nach oben

Erschienen in:

01.10.2012 | Original Article

Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors

verfasst von: Joanna M. Brell, Smitha S. Krishnamurthi, Linda Rath, Joseph A. Bokar, Panayiotis Savvides, Joseph Gibbons, Matthew M. Cooney, Neal J. Meropol, Percy Ivy, Afshin Dowlati

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2012

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy.

Methods

We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale.

Results

Two different MTDs were determined. The schedule of gemcitabine 800 mg/m2 on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m2 on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m2 on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily.

Conclusions

This combination is well-tolerated and has significant clinical activity.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRef

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550PubMedCrossRef

Hecht JR, Trarbach T, Hainsworth JD, Major P, Jager E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D (2011) Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 29: 1997–2003

Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrao Miziara JE, Balint B, De Marinis F, Keller A, Aren O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 28: 1835–1842

Awasthi N, Schwarz MA, Schwarz RE (2011) Antitumour activity of sunitinib in combination with gemcitabine in experimental pancreatic cancer. HPB (Oxford) 13: 597–604

Casneuf VF, Demetter P, Boterberg T, Delrue L, Peeters M, Van Damme N (2009) Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: an experimental study with a multitarget tyrosine kinase inhibitor (sunitinib), gemcitabine and radiotherapy. Oncol Rep 22:105–113PubMedCrossRef

Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734–745PubMedCrossRef

Yoon CY, Lee JS, Kim BS, Jeong SJ, Hong SK, Byun SS, Lee SE (2011) Sunitinib malate synergistically potentiates anti-tumor effect of gemcitabine in human bladder cancer cells. Korean J Urol 52: 55–63

Pandya SS, Mier JW, McDermott DF, Cho DC (2011) Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int 108: E245–E249

10.

Reck M, Frickhofen N, Cedres S, Gatzemeier U, Heigener D, Fuhr HG, Thall A, Lanzalone S, Stephenson P, Ruiz-Garcia A, Chao R, Felip E (2010) Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: a phase I dose-escalation study. Lung Cancer 70: 180–187

11.

Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRef

12.

Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD (2010) Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 28: 3605–3610

13.

Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O’Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM (2010) Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 28: 3617–3622

14.

Tran Cao HS, Bouvet M, Kaushal S, Keleman A, Romney E, Kim G, Fruehauf J, Imagawa DK, Hoffman RM, Katz MH (2010) Metronomic gemcitabine in combination with sunitinib inhibits multisite metastasis and increases survival in an orthotopic model of pancreatic cancer. Mol Cancer Ther 9: 2068–2078

15.

Bharthuar A, Pearce L, Litwin A, LeVea C, Kuvshinoff B, Iyer R (2009) Metastatic pancreatic adenocarcinoma and renal cell carcinoma treated with gemcitabine and sunitinib malate. A case report. JOP 10:523–527PubMed

Titel: Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors
verfasst von: Joanna M. Brell
Smitha S. Krishnamurthi
Linda Rath
Joseph A. Bokar
Panayiotis Savvides
Joseph Gibbons
Matthew M. Cooney
Neal J. Meropol
Percy Ivy
Afshin Dowlati
Publikationsdatum: 01.10.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-1936-5

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors