FLO +/- Pazopanib as First-line Treatment in Advanced Gastric Cancer
Status:
Completed
Trial end date:
2017-12-14
Target enrollment:
Participant gender:
Summary
The prognosis of advanced gastric cancer and adenocarcinoma of the gastro-esophageal (GE)
junction is poor. Even with modern chemotherapy the median survival ranges around 8-10
months.
Inhibition of neoangiogenesis seems to be a very promising approach in gastric cancer.
Vascular endothelial growth factor (VEGF) acts as one of the most potent stimulating agents
of angiogenesis, and several strategies targeting the VEGF signaling pathway have been
developed, including anti-VEGF antibodies, soluble receptors binding directly to VEGF ligand,
anti-VEGF receptor (VEGFR) antibodies and VEGFR tyrosine kinase inhibitors. The breakthrough
in the clinical development of anti-angiogenic therapy against colorectal cancer came in 2003
with a large prospective, randomized clinical trial of bevacizumab, a monoclonal antibody
directed against VEGF. Anti-angiogenic therapy has introduced a highly effective, completely
new mode of action in this area and is the new standard of care in advanced colorectal
cancer.
The concept of VEGF inhibition is also very promising in gastric cancer. Bevacizumab was
investigated in combination with irinotecan and cisplatin in a phase-II trial, including 47
patients with gastric and GE-junction carcinoma. Bevacizumab could safely be given and could
improve time to tumor progression by 75% compared to historical controls. Several phase-II
trials confirm the tolerability and promising efficacy of bevacizumab in gastric cancer
(Bevacizumab + Docetaxel/Oxaliplatin; FOLFOX + Bevacizumab; Docetaxel/Cisplatin/Irinotecan +
Bevacizumab). These results were so promising that randomized phase-III trials in the
1st-line and perioperative setting are under way (AVAGAST-trial: Cisplatin /Capecitabine +/-
bevacizumab 1st line ; MAGIC-B-trial : ECX +/- bevacizumab perioperative).
Tyrosin kinase inhibitors which inhibit VEGF receptors and EGFR are also investigated in
gastric cancer with promising efficacy. Pazopanib, an orally available tyrosine kinase
inhibitor, selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2
and -3, c-kit and platelet derived growth factor receptor (PDGF-R), which results in
inhibition of angiogenesis in tumors in which these receptors are upregulated. Pazopanib has
the advantage of being an orally available anti-angiogenesis component.
Pazopanib shows promising activity in phase-II trials in renal cell cancer, breast cancer,
soft tissue sarcoma and non small cell lung cancer. A phase-III trial of pazopanib in renal
cell cancer (NCT00334282) is completed and resulted in the approval of Pazopanib for this
disease. A phase-III trial in soft tissue sarcoma (NCT00753688) is currently performed.
In phase-I trials, pazopanib was investigated in combination with FOLFOX and
Capecitabine/Oxaliplatin. FOLFOX could be administered in full dose with 800 mg pazopanib. In
Cape/Ox, capecitabine had to be reduced to 850mg/m² bd.
5-FU- and oxaliplatin-based regimens are one of the established treatment standards for
1st-line therapy in metastatic gastric cancer. The efficacy of 5-FU, leukovorin and
oxaliplatin (FLO) compared to 5-FU, cisplatin could be confirmed in a randomized phase-III
trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). FLO has a favorable toxicity
profile. In Germany, FLO is a widely used combination for advanced gastric cancer and is a
recommended regimen in the new German S3-guidelines 2011.
The investigators therefore want to examine FLO + pazopanib.