Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma

被引:247
作者
Feldman, Darren R.
Baum, Michael S.
Ginsberg, Michelle S.
Hassoun, Hani
Flombaum, Carlos D.
Velasco, Susanne
Fischer, Patricia
Ronnen, Ellen
Ishill, Nicole
Patil, Sujata
Motzer, Robert J. [1 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Genitourinary Oncol Serv, New York, NY 10021 USA
关键词
ENDOTHELIAL GROWTH-FACTOR; THROMBOTIC MICROANGIOPATHY; ANGIOGENIC FACTORS; VEGF INHIBITION; PLATELET; HYPERTENSION; SORAFENIB; ANTIBODY; COUNTS;
D O I
10.1200/JCO.2008.19.0108
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose Both bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC. Patients and Methods Three cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information. Results Of 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%. Conclusion In this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.
引用
收藏
页码:1432 / 1439
页数:8
相关论文
共 28 条
  • [1] Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity
    Azad, Nilofer S.
    Posadas, Edwin M.
    Kwitkowski, Virginia E.
    Steinberg, Seth M.
    Jain, Lokesh
    Annunziata, Christina M.
    Minasian, Lori
    Sarosy, Gisele
    Kotz, Herbert L.
    Premkumar, Ahalya
    Cao, Liang
    McNally, Deborah
    Chow, Catherine
    Chen, Helen X.
    Wright, John J.
    Kohn, Elise C.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (22) : 3709 - 3714
  • [2] Pre-eclampsia: Clinical manifestations and molecular mechanisms
    Baumwell, Suzanne
    Karumanchi, S. Ananth
    [J]. NEPHRON CLINICAL PRACTICE, 2007, 106 (02): : C72 - C81
  • [3] COONEY MM, 2007, J CLIN ONCOL S, V25, pS652
  • [4] Dosquet C, 1997, CLIN CANCER RES, V3, P2451
  • [5] VEGF inhibition and renal thrombotic microangiopathy
    Eremina, Vera
    Jefferson, J. Ashley
    Kowalewska, Jolanta
    Hochster, Howard
    Haas, Mark
    Weisstuch, Joseph
    Richardson, Catherine
    Kopp, Jeffrey B.
    Kabir, M. Golam
    Backx, Peter H.
    Gerber, Hans-Peter
    Ferrara, Napoleone
    Barisoni, Laura
    Alpers, Charles E.
    Quaggin, Susan E.
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (11) : 1129 - 1136
  • [6] Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial
    Escudier, Bernard
    Pluzanska, Anna
    Koralewski, Piotr
    Ravaud, Alain
    Bracarda, Sergio
    Szczylik, Cezary
    Chevreau, Christine
    Filipek, Marek
    Melichar, Bohuslav
    Bajetta, Emilio
    Gorbunova, Vera
    Bay, Jacques-Olivier
    Bodrogi, Istvan
    Jagiello-Gruszfeld, Agnieszka
    Moore, Nicola
    [J]. LANCET, 2007, 370 (9605) : 2103 - 2111
  • [7] Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma
    Frangie, Carlos
    Lefaucheur, Carmen
    Medioni, Jacques
    Jacquot, Christian
    Hill, Garry S.
    Nochy, Dominique
    [J]. LANCET ONCOLOGY, 2007, 8 (02) : 177 - 178
  • [8] GEORGE DJ, 2007, J CLIN ONCOL, V25
  • [9] Glusker P, 2006, NEW ENGL J MED, V354, P980
  • [10] Prognostic importance of serum vascular endothelial growth factor in relation to platelet and leukocyte counts in human renal cell carcinoma
    Jacobsen, J
    Grankvist, K
    Rasmuson, T
    Ljungberg, B
    [J]. EUROPEAN JOURNAL OF CANCER PREVENTION, 2002, 11 (03) : 245 - 252