokinetics of cediranib at dose level 3 demonstrated a 46% to 77% increase in area under the curve (0-24 hours) on cycle 1 day 1 compared with historical controls. Four patients attained partial remissions: inflammatory breast cancer (-54%), basal cell carcinoma (-33%), alveolar soft part sarcoma (-33%), and synovial sarcoma (-32%). Patients with a lower circulating tumor cell count (30) at the predose period had a longer time to tumor progression (P = .024, log-rank test).Cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks was found to be the RP2D. Activity in several tumor types was noted. Central nervous system bleeding and severe hypertension were observed at doses above the RP2D.
- Published
- 2013
29. Physical and chemical stability of high-dose ifosfamide and mesna for prolonged 14-day continuous infusion
- Author
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Kirk S. Culotta, Alan L. Myers, Jitesh D. Kawedia, Yanping Zhang, Peter M. Anderson, Chelsey M McIntyre, and Mark A. Kramer
- Subjects
Chemical Phenomena ,medicine.medical_treatment ,Sodium ,Drug Storage ,chemistry.chemical_element ,Pharmacology ,High-performance liquid chromatography ,Drug Stability ,Outpatients ,medicine ,Humans ,Pharmacology (medical) ,Ifosfamide ,Infusions, Intravenous ,Saline ,Mesna ,Chemotherapy ,Chromatography ,business.industry ,Drug Combinations ,Pharmaceutical Solutions ,Oncology ,chemistry ,Toxicity ,Chemical stability ,business ,medicine.drug - Abstract
Purpose Ifosfamide plus mesna have been used recently in a high-dose regimen that allows this chemotherapy to be given to outpatients with less toxicity over 14 days using a portable pump. However, there is a need for published stability information. The aim of this study was to investigate the physicochemical stability of ifosfamide with mesna in normal saline at room temperature over a prolonged period of 14 days. Methods Infusion solutions of 1:1 ifosfamide and mesna at final concentrations of 10, 20 and 30 mg/mL were prepared with 0.9% sodium chloride in PVC bags. Solutions were stored at room temperature. Concentrations of ifosfamide and mesna were measured at 0 and 1, 3, 7 and 14 days using a stability-indicating reversed phase high-performance liquid chromatography (HPLC) assay with ultraviolet detection. Results Ifosfamide and mesna were both physicochemically stable (>94%) for 14 days in all tested infusion solutions (10, 20 and 30 mg/mL). Conclusions Our stability data indicate that ifosfamide and mesna (1:1) combination can be administered as a prolonged continuous infusion with portable pump in an outpatient setting without replacement of the infusion bag. We suggest 20 mg/mL as a reasonable concentration for infusion rates of about 2-4 cc/hr over prolonged periods of time.
- Published
- 2013
30. Erratum to: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases
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Siqing Fu, Kirk S. Culotta, Gerald S. Falchook, David S. Hong, Alan L. Myers, Yan-Ping Zhang, Aung Naing, Filip Janku, Ming-Mo Hou, and Razelle Kurzrock
- Subjects
Pharmacology ,Cancer Research ,Oncology ,Pharmacology (medical) ,Toxicology - Published
- 2016
31. Busulfan and metronidazole: an often forgotten but significant drug interaction
- Author
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Roy B. Jones, Kirk S. Culotta, Borje S. Andersson, and Alison M. Gulbis
- Subjects
Male ,Transplantation Conditioning ,Metabolic Clearance Rate ,ThioTEPA ,Pharmacology ,Therapeutic index ,Metronidazole ,medicine ,Clofarabine ,Humans ,Pharmacology (medical) ,Drug Interactions ,Child ,Antineoplastic Agents, Alkylating ,Busulfan ,Enterocolitis, Pseudomembranous ,medicine.diagnostic_test ,business.industry ,Clostridioides difficile ,Area under the curve ,Drug interaction ,Myeloablative Agonists ,Anti-Bacterial Agents ,Leukemia, Myeloid, Acute ,Therapeutic drug monitoring ,Drug Monitoring ,business ,medicine.drug ,Half-Life - Abstract
Objective: To report the case of a clinically significant drug interaction between intravenous busulfan and oral metronidazole observed through busulfan therapeutic drug monitoring (TDM). Case Summary: A 7-year-old boy with a history of myelodysplasia that progressed to acute myeloid leukemia received busulfan with therapeutic drug monitoring (TDM), clofarabine, and thiotepa as a pretransplant conditioning regimen for a cord blood transplant. The patient received metronidazole the day after a busulfan test dose of 0.5 mg/kg was administered. On the day of the first busulfan therapeutic dose, TDM was performed and the clearance of busulfan was significantly decreased by 46%. After 2 doses of busulfan therapy, the course area under the curve was exceeded, requiring discontinuation of busulfan. Metronidazole is not known to affect glutathione or the glutathione S-transferase AI (GSTA1) enzyme system or cytochrome P450 (CYP) 3A4. Discussion: Busulfan is a bifunctional alkylating agent widely used in pretransplant conditioning regimens in patients undergoing stem cell transplantation for hematologic malignancies. Busulfan metabolism is best described by hepatic conjugation to glutathione by GSTA1, although some CYP-dependent pathways have been described. Currently there is 1 publication describing the drug interaction between oral busulfan and oral metronidazole, in which concomitant use of metronidazole resulted in higher busulfan trough concentrations and higher risk of veno-occlusive disease. Our case represents a possible drug interaction based on the Horn Drug Interaction Probability Scale. Conclusions: Though the mechanistic basis for this interaction is unknown, the risks and benefits of using metronidazole during and in close proximity to busulfan should be carefully considered and therapeutic alternatives to metronidazole should be used when appropriate.
