PMID- 24817603
OWN - NLM
STAT- MEDLINE
DCOM- 20140926
LR  - 20181202
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 74
IP  - 1
DP  - 2014 Jul
TI  - Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative 
      study of dual antiangiogenic inhibition using bevacizumab in combination with 
      sorafenib in patients with advanced malignant melanoma.
PG  - 77-84
LID - 10.1007/s00280-014-2479-8 [doi]
AB  - PURPOSE: Melanomas are vascular tumors with a high incidence of BRAF mutations 
      driving tumor proliferation. Complete inhibition of vascular endothelial growth 
      factor (VEGF) signaling has potential for enhanced antitumor efficacy. METHODS: 
      Patients with advanced melanoma and adequate organ function were eligible. 
      Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was 
      administered 5 mg/kg intravenously every 14 days. The primary objective was to 
      determine clinical biological activity. The secondary objectives were safety, 
      tolerability, and time to progression (TTP). Pharmacodynamic analysis included 
      serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, 
      C1D15 and C2D1. The study was terminated during the first stage of a Simon 
      two-stage design, after 14 of planned 21 subjects were enrolled. RESULTS: Of the 
      14 patients who received treatment, no objective tumor responses were observed. 
      Stable disease (SD) >/=16 weeks was observed in 57 % patients, including three 
      patients with SD lasting >/=1 year. Median TTP was 32 weeks. The most frequently 
      reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), 
      fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 
      drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and 
      thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced 
      longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A 
      similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach 
      statistical significance. CONCLUSIONS: Combined VEGF/VEGFR blockade using 
      bevacizumab with sorafenib shows clinical activity. The linkage between VEGF 
      levels and time to tumor progression needs further exploration.
FAU - Mahalingam, Devalingam
AU  - Mahalingam D
AD  - Institute for Drug Development, Cancer Therapy and Research Center, University of 
      Texas Health Science Center at San Antonio, San Antonio, TX, USA, 
      Mahalingam@uthscsa.edu.
FAU - Malik, Laeeq
AU  - Malik L
FAU - Beeram, Muralidhar
AU  - Beeram M
FAU - Rodon, Jordi
AU  - Rodon J
FAU - Sankhala, Kamalesh
AU  - Sankhala K
FAU - Mita, Alain
AU  - Mita A
FAU - Benjamin, Daniel
AU  - Benjamin D
FAU - Ketchum, Norma
AU  - Ketchum N
FAU - Michalek, Joel
AU  - Michalek J
FAU - Tolcher, Anthony
AU  - Tolcher A
FAU - Wright, John
AU  - Wright J
FAU - Sarantopoulos, John
AU  - Sarantopoulos J
LA  - eng
SI  - ClinicalTrials.gov/NCT00387751
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140510
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Biomarkers)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
SB  - IM
MH  - Angiogenesis Inhibitors/administration & dosage/adverse effects/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized/administration & dosage/adverse 
      effects/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse 
      effects/*therapeutic use
MH  - Bevacizumab
MH  - Biomarkers/blood
MH  - Disease Progression
MH  - Drug Monitoring
MH  - Early Termination of Clinical Trials
MH  - Feasibility Studies
MH  - Female
MH  - Hand-Foot Syndrome/physiopathology
MH  - Humans
MH  - Hypertension/chemically induced/physiopathology
MH  - Kinetics
MH  - Male
MH  - Melanoma/blood/*drug therapy/pathology
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Niacinamide/administration & dosage/adverse effects/*analogs & 
      derivatives/therapeutic use
MH  - Phenylurea Compounds/administration & dosage/adverse effects/*therapeutic use
MH  - Protein Kinase Inhibitors/administration & dosage/adverse effects/*therapeutic 
      use
MH  - Receptors, Vascular Endothelial Growth Factor/*antagonists & 
      inhibitors/blood/chemistry
MH  - Severity of Illness Index
MH  - Sorafenib
MH  - Vascular Endothelial Growth Factors/blood/chemistry
EDAT- 2014/05/13 06:00
MHDA- 2014/09/27 06:00
CRDT- 2014/05/13 06:00
PHST- 2014/02/16 00:00 [received]
PHST- 2014/04/28 00:00 [accepted]
PHST- 2014/05/13 06:00 [entrez]
PHST- 2014/05/13 06:00 [pubmed]
PHST- 2014/09/27 06:00 [medline]
AID - 10.1007/s00280-014-2479-8 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2014 Jul;74(1):77-84. doi: 10.1007/s00280-014-2479-8. 
      Epub 2014 May 10.