Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer

Kordes, S.; Klümpen, H. J.; Weterman, M. J.; Schellens, J. H. M.; Richel, D. J.; Wilmink, J. W.

doi:10.1007/s00280-015-2730-y

Cited by 71Pancreatic and Hepatic Oncology ResearchPI3K/AKT/mTOR signaling in cancerPancreatitis Pathology and Treatment

Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer

Open access

Kordes, S., Klümpen, H. J., Weterman, M. J., Schellens, J. H. M., Richel, D. J., Wilmink, J. W.·2015·Cancer Chemotherapy and Pharmacology

DOI 10.1007/s00280-015-2730-yPMC PMC4441736

Open this paper in CoChat — free account Open PDF

Abstract

PURPOSE: The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients. METHODS: Patients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate. RESULTS: In total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3). CONCLUSIONS: The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1007/s00280-015-2730-y

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Adding mTOR inhibitors to gemcitabine-based chemotherapy did not significantly improve clinical activity.
“Combination of these inhibitors with gemcitabine-based chemotherapy also did not yield significant improvement in clinical activity (92, 93).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [93]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

New Guidelines to Evaluate the Response to Treatment in Solid Tumors
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A. T., Christian, M. C., et al. (2000) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/92.3.205 · Cited by 15,660 · see citing works
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Conroy, T., Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., Adenis, A., Raoul, J.-L., Gourgou-Bourgade, S., de la Fouchardière, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1011923 · Cited by 7,810 · see citing works
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.
Burris, H. A., Moore, M. J., Andersen, J., Green, M. R., Rothenberg, M. L., Modiano, M., Cripps, M. C., Portenoy, R. K., Storniolo, A. M., Tarassoff, P. G., et al. (1997) · Journal of Clinical Oncology · doi:10.1200/jco.1997.15.6.2403 · Cited by 5,895 · see citing works
Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial
Motzer, R. J., Escudier, B., Oudard, S., Hutson, T. E., Porta, C., Bracarda, S., Grünwald, V., Thompson, J. A., Figlin, R. A., Hollaender, N., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61039-9 · Cited by 3,019 · see citing works
Everolimus for Advanced Pancreatic Neuroendocrine Tumors
Yao, J. C., Shah, M. H., Ito, T., Lombard‐Bohas, C., Wolin, E. M., Cutsem, E. V., Hobday, T. J., Okusaka, T., Capdevila, J., de Vries, E. G. E., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1009290 · Cited by 2,879 · see citing works
Current development of mTOR inhibitors as anticancer agents
Faivre, S. J., Kroemer, G., & Raymond, É. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2062 · Cited by 998 · see citing works
Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations
LoPiccolo, J., Blumenthal, G. M., Bernstein, W. B., & Dennis, P. A. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2007.11.003 · Cited by 804 · see citing works
The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent
Gehan, E. A. (1961) · Journal of Chronic Diseases · doi:10.1016/0021-9681(61)90060-1 · Cited by 674 · see citing works
Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer
Baselga, J. M., Семиглазов, В. Ф., van Dam, P., Manikhas, A., Bellet, M., Mayordomo, J. I., Campone, M., Kubista, E., Greil, R., Bianchi, G., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.8391 · Cited by 635 · see citing works
Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors
Tabernero, J. M., Rojo, F., Calvo, E., Burris, H. A., Judson, I. R., Hazell, K., Martinelli, E., y Cajal, S. R., Jones, S. F., Vidal, L., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.5482 · Cited by 537 · see citing works
First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous5-fluorouracil/leucovorin
Cassidy, J., Twelves, C. J., Cutsem, E. V., Hoff, P. M., Bajetta, E., Boyer, M. J., Bugat, R., Burger, U., Garin, A., Graeven, U., et al. (2002) · Annals of Oncology · doi:10.1093/annonc/mdf089 · Cited by 531 · see citing works
The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 Translation
Beuvink, I., Boulay, A., Fumagalli, S., Zilbermann, F., Ruetz, S., O’Reilly, T., Natt, F., Hall, J., Lane, H. A., & Thomas, G. (2005) · Cell · doi:10.1016/j.cell.2004.12.040 · Cited by 484 · see citing works
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid Tumors
O’Donnell, A. E., Faivre, S. J., Burris, H. A., Rea, D. W., Papadimitrakopoulou, V. A., Shand, N., Lane, H. A., Hazell, K., Zoellner, U., Kovarik, J. M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.0988 · Cited by 478 · see citing works
A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt
Aoki, M., Blazek, E., & Vogt, P. K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.1.136 · Cited by 306 · see citing works
Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer
Wolpin, B. M., Hezel, A. F., Abrams, T., Blaszkowsky, L. S., Meyerhardt, J. A., Chan, J. A., Enzinger, P. C., Allen, B., Clark, J. W., Ryan, D. P., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.9514 · Cited by 297 · see citing works
Randomized Phase II Study Comparing Two Schedules of Everolimus in Patients With Recurrent/Metastatic Breast Cancer: NCIC Clinical Trials Group IND.163
Ellard, S. L., Clemons, M. J., Gelmon, K. A., Norris, B. D., Kennecke, H. F., Chia, S., Pritchard, K. I., Eisen, A. F., Vandenberg, T. A., Taylor, M., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.21.3033 · Cited by 259 · see citing works
A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy
Bodoky, G., Timcheva, C., Spigel, D. R., La Stella, P. J., Ciuleanu, T. E., Pover, G., & Tebbutt, N. C. (2012) · Investigational New Drugs · doi:10.1007/s10637-011-9687-4 · Cited by 236 · see citing works
RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model
Mabuchi, S., Altomare, D. A., Cheung, M., Zhang, L., Poulikakos, P. I., Hensley, H. H., Schilder, R. J., Ozols, R. F., & Testa, J. R. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2770 · Cited by 233 · see citing works
Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab
André, F., Campone, M., O'Regan, R. M., Manlius, C., Massacesi, C., Tarek, S., Mukhopadhyay, P., Soria, J., Naughton, M., & Hurvitz, S. A. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.8549 · Cited by 207 · see citing works
A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer
Amato, R. J., Jac, J., Giessinger, S., et al. (2009) · Cancer · doi:10.1002/cncr.24280 · Cited by 201 · see citing works
Phase II Study of Oral Capecitabine in Patients With Advanced or Metastatic Pancreatic Cancer
Cartwright, T. H. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.20.1.160 · Cited by 185 · see citing works
Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors
Soria, J., Shepherd, F. A., Douillard, J., Wolf, J., Giaccone, G., Crinò, L., Cappuzzo, F., Sharma, S., Gross, S. H., Dimitrijević, S., et al. (2009) · Annals of Oncology · doi:10.1093/annonc/mdp060 · Cited by 163 · see citing works
The Novel mTOR Inhibitor RAD001 (Everolimus) Induces Antiproliferative Effects in Human Pancreatic Neuroendocrine Tumor Cells
Zitzmann, K., Toni, E. N. D., Brand, S., et al. (2007) · Neuroendocrinology · doi:10.1159/000100057 · Cited by 161 · see citing works
Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors
Punt, C. J. A., Boni, J. P., Bruntsch, U., Peters, M. E. W. J., & Thielert, C. (2003) · Annals of Oncology · doi:10.1093/annonc/mdg248 · Cited by 117 · see citing works
Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis
Seeliger, H., Guba, M. O., Kleespies, A., Jauch, K., & Bruns, C. J. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9077-8 · Cited by 113 · see citing works
Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall‐cell lung cancer
Milton, D. T., Riely, G. J., Azzoli, C. G., et al. (2007) · Cancer · doi:10.1002/cncr.22816 · Cited by 98 · see citing works
Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours
Campone, M., Lévy, V., Bourbouloux, E., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604851 · Cited by 97 · see citing works
Phase II Study of Oral Capecitabine in Patients With Advanced or Metastatic Pancreatic Cancer
Cartwright, T. H., Cohn, A. L., Varkey, J. A., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.20.1.160 · Cited by 95 · see citing works
Symptom profiles and palliative care in advanced pancreatic cancer—a prospective study
Labori, K. J., Hjermstad, M. J., Wester, T. E., Buanes, T. A., & Loge, J. H. (2006) · Supportive Care in Cancer · doi:10.1007/s00520-006-0067-0 · Cited by 83 · see citing works
Bevacizumab and everolimus in the treatment of patients with metastatic melanoma
Hainsworth, J. D., Infante, J. R., Spigel, D. R., et al. (2010) · Cancer · doi:10.1002/cncr.25320 · Cited by 78 · see citing works
Phase I Clinical and Pharmacokinetic Study of RAD001 (Everolimus) Administered Daily to Japanese Patients with Advanced Solid Tumors
Okamoto, I., Doi, T., Ohtsu, A., et al. (2009) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyp120 · Cited by 75 · see citing works
Blockage of 2-Deoxy- d -Ribose-Induced Angiogenesis with Rapamycin Counteracts a Thymidine Phosphorylase-Based Escape Mechanism Available for Colon Cancer under 5-Fluorouracil Therapy
Seeliger, H., Guba, M. O., Koehl, G. E., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-1176-3 · Cited by 67 · see citing works
Everolimus (RAD) Inhibits In Vivo Growth of Murine Squamous Cell Carcinoma (SCC VII)
Khariwala, S. S., Kjærgaard, J., Lorenz, R. R., et al. (2006) · The Laryngoscope · doi:10.1097/01.mlg.0000210544.64659.35 · Cited by 48 · see citing works
Synergistic antiproliferative effect of mTOR inhibitors in combination with 5‐fluorouracil in scirrhous gastric cancer
Matsuzaki, T., Yashiro, M., Kaizaki, R., et al. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01315.x · Cited by 41 · see citing works
Synergistic effect of mTOR inhibitor rapamycin and fluorouracil in inducing apoptosis and cell senescence in hepatocarcinoma cells
Bu, X., Chen, L., Jia, F., Guo, X., Zhang, L., Wu, M.-C., & Wei, L. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.3.5366 · Cited by 37 · see citing works
Phase II trial of capecitabine and everolimus (RAD001) combination in refractory gastric cancer patients
Lee, S. J., Lee, J.-T., Lee, J., et al. (2013) · Investigational New Drugs · doi:10.1007/s10637-013-0022-0 · Cited by 33 · see citing works
Results of a phase 1 clinical trial investigating a combination of the oral mTOR-inhibitor Everolimus (E, RAD001) and Gemcitabine (GEM) in patients (pts) with advanced cancers
Pacey, S., Rea, D. W., Steven, N. M., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.22.90140.3120 · Cited by 26 · see citing works
Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies
Deenen, M. J., Klümpen, H., Richel, D. J., Sparidans, R. W., Weterman, M. J., Beijnen, J. H., Schellens, J. H. M., & Wilmink, J. W. (2011) · Investigational New Drugs · doi:10.1007/s10637-011-9723-4 · Cited by 23 · see citing works
Self-citation
Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer
Joka, M., Boeck, S. H., Zech, C. J., et al. (2014) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000000146 · Cited by 15 · see citing works