- Published
- 2011
32. Phase I trial of hepatic arterial infusion of nanoparticle albumin-bound paclitaxel: toxicity, pharmacokinetics, and activity
- Author
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Kirk S. Culotta, Chaan S. Ng, Razelle Kurzrock, Siqing Fu, Gerald S. Falchook, Aung Naing, Timothy Madden, David S. Hong, Stacy L. Moulder, and David C. Madoff
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,Nausea ,Antineoplastic Agents ,Pharmacology ,Gastroenterology ,Hepatic arterial infusion ,Pharmacokinetics ,Internal medicine ,Albumins ,Medicine ,Humans ,Infusions, Intra-Arterial ,Adverse effect ,Aged ,business.industry ,Liver Neoplasms ,Area under the curve ,Cancer ,Middle Aged ,medicine.disease ,Radiography ,Treatment Outcome ,Oncology ,Toxicity ,Vomiting ,Female ,medicine.symptom ,business - Abstract
Because liver involvement in patients with metastatic cancer has limited options and poor outcomes, we conducted a phase I study to determine the safety, activity, and pharmacokinetic characteristics of hepatic arterial infusion of nanoparticle albumin–bound paclitaxel (HAI nab-paclitaxel). Cohorts of three patients having predominant hepatic metastases received HAI nab-paclitaxel at three dose levels (180, 220, and 260 mg/m2, respectively) infused for more than 1 hour every 3 weeks (3 + 3 design). Some patients participated in comparative pharmacokinetic studies (i.v. vs. HAI), receiving their first course i.v., to determine peak concentrations and effect of first-pass hepatic extraction compared with subsequent courses administered by HAI. The highest dose level was expanded to determine the safety and activity of HAI nab-paclitaxel. Thirty-eight patients were treated. There were no dose-limiting toxicities at doses up to 260 mg/m2. Common adverse events included alopecia, fatigue, myelosuppresion, nausea, and vomiting. Three patients had stable disease for 4 or more months and 2 patients (1 of 12 with breast cancer and 1 of 1 with cervical cancer) achieved a partial response lasting for 5 and 15 months, respectively. Peak concentrations were lower (∼50%) with greater hepatic extraction of drug (∼42%) following HAI than i.v. infusion based on area under the curve comparison of drug exposure. HAI nab-paclitaxel showed partial hepatic extraction. At doses 260 mg/m2 or less given for 1 hour every 3 weeks, the treatment was well-tolerated and showed activity in advanced cancer patients with predominant liver metastases. Mol Cancer Ther; 10(7); 1300–7. ©2011 AACR.
- Published
- 2011
33. T cell CD3 receptor zeta (TCRzeta)-chain expression in children with idiopathic nephrotic syndrome
- Author
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Kirk S. Culotta, Arnold H. Zea, Augusto C. Ochoa, Diego Aviles, Matti V. Vehaskari, and Jennifer Manning
- Subjects
Male ,medicine.medical_specialty ,Nephrotic Syndrome ,Lymphocyte ,T cell ,CD3 ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Gene Expression ,Enzyme-Linked Immunosorbent Assay ,Polymerase Chain Reaction ,Recurrence ,Internal medicine ,Medicine ,Humans ,RNA, Messenger ,Receptor ,Child ,biology ,business.industry ,T-cell receptor ,Remission Induction ,Interleukin ,medicine.disease ,Flow Cytometry ,medicine.anatomical_structure ,Endocrinology ,Nephrology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,Leukocytes, Mononuclear ,Female ,Signal transduction ,business ,Nephrotic syndrome ,Signal Transduction - Abstract
Children with idiopathic nephrotic syndrome (INS) have an increased risk of developing life-threatening infections. Several studies have demonstrated functional abnormalities in the T lymphocytes of patients with nephrotic syndrome. Although T cells are activated in INS during relapse, as indicated by an increased expression of interleukin (IL)-2 receptor, these cells have a decreased ability to proliferate. The T-cell receptor (TCR) plays an important role in signal transduction and T cell activation, with the TCR-zeta (TCRzeta) chain being a key element in early signaling. We measured the expression of the TCRzeta chain in patients with INS (steroid resistant and steroid sensitive) during relapse and remission by flow cytometry and by PCR ELISA. The results showed a significant decrease in the expression of the TCRzeta chain at both the protein and mRNA level in INS patients during relapse as compared with normal controls (p0.05). In contrast, when patients with INS achieved remission, the expression of TCRzeta normalized and was similar to that expressed in normal controls. Therefore, a decreased expression of the TCRzeta chain may explain the abnormal function of T cells in patients with INS, and it may also contribute to the increased risk for infections seen in these patients.
