March 2, 2001

VICC leads new cancer drug study

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Dr. Mace Rothenberg is the principal investigator of the Phase III trial. (photo by Dana Johnson)

VICC leads new cancer drug study

The Vanderbilt-Ingram Cancer Center is leading one of two national studies of a new drug that may offer hope for patients with recurrent colorectal cancer.

Dr. Mace L. Rothenberg, Ingram Associate Professor of Cancer Research, is the principal investigator of a Phase III trial designed to determine the activity of oxaliplatin in patients with metastatic colorectal cancer that has progressed following first-line chemotherapy.

Oxaliplatin is a platinum-derivative that is related to cisplatin and carboplatin, two of the most effective drugs used against cancer. Oxaliplatin contains a structural modification that changes – and in some ways enhances – its anti-tumor activity against certain cancers. This difference is most pronounced against cancers arising in the colon or rectum.

“In a screening test performed by the National Cancer Institute, oxaliplatin had significant activity against six of eight human tumor cell lines, while cisplatin and carboplatin were totally inactive against all eight,” said Rothenberg. “This activity has also been seen in clinical trials of oxaliplatin, where response rates as high as 60 percent have been seen in patients with advanced stage colorectal cancer.

Clinical data on oxaliplatin comes primarily from clinical trials performed in France. “In randomized Phase III studies performed there, response rate and time to tumor progression were significantly enhanced by oxaliplatin,” he said.

Response rate and time to progression are two commonly used endpoints in clinical trials to evaluate drug effectiveness. Response rate takes into account the proportion of tumors that shrink by a pre-determined percentage (usually 50 percent), while time to progression reflects how long a tumor was held in check before it began to grow again. On the basis of these data, oxaliplatin gained regulatory approval in France in 1996 and is now approved in many countries in Europe, Central and South America and Asia.

In March of last year, the manufacturer of oxaliplatin, Sanofi-Synthelabo, sought approval from the U.S. Food and Drug Administration. During that presentation, the Oncologic Drugs Advisory Committee, an independent panel of experts that advises the FDA on matters relating to cancer drug development, focused on an ironic aspect to the European data: despite substantial improvements in response rate and time to tumor progression, oxaliplatin did not significantly improve survival.

The advisory panel, which included Dr. David Johnson, Cornelius Abernath Craig Chair and Director o Oncology, turned down the request for new drug approval. The committee cited the failure of oxaliplatin to improve survival and the increased toxicity experienced by these patients as the primary reason for their decision.

“The committee’s standard for approval is that, for a new cytotoxic drug that adds toxicity, you must see improved survival,” Rothenberg said.

“In one way, this was a disappointment because there is tantalizing evidence that oxaliplatin is active against colorectal cancer. However, something good came out of this adverse decision. It prompted the rapid development and implementation of two North American trials designed to assess the drug’s effectiveness.

“If oxaliplatin is an active drug, then these trials will demonstrate that in a definitive way. If, on the other hand, the activity of oxaliplatin is more apparent than real, then these trials will also be valuable and will allow us to redirect our efforts to other promising compounds.”

Overall, the two trials will be conducted in more than 100 centers in the United States and Canada and aim to enroll a total of more than 1,200 patients whose advanced colorectal cancer has recurred after standard “front-line” treatment.

The study that Rothenberg is leading and which will be offered at Vanderbilt-Ingram will enroll patients who have already undergone treatment with a combination of the drugs irinotecan, 5-fluorouracil (5-FU) and leucovorin. Patients will be randomly assigned to one of three arms: one group will receive oxaliplatin alone; another will receive a regimen of 5-fluorouacil and leucovorin; and the third group will receive oxaliplatin in combination with the two other drugs.

The other study, chaired by Dr. Daniel Haller of the University of Pennsylvania, is being conducted in patients whose colorectal cancer has progressed after receiving 5-FU and leucovorin, without irinotecan, as their front-line therapy. These patients will be randomly assigned to receive either irinotecan or irinotecan in combination with oxaliplatin.

The trials will address not only response rate, time to progression and overall survival, but will also examine effects of the treatment on tumor-related symptoms.

“Patients with advanced colorectal cancer may experience weight loss, abdominal pain, nausea, loss of appetite, and bloating… all of which can be very uncomfortable,” Rothenberg said. “An important beneficial effect of therapy would be the alleviation of existing symptoms or a delay in the onset of tumor-related symptoms. We are collecting this data in a standardized fashion in both trials. This could provide important insights on the benefit of oxaliplatin, above and beyond its effect on survival.

“Ultimately, our goal is to help patients with cancer live as well as possible for as long as possible.”