Browsing by Author "Sweeney, Christopher J."

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    A Phase I and Pharmacokinetic Trial of Erlotinib in Combination with Weekly Docetaxel in Patients with Taxane-Naive Malignancies
    (American Association of Cancer Research, 2008-02) Chiorean, E. Gabriela; Porter, Jennifer M.; Foster, Anne E.; Omari, Amal S.H. Al; Yoder, Christy A.; Fife, Karen L.; Strother, R. Matthew; Murry, Daryl J.; Yu, Menggang; Jones, David R.; Sweeney, Christopher J.; Biostatistics, School of Public Health
    Purpose: This study aimed to define the maximum tolerated dose of weekly docetaxel combined with daily erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor. Experimental Design: Patients with any solid tumor received 150 mg erlotinib with escalating doses of docetaxel (20, 25, 30, and 35 mg/m2) on days 1, 8, and 15 every 28 days. The pharmacokinetics of docetaxel and erlotinib was determined on cycle 2, day 1. Erlotinib was given for a maximum of 12 cycles and docetaxel was given for up to 6 cycles. Results: Twenty-five patients (17 males and 8 females) were enrolled with a median age of 56 years (range, 34-76); Eastern Cooperative Oncology Group performance status of 0/1 was 20/5. One patient had a dose-limiting toxicity in cycle 1 at the 25 mg/m2 level (grade 3 enterocolitis). At 35 mg/m2 docetaxel dose level, 6 of 10 patients required dose reductions to 30 mg/m2 beyond cycle 1 due to neutropenia (3 patients) and mucositis, increased bilirubin, and diarrhea (1 patient each). The clearance of docetaxel and erlotinib of 61.7 and 8.16 L/h, respectively, did not seem to differ from historical controls. Responses were seen in non–small cell lung cancer, prostate cancer, and hepatobiliary cancers, including a complete response lasting 36+ months in a patient with hepatocellular carcinoma. Conclusion: Although no maximum tolerated dose was reached in cycle 1 with 35 mg/m2 docetaxel, repetitive dosing proved intolerable in a substantial number of patients; thus, the recommended phase II dose of weekly docetaxel is 30 mg/m2 when combined with 150 mg of daily erlotinib.
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    Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors
    (AACR, 2020-10) Chiorean, E. Gabriela; Perkins, Susan M.; Strother, R. Matthew; Younger, Anne; Funke, Jennifer M.; Shahda, Safi G.; Hahn, Noah M.; Sandrasegaran, Kumar; Jones, David R.; Skaar, Todd C.; Schneider, Bryan P.; Sweeney, Christopher J.; Matei, Daniela E.; Medicine, School of Medicine
    VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).
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    Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer
    (American Association for Cancer Research, 2022) Sweeney, Christopher J.; Percent, Ivor J.; Babu, Sunil; Cultrera, Jennifer L.; Mehlhaff, Bryan A.; Goodman, Oscar B.; Morris, David S.; Schnadig, Ian D.; Albany, Costantine; Shore, Neal D.; Sieber, Paul R.; Guba, Susan C.; Zhang, Wei; Wacheck, Volker; Donoho, Gregory P.; Szpurka, Anna M.; Callies, Sophie; Lin, Boris Kin; Bendell, Johanna C.; Medicine, School of Medicine
    Purpose: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. Patients and methods: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. Results: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). Conclusions: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.
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    Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium
    (American Society of Clinical Oncology, 2021) Gillessen, Silke; Sauvé, Nicolas; Collette, Laurence; Daugaard, Gedske; de Wit, Ronald; Albany, Costantine; Tryakin, Alexey; Fizazi, Karim; Stahl, Olof; Gietema, Jourik A.; De Giorgi, Ugo; Cafferty, Fay H.; Hansen, Aaron R.; Tandstad, Torgrim; Huddart, Robert A.; Necchi, Andrea; Sweeney, Christopher J.; Garcia-Del-Muro, Xavier; Heng, Daniel Y. C.; Lorch, Anja; Chovanec, Michal; Winquist, Eric; Grimison, Peter; Feldman, Darren R.; Terbuch, Angelika; Hentrich, Marcus; Bokemeyer, Carsten; Negaard, Helene; Fankhauser, Christian; Shamash, Jonathan; Vaughn, David J.; Sternberg, Cora N.; Heidenreich, Axel; Beyer, Jörg; International Germ Cell Cancer Classification Update Consortium; Medicine, School of Medicine
    Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. Materials and methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set. Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update). Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
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    Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium
    (American Society of Clinical Oncology, 2021) Beyer, Jörg; Collette, Laurence; Sauvé, Nicolas; Daugaard, Gedske; Feldman, Darren R.; Tandstad, Torgrim; Tryakin, Alexey; Stahl, Olof; Gonzalez-Billalabeitia, Enrique; De Giorgi, Ugo; Culine, Stéphane; de Wit, Ronald; Hansen, Aaron R.; Bebek, Marko; Terbuch, Angelika; Albany, Costantine; Hentrich, Marcus; Gietema, Jourik A.; Negaard, Helene; Huddart, Robert A.; Lorch, Anja; Cafferty, Fay H.; Heng, Daniel Y. C.; Sweeney, Christopher J.; Winquist, Eric; Chovanec, Michal; Fankhauser, Christian; Stark, Daniel; Grimison, Peter; Necchi, Andrea; Tran, Ben; Heidenreich, Axel; Shamash, Jonathan; Sternberg, Cora N.; Vaughn, David J.; Duran, Ignacio; Bokemeyer, Carsten; Patrikidou, Anna; Cathomas, Richard; Assele, Samson; Gillessen, Silke; International Germ Cell Cancer Classification Update Consortium; Medicine, School of Medicine
    Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. Materials and methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.