- Published
- 2008
34. Decreased expression of CD3zeta and nuclear transcription factor kappa B in patients with pulmonary tuberculosis: potential mechanisms and reversibility with treatment
- Author
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Hae-Joon Park, Jovanny Zabaleta, Luis F. García, Carol M. Mason, Arnold H. Zea, Augusto C. Ochoa, Kirk S. Culotta, and Juzar Ali
- Subjects
Adult ,Male ,Cellular immunity ,CD3 Complex ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Statistics as Topic ,Gene Expression ,Electrophoretic Mobility Shift Assay ,Mycobacterium tuberculosis ,Immune system ,medicine ,Immunology and Allergy ,Humans ,Hypersensitivity, Delayed ,RNA, Messenger ,Antigen-presenting cell ,Tuberculosis, Pulmonary ,Aged ,biology ,Arginase ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Tuberculin Test ,NF-kappa B ,Middle Aged ,biology.organism_classification ,Flow Cytometry ,Interleukin 10 ,Infectious Diseases ,Cytokine ,medicine.anatomical_structure ,Delayed hypersensitivity ,Immunology ,Leukocytes, Mononuclear ,Cytokines ,Female ,business - Abstract
BACKGROUND The protective immune response against Mycobacterium tuberculosis relies both on antigen-presenting cells and on T lymphocytes. In patients with different forms of tuberculosis, varying degrees of T cell function--ranging from positive delayed-type hypersensitivity, in asymptomatic infected healthy individuals, to the absence of the response, in patients with miliary or pulmonary tuberculosis (PTB)--have been reported. The decreased expression of CD3zeta reported in T cells from patients with either cancer or leprosy has provided possible explanations for the altered immune response observed in these diseases. METHODS The present study aimed to compare the expression of CD3zeta , nuclear transcription factor- kappa B (NF- kappa B), arginase activity, and cytokine production in 20 patients with PTB, in 20 tuberculin-positive asymptomatic subjects, and in 14 tuberculin-negative control subjects. RESULTS Compared with those in tuberculin (purified protein derivative)-negative control subjects, peripheral-blood T lymphocytes from patients with active PTB had significantly (P < .001) decreased expression of CD3zeta and absence of the p65/p50 heterodimer of NF- kappa B. These alterations were reversed only in patients who responded to treatment. Also reported here for the first time is that the presence of arginase activity in peripheral-blood mononuclear-cell lysates of patients with PTB parallels high production of interleukin-10. CONCLUSIONS The presence of arginase could, in part, explain the decreased expression of CD3zeta . These findings provide a novel mechanism that may explain the T cell dysfunction observed in patients with PTB.
- Published
- 2006
35. Abstract CT201: Phase I study of 5-azacytidine and oxaliplatin in patients with advanced cancers relapsed or refractory to platinum compounds
- Author
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Jean Pierre J. Issa, Gerald S. Falchook, Guangan He, Siqing Fu, Yang Ye, Ignacio I. Wistuba, Rabih Said, Aung Naing, Sarina Anne Piha-Paul, Kenneth R. Hess, Apostolia Maria Tsimberidou, Ralph Zinner, Woonbok Chung, Kirk S. Culotta, Jaroslav Jelinek, Zahid H. Siddik, David J. Stewart, Razelle Kurzrock, and Jaime Rodriguez-Canales
- Subjects
Cisplatin ,Cancer Research ,medicine.medical_specialty ,Anemia ,business.industry ,Cancer ,medicine.disease ,Gastroenterology ,Carboplatin ,Oxaliplatin ,Surgery ,chemistry.chemical_compound ,Oncology ,chemistry ,Hypomethylating agent ,Refractory ,Internal medicine ,medicine ,Adverse effect ,business ,medicine.drug - Abstract
Purpose: To explore whether the hypomethylating agent 5-azacytidine (5-aza) restores platinum sensitivity. Experimental Design: Patients with advanced cancer relapsed/refractory to platinum compounds were treated with 5-aza 20-50 mg/m2/d IV (D 1-5) and oxaliplatin 15-30 mg/m2/d IV (D 2-5) (“3+3” design escalation phase followed by expansion phase; NCT01039155). PK studies were performed. Global DNA and gene-specific methylation changes (baseline to D12) in blood and tissue, tissue platinum level, and CTR1 (copper transporter involved in platinum uptake) expression were assessed (expansion phase). Results: Overall, 37 patients were treated (median age, 59 yrs; men, 49%; prior: oxaliplatin, 68%; carboplatin, 30%; cisplatin, 16%) (escalation, n=21; expansion, n=16). No DLT was noted at the maximum dose level tested (5-aza, 50 mg/m2/d; oxaliplatin 30 mg/m2/d; used in expansion phase). The most common adverse events were anemia (49% of pts.) and fatigue (32%). LINE-1 was measured (surrogate for global DNA methylation) in pre- and post-treatment blood samples (9 patients) and in tumor samples (7 patients). All blood samples showed reduction in global DNA methylation (baseline to D12) (median, -22%; range, [-32%, -12%], p The mean cytoplasmic CTR1 score was 217.5 and 177.5 on D1 and D12, respectively (mean difference, -40; 95% CI: -69.1,-10.9; p=.02). The respective mean nuclear CTR1 score was 67.5 and 42.5 (mean difference, -25; 95% CI: -55.5,+5.5; p=.08). Oxaliplatin (D2) and 5-aza (D1 and 5) mean systemic exposure based on plasma AUCall resulted in a dose-dependent trend (oxaliplatin 15 to 30 mg/m2, 704.3 to 1149.0 hr·ng/mL; 5-aza 20 to 50 mg/m2, 112.5 to 404.5 [D1] and 143.7 to 426.5 hr·ng/mL [D5]). When the same dose of oxaliplatin was used with increasing doses of 5-aza from 25-50 mg/m2, a reduction in mean oxaliplatin exposure was noted (AUCinf: 1919.4 to 1455.9 hr·ng/mL). No significant differences in other non-compartmental modeled parameters estimated were observed. The total tumor oxaliplatin level was measured in 7 patients. The pre-dose levels ranged from Conclusion: 5-aza combined with oxaliplatin was safe. Hypomethylation was inconsistent in tumor tissue, the CTR1 score decreased and the tumor oxaliplatin level increased. Citation Format: Apostolia M. Tsimberidou, Kirk Culotta, Ignacio Wistuba, Siqing Fu, Aung Naing, Gerald Falchook, Sarina Piha-Paul, Ralph Zinner, Jaime Rodriguez-Canales, Guangan He, Zahid H. Siddik, Jaroslav Jelinek, Woonbok Chung, Yang Ye, Rabih Said, Kenneth Hess, David J. Stewart, Razelle Kurzrock, Jean-Pierre Issa. Phase I study of 5-azacytidine and oxaliplatin in patients with advanced cancers relapsed or refractory to platinum compounds. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT201. doi:10.1158/1538-7445.AM2014-CT201
- Published
- 2014
36. A phase I study of the anti-IGF-1R monoclonal antibody (MoAb), IMC-A12 (I), and everolimus (E) in well-differentiated neuroendocrine tumors (WD NET)
- Author
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Sanjay Gupta, James C. Yao, Alexandria T. Phan, Funda Meric-Bernstam, Arvind Dasari, Kirk S. Culotta, Ishwaria Mohan Subbiah, Kenneth R. Hess, Daniel M. Halperin, Asif Rashid, Sai Ching J. Yeung, Helen X. Chen, and Mei Dong
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Everolimus ,medicine.drug_class ,business.industry ,Neuroendocrine tumors ,Insulin-Like Growth Factor Receptor ,medicine.disease ,Monoclonal antibody ,Phase i study ,Endocrinology ,Pharmacokinetics ,Pharmacodynamics ,Internal medicine ,medicine ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
232 Background: Octreotide LAR (LAR) and E have well known anti-cancer effects in WD NETs. Preclinical data also show that inhibition of the insulin like growth factor receptor (IGF-1R) may sensitize NETs to mTOR inhibitors such as E. Methods: Patients (pts) with WD NETs, ECOG performance status ≤ 2 and adequate organ function were treated with LAR 20 mg IM q 21days (d), E 10 mg po daily and escalating doses of I iv q 21 d in 21 d cycles in cohorts of 6 until maximum tolerated dose (MTD). Recommended phase II dose (RP2D) was defined as dose level below MTD. An expansion cohort of 9 pts was planned at RP2D. Plasma samples for everolimus pharmacokinetics (PK), IGF, mTOR pathway pharmacodynamics (PD) in addition to paired tissue biopsies were obtained. Results: 19 pts with previously treated (median prior systemic therapy, 1, range 0-3) WDNET (4 pancreatic NET, 11 carcinoid, 4 unknown primary) were enrolled in this single institution study. Ten pts in dose escalation and 9 in expansion phases received a median of 8.5 cycles (range, 3-19+). Dose limiting toxicities (DLTs) were grade (g) 3 mucositis in 2 pts at 2nddose level of I 15 mg/m2 q 21 d. Most frequent adverse events (AEs) observed while on study were fatigue, hyperlipidemia, weight loss (74%), dysguesia (68%), hyperglycemia and mucositis (63%). Most common g3 AEs were fatigue (21%), mucositis, transaminitis and electrolyte disturbances (all 11%). Other g 3 AEs included anorexia, anemia, injury, retinal detachment, dehydration and thromboembolism. One g 4 AE of hyperglycemia was noted during the expansion phase. One pt with pancreatic NET had confirmed partial response and 17 had stable disease as best response. The median progression free survival was 34+ weeks. Conclusions: The RP2D of this combination is I 10 mg/m2, LAR 20 mg IM q 21 d, E 10 mg po daily. PK, PD and other correlative analyses are ongoing and will be presented at the meeting. Although adequate safety and a sign of activity were noted in this study, these will need to be reconciled with data from larger studies of anti-IGF-1R MoAb in NET and other cancers that have been disappointing. Clinical trial information: NCT01204476.
