FLO +/- Pazopanib as First-line Treatment in Advanced Gastric Cancer

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.

Conditions

• Advanced Gastric Cancer

Interventions

DRUG

Pazopanib

Adding Pazopanib to a standard chemotherapy consisting of FLO. 800 mg (2x400mg or 4x200mg) Pazopanib per day should be taken orally without food at least one hour before or two hours after a meal. Pazopanib will be given d1-14 each cycle (2 weeks cycles) with 12 cycles of chemotherapy FLO (d 1, each cycle). After 12 cycles chemotherapy FLO will be discontinued and Pazopanib will be given alone until disease progression

DRUG

5-FU, Oxaliplatin, Leukovorin (FLO)

Oxaliplatin 85 mg/m2 2h iv Leucovorin 200mg/m2 2h - iv FU 2600mg/m2 24h iv q2w for 12 cycles

Sponsors & Collaborators

• Charite University, Berlin, Germany

  lead OTHER

Principal Investigators

• Peter Thuss-Patience, MD · Charite University medicine

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2011-11-30

Primary Completion

2017-12-14

Completion

2017-12-14

Countries

• Germany

Study Locations