A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

Hill, Marisa; Li, Xiaobai; Kim, Sharon; Campbell, Angela; Culler, Kristy; Bloomston, Mark; Zalupski, Mark M.; Hejna, Gwen; Bekaii‐Saab, Tanios

doi:10.1007/s00280-010-1348-3

Cited by 8 publications

(10 citation statements)

References 20 publications

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“…Seven prospective clinical trials were included in these analyses (Table ) . All trials involved gemcitabine‐based therapy, and 4 trials included bevacizumab.…”

Section: Resultsmentioning

confidence: 99%

“…The current study was an analysis of pooled data from 7 prospective, single‐arm, phase 1/2 or phase 2 trials of gemcitabine‐based regimens conducted at the Ohio State University, University of Michigan, Roswell Park Cancer Institute, University of California at San Francisco, The University of Texas MD Anderson Cancer Center, and the University of Oklahoma (Table ) . Raw data were collected from each clinical trial database before pooled analysis, including patient demographics, known prognostic factors (including disease stage, Eastern Cooperative Oncology Group [ECOG] performance status, baseline CA 19‐9, and change in CA 19‐9 with treatment), b‐alb level (< 3.4 g/dL or ≥ 3.4 g/dL) measured within 7 days of treatment initiation, and clinical outcome measures (including objective response rate [ORR], disease control rate [DCR; ORR plus stable disease lasting ≥ 16 weeks], TTP, and OS) for all patients.…”

Section: Methodsmentioning

confidence: 99%

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Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: A pooled analysis of 7 prospective trials of gemcitabine‐based therapy with or without bevacizumab

Pant

Martin

Geyer

et al. 2014

Cancer

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BACKGROUND Phase 3 studies of bevacizumab in patients with advanced pancreatic cancer (APCA) demonstrated no improvement in outcome. To the authors’ knowledge, no validated predictive biomarkers for bevacizumab exist, although emerging data suggest that subsets of patients with APCA may benefit from treatment with bevacizumab. The authors evaluated baseline serum albumin (b-alb) as a predictive biomarker in a pooled analysis from 7 prospective clinical trials of gemcitabine-based therapy with or without bevacizumab. METHODS Data were collected from individual databases from 7 prospective clinical trials. Patients were grouped by exposure to bevacizumab and by b-alb level (≥ 3.4 g/L or < 3.4 g/dL). Overall survival (OS), time to disease progression (TTP), overall response rate, and disease control rate (overall response rate plus stable disease lasting ≥ 16 weeks) were compared between groups. Univariate and multivariable analyses of prognostic factors were performed. RESULTS A total of 264 patients were included. The median age was 59 years (range, 31 years-85 years) and all patients had stage IV disease per TNM staging. Normal b-alb was associated with significantly improved median OS (10.2 months vs 4.1 months; P =.0001), median TTP (6.2 months vs 3.7 months; P = 0.0488), and disease control rate (71% vs 46%; P =.007) for patients receiving bevacizumab, but not for those treated without bevacizumab. Multivariable analysis revealed a significant influence of normal b-alb on OS (P =.0008) and TTP (P =.033). CONCLUSIONS Patients with APCA with normal b-alb derive benefit from treatment with bevacizumab. Future prospective investigations of bevacizumab in patients with APCA should consider selecting patients with normal b-alb to maximize potential benefit.

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“…Seven prospective clinical trials were included in these analyses (Table ) . All trials involved gemcitabine‐based therapy, and 4 trials included bevacizumab.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: A pooled analysis of 7 prospective trials of gemcitabine‐based therapy with or without bevacizumab

Pant

Martin

Geyer

et al. 2014

Cancer

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“…Retrospective analyses of GTX noted response rates between 11 and 40%, and median OS of B11 months [35,53], but superior OS of 25 months was seen in patients with locally advanced disease [35]. Prospective phase II studies confirmed responses up to 40% and median OS ranging from 7 to 14.5 months, and a preliminary correlation with benefit in patients with high pMEK expression [32][33][34]36]. The GTX regimen, while used extensively and with variable dosing schedules in the community, is limited by increased toxicity [grade 3/4 neutropenia (29%), fatigue, diarrhea, mucositis, and hand-foot skin reaction (8% each)].…”

Section: Docetaxelmentioning

confidence: 99%

Taxanes

Chiorean¹,

Hoff²

2014

Anti-Cancer Drugs

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Taxanes are core therapeutic components for several advanced malignancies, and have been studied extensively in pancreatic adenocarcinomas with mixed results. Although the triplet combination FOLFIRINOX improves outcomes for patients with metastatic disease, it is compounded by significant toxicity, and novel regimens, rationally designed and based on thorough mechanistic activity on the tumor targets, are clearly needed. Solvent-based taxanes, docetaxel and paclitaxel, have little activity as single agents, but combinations with fluoropyrimidines and gemcitabine show efficacy, albeit they have not undergone testing in phase III trials. Pancreatic cancer is characterized by an abundant desmoplastic, fibroinflammatory and hypoperfused stroma, which has been blamed for its overall chemoresistance. Nanoparticle bound paclitaxel (nab-paclitaxel) has been pharmacologically designed as a novel water-soluble agent, with improved therapeutic index compared with the cremophor-based formulation, capable of achieving higher systemic exposure. In preclinical systems, when combined with gemcitabine, nab-paclitaxel increased intratumoral gemcitabine delivery, possibly due to inducing stromal 'collapse' and through inhibition of the gemcitabine-catabolizing enzyme cytidine deaminase. Most recently, the combination of nab-paclitaxel and gemcitabine demonstrated significant survival benefit with good tolerability in metastatic pancreatic cancer in the phase III trial MPACT, and now represents one of the gold-standard regimens for this disease. Although taxanes are overall potent chemotherapeutics for various cancers, it is clear that for meaningful results in pancreatic adenocarcinomas, rationally designed combinations and novel technologies for drug delivery are likely to be most successful.

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“…Other agents of interest include curcumin (a natural product) [6], leucovorin (an adjuvant agent) [6], tegafur (a prodrug of 5-FU) [148,149], and MGCD0103 and valproic acid (HDAC inhibitors) [150]. In particular, notable combinations under study include GTX (gemcitabine, docetaxel, and capecitabine) [151,152], GemOx (gemcitabine, oxaliplatin) [153], GemOxCet (gemcitabine, oxaliplatin, cetuximab), and Gemoxel (gemcitabine, oxaliplatin, capecitabine) [154]. Nonetheless, novel combinations not including gemcitabine such as Xeliri (capecitabine, irinotecan) [155], Folfiri (leucovorin, 5-FU, irinotecan) [155], and Folfirinox (leucovorin, 5-FU, irinotecan, oxaliplatin) [156] have also shown promise in combating pancreatic cancer, although more studies are needed to determine toxicity and efficacy profiles.…”

Section: Novel Therapeutic Combinations With Gemcitabinementioning

confidence: 99%

Overcoming nucleoside analog chemoresistance of pancreatic cancer: A therapeutic challenge

Hung¹,

Mody²,

Govindarajan³

2012

Cancer Letters

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A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

Cited by 8 publications

References 20 publications

Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: A pooled analysis of 7 prospective trials of gemcitabine‐based therapy with or without bevacizumab

Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: A pooled analysis of 7 prospective trials of gemcitabine‐based therapy with or without bevacizumab

Taxanes

Overcoming nucleoside analog chemoresistance of pancreatic cancer: A therapeutic challenge

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