- Published
- 2014
37. Improvement of clinical response and biomarkers byCamellia sinensis(green tea) extract in patients with high-risk oral premalignant lesions
- Author
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Dingxie Liu, Y. M. Sagesaka, A. Gillenwatre, Jack W. Martin, Wei Hong, Li Mao, Ximing Tang, Adel K. El-Naggar, Anne Tsao, Vassiliki A. Papadimitrakopoulou, Kirk S. Culotta, J. Jack Lee, and Ignacio I. Wistuba
- Subjects
Complementary and alternative medicine ,Traditional medicine ,business.industry ,Medicine ,Camellia sinensis ,In patient ,Green tea extract ,business - Published
- 2010
38. Phase I trial of sorafenib, bevacizumab, and temsirolimus in advanced solid tumors
- Author
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Kirk S. Culotta, Robert L. Coleman, Shannon N. Westin, Vivek Subbiah, Jennifer J. Wheler, Aung Naing, Razelle Kurzrock, Diana L. Urbauer, Apostolia Maria Tsimberidou, Siqing Fu, Ralph Zinner, Melody L. Smart, Sarina Anne Piha-Paul, Filip Janku, Karen H. Lu, Gerald Steven Falchook, Navdeep Pal, and David S. Hong
- Subjects
Oncology ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,business.industry ,Drug resistance ,Pharmacology ,Temsirolimus ,Pharmacokinetics ,Planned Dose ,Internal medicine ,Toxicity ,medicine ,Every Three Weeks ,business ,medicine.drug - Abstract
2611 Background: Pathway crosstalk and emergence of drug resistance have limited the activity of targeted therapies, including anti-angiogenic agents and mTORC1 inhibitors. However, this vulnerability may be addressed by rationally combining targeted therapies to improve outcomes. We sought to determine the MTD/recommended phase II dose and define the pharmacokinetics (PK) of the combination of sorafenib (S), bevacizumab (B), and temsirolimus (T) in patients with advanced solid tumors. Methods: S was given once or twice daily, B was given intravenously every three weeks, and T was given intravenously weekly. Doses were escalated in a stair-step dose escalation with 6 planned dose levels (DL) in a standard 3+3 design. Responses were defined using RECIST 1.1. Results: To date, 51 patients have been enrolled. Three patients withdrew consent after only one dose. One dose-limiting toxicity (DLT) occurred at DL 5 (grade 4 fatigue, pain) and one DLT occurred at DL 6 (G3 headache). However, 5/6 patients required dose reduction on DL6 (G2 nausea, fatigue, hand/foot syndrome, rash). Thus, DL5 (B 10mg/kg, T 20mg, S 200mg twice daily) is being explored in dose expansion (N=10) and tumor expansion cohorts as the recommended phase II dose. The most common adverse events (>10%) were fatigue (69%; G3/4 6%), nausea (38%, G3/4 2%), pain (35%, G3/4 10%), thrombocytopenia (33%, G3/4 8%), mucositis (33%, 0%), constipation (29%, G3/4 0%), hand/foot syndrome (23%, G3/4 0%), rash (19%, G3/4 0%), hypertension (17%, 0%), neuropathy (17%, G3/4 0%), diarrhea (15%, G3/4 6%), vomiting (15%, G3/4 2%), headache (12%, G3/4 2%), and hypertriglyceridemia (10%, G3/4 2%). Of 34 patients evaluable for response, 4 had PR including ovarian (-57%, +6m), gastric (-46%, +5m), colorectal (-32%, +5 m), and thyroid (-31%, +6m) cancer. Eight patients had SD for greater than 4 months including ovarian (0%, +7m), colorectal (-5%, +8m), endometrial (-26%, +5m; -16%, +4m; -15%, +6m), leiomyosarcoma (-5%, +6m), squamous lung cancer (-6%, +6m), and triple negative breast (-15%, +4m) cancer. Conclusions: The combination of S, B, and T is well tolerated and demonstrates preliminary evidence of tumor activity in a variety of solid tumors. PK studies at the recommended phase II dose are ongoing. Clinical trial information: NCT01187199.