Flagged first, then by citations

Sorted by citations

KRAS mutation in pancreatic cancer
Luo, J. (2021) · Seminars in Oncology · doi:10.1053/j.seminoncol.2021.02.003 · Cited by 360 · see citing works
Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications
Hu, H.-F., Ye, Z., Qin, Y., Xu, X.-W., Yu, X.-J., Zhuo, Q.-F., & Ji, S.-R. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00584-2 · Cited by 149 · see citing works
Gemcitabine combined with the mTOR inhibitor temsirolimus in patients with locally advanced or metastatic pancreatic cancer. a hellenic cooperative oncology group phase I/II study
Karavasilis, V., Samantas, E., Koliou, G.-A., Kalogera-Fountzila, A., Pentheroudakis, G., Varthalitis, I., Linardou, H., Rallis, G., Skondra, M., Papadopoulos, G., et al. (2018) · Targeted Oncology · doi:10.1007/s11523-018-0605-y · Cited by 27 · see citing works
Phase Ib and pharmacokinetics study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with advanced solid tumors
Lim, A. R., Kim, B., Kim, J. H., Hyun, M. H., Park, K. H., Kim, Y. H., & Lee, S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1390452 · Cited by 10 · see citing works

Long-term response to mTOR inhibitors (everolimus) in mRCC patients: Single institution experience
Huszno, J., & Nowara, E. (2016) · European Urology Supplements · doi:10.1016/s1569-9056(16)30498-5
A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer
Amato, R. J., Jac, J., Giessinger, S., et al. (2009) · Cancer · doi:10.1002/cncr.24280 · Cited by 201 · see citing works
DE NOVO USE OF MTOR INHIBITOR EVEROLIMUS IN COMBINATION WITH MYCOPHANOLATE SODIUM IN PATIENTS UNDERGONE ORTHOTOPIC LIVER TRANSPLANTATION
Antoniou, E., Dimitroulis, D., Mantas, D., et al. (2008) · Transplantation · doi:10.1097/01.tp.0000331542.96232.df
359 Phase Ib and pharmacokinetic studies of Everolimus (RAD001), a novel oral mTOR-inhibitor, with paclitaxel in patients with advanced solid tumors
Campone, M., Lévy, V., Delecroix, V., et al. (2004) · European Journal of Cancer Supplements · doi:10.1016/s1359-6349(04)80366-5 · Cited by 1 · see citing works
Supplementary Figures S1-S3 from Effects of mTOR Inhibitor Everolimus (RAD001) on Bladder Cancer Cells
Chiong, E., Lee, I.-L., Dadbin, A., et al. (2023) · doi:10.1158/1078-0432.22442768.v1

Authors: Kordes, S., Klümpen, H. J., Weterman, M. J., Schellens, J. H. M., Richel, D. J., & Wilmink, J. W.
Affiliations: Amsterdam UMC Location University of Amsterdam (NL)
Utrecht University (NL)
Corresponding author: Kordes, S.
ORCID: Kordes, S.
Klümpen, H. J.
Schellens, J. H. M.
Wilmink, J. W.
Venue: Cancer Chemotherapy and Pharmacology
Publisher: Springer Science and Business Media LLC
Published: 2015-03-31
Volume: 75
Issue: 6
Pages: 1135-1141
ISSN: 0344-5704 (ISSN-L)
1432-0843
DOI: 10.1007/s00280-015-2730-y
PMC: PMC4441736
OpenAlex: W2073012031
Cited by: 71
References: 39
Citations by year: 2026: 4 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 7 · 2015: 4
FWCI: 4.22
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: Cancer Chemotherapy and Pharmacology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Pure Amsterdam UMC (submittedVersion, cc-by)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
Keywords: capecitabine, everolimus, mTOR inhibitors, advanced pancreatic cancer, pancreatic ductal adenocarcinoma, combination chemotherapy, oral anticancer therapy, drug toxicity, hyperglycemia, hand-foot syndrome, response rate, progression-free survival, overall survival
MeSH terms: Everolimus, Capecitabine, Adenocarcinoma, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Female, Fluorouracil, Humans, Male, Middle Aged, Pancreatic Neoplasms, Survival Rate, Disease-Free Survival, Sirolimus, Protein Kinase Inhibitors, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks