Targeting the Hedgehog Pathway in Stomach Cancer
Name of the Trial
Phase II Randomized Study of FOLFOX Chemotherapy With Versus Without Hedgehog Antagonist GDC-0449 in Patients With Advanced Gastric or Gastroesophageal Junction Carcinoma (NYCC-09-0356). See the protocol summary.
Dr. Deirdre Cohen, New York University Cancer Center
Why This Trial Is ImportantStomach cancer is one of the leading causes of cancer-related deaths worldwide. Although the overall incidence of stomach cancer has been declining in the United States, the rates of cancers of the upper stomach (called the proximal stomach) and gastroesophageal junction (where the esophagus enters the stomach) have been increasing over the past 20 years, especially in people younger than age 40. Surgical resection can be potentially curative, but most patients are not diagnosed until after the cancer has spread and can no longer be removed surgically.
Clinical trials have shown that patients who have advanced stomach cancer that cannot be removed surgically live longer if they are treated with chemotherapy compared to best supportive care. However, substantial improvements in long-term survival have not been obtained using standard chemotherapy agents alone.
Doctors are currently exploring the use of a new drug, called GDC-0449, in patients with advanced, inoperable stomach cancer. GDC-0449 targets a signaling pathway called the Hedgehog pathway, which is active in developing embryos and helps regulate cell proliferation and maintenance in many adult tissues. Abnormal activation of the Hedgehog pathway has been observed in a number of human cancers, including stomach cancer. Adding GDC-0449 to standard chemotherapy may be more effective than standard chemotherapy alone in prolonging the survival of patients with advanced stomach cancer.
This phase II trial will recruit patients with inoperable cancer of the stomach or gastroesophageal junction who have not been previously treated for advanced disease. The patients will be randomly assigned to receive either the combination chemotherapy regimen FOLFOX plus GDC-0449 or FOLFOX plus a placebo. Doctors want to see if adding GDC-0449 to FOLFOX will improve progression-free survival. They will also assess the relationship between several biological characteristics of the patients and their clinical outcomes.
“The Hedgehog pathway is thought to be one of the driving forces leading to cancer growth in gastric and gastroesophageal junction cancer,” said Dr. Cohen. “The premise, based on solid preclinical research, is that inhibiting this pathway will lead to increased cancer cell death.
“FOLFOX chemotherapy is one of the accepted standards for this cancer, so patients will receive either the standard of care, or the standard of care plus this experimental drug,” Dr. Cohen explained. “In phase I testing, GDC-0449 was very well tolerated and had no dose-limiting toxicities, so we’re hopeful that it won’t add toxicity to the FOLFOX regimen.”