- Published
- 2013
39. Abstract LB-231: Phase Ib dose escalation and biomarker study of MK2206 in combination with standard doses of weekly paclitaxel in patients with locally advanced or metastatic solid tumors with expansion in advanced breast cancer
- Author
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Eric P. Winder, Ian E. Krop, Lisa M. Norberg, Ana M. Gonzalez-Angulo, Kirk S. Culotta, Stacy Moulder-Thompson, Funda Meric-Bernstam, Sarina Anne Piha-Paul, Vivianne Velez-Bravo, Razelle Kurzrock, Timothy Madden, Yisheng Li, Apostolia Maria Tsimberidou, Austin Doyle, and Gordon B. Mills
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Head and neck cancer ,Cancer ,Pharmacology ,medicine.disease ,Metastatic breast cancer ,chemistry.chemical_compound ,Paclitaxel ,chemistry ,Internal medicine ,Toxicity ,medicine ,Adverse effect ,Ovarian cancer ,business - Abstract
Background: AKT protein kinase is activated in a large proportion of human solid tumors. Increased levels of AKT phosphorylation and PTEN loss predict poor outcome. Synergistic or additive inhibitory effects have been observed on proliferation/viability of breast cancer cell lines when MK2206, allosteric inhibitor of AKT, is given in combination with taxanes. Primary goals: determine the maximum tolerated dose (MTD) of the combination of MK2206 and weekly paclitaxel and to determine safety and activity of the combination in metastatic breast cancer. Secondary objectives included pharmacokinetics (PK), pharmacodynamic (PD) studies in tissue and blood, and toxicity. Methods: Phase Ib 3+3 dose escalation study. Patients were treated using continuous weekly dosing. A fixed dose of paclitaxel was given at 80mg/m2 weekly on day 1, followed by MK2206 PO on day 2. During dose escalation: MK2206 was escalated using 3 levels: 90mg, 135mg, 200mg. For expansion: MK2206 was given at the MTD of 200mg po. Treatment was continued until tumor progression, excessive toxicity, or patient (pt) request. Blood was collected for PK and PD markers as scheduled. Sequential tumor biopsies were completed in most patients. A cycle consisted of 3 weeks of therapy and DLT was defined as unacceptable toxicity occurring during the first cycle. Results: 23 patients were treated, 9 in the dose escalation and 14 in the dose expansion. Four patients were replaced at dose expansion due to lack of compliance, early progression or intolerance at first dose (2 of these pts were included in the toxicity analysis). Median age was 55 years, 4 male and 19 female. Dose escalation was completed with no DLT. CTCAE Grade ≥3 adverse events were G3 fatigue (2/9 pts), and G3 rash (1/9 pts), and G3 nail infection (1/9 pts). CTCAE in expansion phase will be reported and included G3/4 rash in at least 4 patients requiring MK2206 dose reduction to 135mg weekly. Based on this, phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK2206 135mg weekly on day 2. Observed clinical activity in the dose escalation included: objective responses in pts with a metastatic breast and a metastatic colon cancers, and stable disease over 15 weeks in 2 pts with ocular melanomas, 1 squamous cell carcinoma of the head and neck and 1 ovarian cancer. Expansion cohort clinical activity will be reported. Baseline molecular testing revealed PTEN low/loss in a pt with colon cancer (best and longest response), and a pt with head and neck cancer (on therapy for 25 weeks). Conclusion: Combined paclitaxel and MK2206 were well tolerated. There was clinical activity in the dose escalation, with PTEN low/loss noted in some patients with prolonged SD or PR. Complete report on dose expansion, molecular correlates will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-231. doi:1538-7445.AM2012-LB-231
- Published
- 2012
40. Abstract 3783: Pharmacokinetics and CNS biodistribution of WP1066, a novel small molecule inhibitor of STAT-3 phosphorylation
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Waldemar Priebe, Amy B. Heimberger, Kirk S. Culotta, Charles A. Conrad, Timothy Madden, Mary Johansen, and Izabela Fokt
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Cancer Research ,Biodistribution ,business.industry ,Pharmacology ,medicine.disease ,Bioavailability ,Oncology ,Pharmacokinetics ,Isoflurane ,Oral administration ,In vivo ,Glioma ,medicine ,Dosing ,business ,medicine.drug - Abstract
Utilizing molecular modeling and medicinal chemistry we have designed and discovered novel, potent small molecule inhibitors of STAT3 activation. WP1066, our lead compound, suppressed several downstream signaling products including c-myc, Bcl-XL and Mcl-1, and induced apoptosis in a panel of malignant gliomas. Further studies demonstrated that WP1066 inhibited, in vivo, the growth of malignant glioma xenografts and decreased levels of phosphorylated STAT3. In order to determine the best dosing schedule for WP1066 we designed a number of in vivo studies to assess the biodistribution of this agent following oral and intravenous administration in a mouse model. For the purposes of this study we developed LC/MS/MS analytical methods capable of quantifying WP1066 extracted from plasma or tissues having a limit of quantification of 1 ng/ml or gm tissue. 80 female mice were assigned to the intravenous arm (16 timepoints, 5 animals per timepoint) and 65 mice to the oral arm (13 timepoints, 5 animals per timepoint). Each mouse received a single administration of 40 mg/kg WP1066 or control vehicle, either orally or intravenously. Blood samples were collected by cardiac puncture under isoflurane anesthesia. At sacrifice blood and brain tissue was collected from groups of animals receiving WP1066. Blood and brain tissue was also collected within 30 minutes of injection in a group of 5 animals receiving control vehicle alone. Blood samples were collected in appropriately labeled heparinized tubes, plasma was generated by centrifugation and frozen at –80°C until analyzed. Brain tissue from all animals was harvested, blotted, weighed, and placed in appropriately labeled cryotubes and frozen at –80°C until analyzed. Following analysis the mean value of 5 measured samples at each timepoint (plasma and brain) were subject to non-compartmental PK analysis. WP1066 showed excellent CNS bioavailability with concurrent brain-to-blood concentration ratios ranging from 10:1 to 100:1, reaching mean CNS and plasma peak concentrations of 57.6 µg/g (162.2 μM) and 0.6 µg /mL (1.8 μM), respectively, following a 40 mg/kg IV bolus administration. CNS penetration following oral administration was similar with tissue and plasma peak concentrations reaching 2.7 µg/g (7.6 μM) and 0.09 µg/mL (0.3 μM), respectively. Oral bioavailability was 36.3% (AUC PO/AUC IV), reaching a mean peak concentration at 0.75 hours postdose with measureable concentrations up to 8 hours after dosing administration. This study demonstrates WP1066 maintains CNS concentrations at many fold higher concentrations than that needed to demonstrate activity in vitro in many cancer cell lines (1 µM). These concentrations were maintained for a significant period of time in this mouse model following a single dose of drug, and support the use of once daily dosing in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3783. doi:1538-7445.AM2012-3783
- Published
- 2012
41. Validation of the phase 0 concept
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J. R. Westin, F. Ouyang, T. Helgason, Shannon N. Westin, David S. Hong, Siqing Fu, L. S. Angelo, Kirk S. Culotta, and R. Kurzrock
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Cancer Research ,medicine.medical_specialty ,Experimental drug ,No-observed-adverse-effect level ,business.industry ,Microdosing ,Clinical study design ,Investigational New Drug ,Pharmacology ,Clinical trial ,Oncology ,Drug development ,MicroDose ,medicine ,Intensive care medicine ,business - Abstract
TPS143 Background: Over 90% of drugs entering Phase I trials eventually fail, however, it is not currently possible to predict failure prior to undergoing costly and lengthy clinical trials. In response, the FDA proposed an “exploratory IND” (investigational new drug), a novel clinical trial design commonly referred to as “Phase 0”, aimed at accelerating the critical path of drug development. Phase 0 trials expose a small number of patients to a single “microdose” (starting at 1/50th of the no observed adverse effect level, NOAEL, from the most sensitive animal species) of an experimental drug with the goal of validating pre-clinical models to aid in the ‘go/no-go’ decision of drug development. The ultimate goal is to allow Phase 0 effective drugs to enter combination studies earlier, and Phase 0 ineffective drugs to avoid further costly development (Kummar S, Nat Rev Cancer 7:131-139, 2007). We are concerned that potentially effective drugs or classes of drugs may be discarded based on a microdosing conc...
- Published
- 2011
42. Dual inhibition of VEGF pathway: Phase I trial of bevacizumab and cediranib in advanced solid tumors
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Ignacio Garrido-Laguna, C. Hinojosa, Luis H. Camacho, Susan Percy Ivy, A. Scamardo, Reena Mistry, Siqing Fu, Sarina Anne Piha-Paul, Suhendan Ekmekcioglu, Gerald Steven Falchook, R. Kurzrock, Aung Naing, Kirk S. Culotta, Sijin Wen, David S. Hong, and Jennifer J. Wheler
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Dual inhibition ,Cancer Research ,Bevacizumab ,business.industry ,Phase i study ,Cediranib ,Oncology ,Vegf pathway ,Phase (matter) ,medicine ,Cancer research ,In patient ,business ,medicine.drug - Abstract
3065 Background: We evaluated the safety of a combination of bevacizumab (B) and a TKI against VEGFR-cediranib (C). Methods: This was a phase I study with 3+3 design in patients (pts) with advanced...
- Published
- 2011
43. Clofarabine (Clo) and Busulfan (Bu) as a Novel Reduced Toxicity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation (HCT) In Patients (pts) with Acute Lymphoblastic Leukemia (ALL)
- Author
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Partow Kebriaei, Elizabeth J. Shpall, Celina Ledesma, Deborah A. Thomas, Kirk S. Culotta, Stefan O. Ciurea, Uday R. Popat, Marcos de Lima, Amin M. Alousi, Richard E. Champlin, and Borje S. Andersson
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medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Minimal residual disease ,Surgery ,Transplantation ,Regimen ,Internal medicine ,medicine ,Mucositis ,Clofarabine ,business ,Busulfan ,medicine.drug - Abstract
Abstract 3484 Allogeneic HCT improves long-term disease control in pts with ALL, but the treatment-related mortality (TRM) associated with most myeloablative transplant conditioning regimens limits the benefits of HCT. Therefore, we investigated a novel regimen consisting of Clo combined with intravenous (i.v.) Bu in patients with ALL undergoing allogeneic HCT. Methods: Clo 40 mg/m2 followed by Bu 130 mg/m2 were infused daily for 4 days followed by hematopoietic cell infusion 2 days later. Bu was infused either as a fixed dose per BSA, or to target an average daily AUC of 5,500 microMol-min for pts up to 60 years of age or 4000 microMol-min for pts greater than 60 years, determined by a test dose of Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus and mini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry. Results: 14 pts (12 B-lineage, 2 T-lineage) with median age 29 years (range 21–64) received an allogeneic matched sibling (n=8) or matched unrelated donor (n=6) HCT in CR1 (n=7, 3 MRD positive), CR2 (n=6, 3 MRD positive), or refractory relapse (n=1). Nine pts had high-risk cytogenetic profiles as defined by the presence of t(9;22), t(4;11), or complex cytogenetics. The median time from diagnosis to HCT was 8.5 months (range 2–115) with a median 2 lines of chemotherapy received (range 1–3). Median days to ANC > 0.5 × 109/L and platelet count > 20 × 109/L were 12 (range 10–14) and 16 (13-23), respectively. The most common toxicity was mucositis (8 grade II, 2 grade III). Grade 3 reversible elevation of liver function tests was noted in 3 pts. No VOD or renal toxicity was noted. One pt with a prior history of stenotrophomas and fungal pneumonia died of pneumonia complications 18 days after HCT. Eleven pts are evaluable for response. All evaluable pts achieved CR clearing MRD by day +30 after HCT. Five pts achieved full donor chimerism at 30 days following HCT, 4 pts remain with mixed chimerism at 60 day assessment following HCT, and 1 pt progressed early. The incidence of grades II-IV acute GVHD is 40% (n=3 grade II GI, n=1 steroid refractory liver); chronic GVHD was not assessed due to short follow-up. With a median follow-up of 3 months among surviving patients (0.4-8), overall and disease-free survival is 92% at 3 months. Two pts in CR2 with persistent MRD at time of HCT progressed at a median 5 months following HCT. Two pts older than 60 years were treated on the reduced Bu dose arm, and both remain in continued remission. Conclusion: The CloBu combination is well-tolerated in this small cohort of patients with high-risk ALL who received a median of 8.5 months of intensive (mainly HCVAD-based) chemotherapy prior to receiving transplant. The clearing of MRD encourages further investigation of this regimen. Longer follow-up is needed to more completely assess disease control. Disclosures: Kebriaei: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfan and Clofarabine for trasplant conditioning. De Lima:Otsuka: Membership on an entity's Board of Directors or advisory committees. Champlin:Otsuka: Research Funding; Genzyme: Consultancy. Andersson:Otsuka: Consultancy.
- Published
- 2010
44. Emergence of oral targeted agents in early clinical development: Experience at M. D. Anderson Cancer Center (MDACC) Clinical and Translational Research Center (CTRC)
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M. A. Kramer, C. D. Stewart, Y. Zhang, Razelle Kurzrock, D. Harleaux-Grant, Timothy Madden, M. Wyles, Kirk S. Culotta, V. Dorsey, and Daniel D. Karp
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Translational research ,Pharmacology ,medicine.disease ,Development experience ,Internal medicine ,medicine ,Center (algebra and category theory) ,business ,Oral therapy - Abstract
3073 Background: Most of the 94 chemotherapeutic agents approved by the FDA since 1949 are given intravenously. Oral therapy is preferred by > 80% of patients because of convenience and ease of adm...
- Published
- 2010
45. A phase I study of hepatic arterial infusion of nab-paclitaxel in patients with predominant hepatic metastases
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Kirk S. Culotta, Chaan S. Ng, Y. Zhang, S. L. Moulder, R. Kurzrock, Siqing Fu, Joann Lim, David C. Madoff, Gerald Steven Falchook, and Aung Naing
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Cancer Research ,medicine.medical_specialty ,Hepatic arterial infusion ,Oncology ,business.industry ,Internal medicine ,Medicine ,In patient ,Refractory cancer ,business ,Gastroenterology ,Phase i study ,Nab-paclitaxel - Abstract
e13044 Background: Previous studies with hepatic arterial infusion (HAI) have demonstrated tumor regressions in patients with refractory cancer and predominant liver metastases. We therefore perfor...
- Published
- 2010
46. The changing face of phase I protocols: A closer look at study requirements
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Razelle Kurzrock, D. Gingher, Roy S. Herbst, N. Bekele, C. Stewart, Scott M. Lippman, V. Dorsey, Daniel D. Karp, Barbara S. Craft, and Kirk S. Culotta
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Cancer Research ,medicine.medical_specialty ,Oncology ,business.industry ,Head (linguistics) ,Medicine ,Medical physics ,Center (algebra and category theory) ,Translational research ,business ,Phase (combat) - Abstract
3061 Background: We have studied our recent experience in the MDACC Clinical Translational Research Center (CTRC), the Phase I Program, and the Dept. of Thoracic/Head & Neck Medical Oncology to compare the extent of regulatory and other requirements for current phase I and II cancer clinical trials. Methods: We developed a comprehensive database, together with a Microsoft Excel spreadsheet matrix to analyze the number and extent of diagnostic and therapeutic requirements for each protocol. We then examined the demands for pharmacokinetic (PK) sampling as well as electrocardiography (ECG) in the first cycle of a protocol as a surrogate for study complexity. Results: Since October, 2002, 250 protocols have been conducted in the CTRC; 54.6% were Phase I clinical trials. We reviewed 65 trials, approximately one quarter of the total. Of these, 48 were phase I trials carried out by the Phase I Program. For comparison, we identified 17 phase II trials managed by the Dept. of Thoracic/Head & Neck Medical Oncology during the same time period. In the phase I trials there were significantly more PKs (mean ± SE = 16.69 ± 1.93) than in the phase II trials (mean ± SE = 1.82 ± 1.17) (p No significant financial relationships to disclose.
- Published
- 2007
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