Raltitrexed in Combination Used in Advanced Colon Cancer

NEW YORK—Patients with advanced colorectal cancer have a median survival of only 12 months with single-agent chemotherapy. New drugs and new drug combinations are being tested in an attempt to find more effective treatments for the disease. A panel of researchers discussed trials of raltitrexed (Tomudex) in combination with other drugs at the Chemotherapy Foundation Symposium XVII.

Raltitrexed, a thymidylate synthase (TS) inhibitor, has been approved for use in Europe and Canada, but not yet in the United States, said panel moderator Joseph R. Bertino, MD, chairman of the Department of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center.

Early findings of a phase I trial of raltitrexed with fluorouracil (5-FU) revealed a synergistic effect between the two drugs when raltitrexed is administered followed by 5-FU, but an antagonistic effect when the order of drug administration is reversed, reported Gary K. Schwartz, MD, of the Division of Solid Tumor Oncology, Memorial Sloan-Kettering.

In the trial, 59 patients (51 of whom had had prior therapy with 5-FU) received escalating doses of the two drugs, with raltitrexed delivered as a 15-minute infusion, followed 24 hours later by a 5-FU bolus. Treatment was repeated every 21 days. The maximum tolerated doses that emerged are 5.5 mg/m² of raltitrexed and 1,200 mg/m² of 5-FU.

The combination is well tolerated, Dr. Schwartz said, with prolonged neutropenia the dose-limiting toxicity. Grade IV mucositis and diarrhea were also seen.

“We observed antitumor response in this heavily pretreated patient population, with an impressive degree of stable disease,” Dr. Schwartz said. The results, he said, warrant phase II studies, but he added that the phase I trial continues and is still enrolling patients.

Raltitrexed Plus Oxaliplatin

Philippe Rougier, MD, professor of hepatogastroenterology and digestive oncology, Hôpital Ambroise Paré, Boulogne, France, reported results of a multicenter phase II French trial of raltitrexed combined with oxaliplatin. Oxaliplatin (investigational in the United States) is a new, platinum-based drug that is structurally and functionally different from carboplatin (Paraplatin) and cisplatin (Platinol). It has been studied as a single agent and in combination with 5-FU, with and without leucovorin, Dr. Rougier said.

In this open-label trial, 3 mg/m² of raltitrexed was delivered as a 15-minute infusion, followed by a 2-hour infusion of oxaliplatin, 130 mg/m², every 3 weeks for six cycles. The study included 62 patients with previously untreated metastatic colorectal cancer.

“The regimen was well tolerated,“ Dr. Rougier said, with only three patients discontinuing treatment because of toxicity. Grade 1-2 neurotoxicity was seen in 97% of patients for a few days following each cycle. Grade 4 neutropenia was seen in 16.5%. There were two treatment-related deaths.

Although only 1.6% of patients achieved a complete response, 61% showed a partial response, for an overall response rate of 62.6%, Dr. Rougier said. The median duration of response was 8.5 months and median time to progression, 6.5 months.

Dr. Rougier called the combination of raltitrexed and oxaliplatin “highly active, convenient, tolerable, and feasible,” but cautioned that it is necessary to monitor neutropenia and diarrhea to avoid severe complications in this patient population.

Irinotecan Plus Raltitrexed

Irinotecan (Camptosar), a topo-isomerase I inhibitor with broad-spectrum activity in a wide variety of cancers, is being tested in combination with raltitrexed in metastatic colorectal cancer in an ongoing phase I trial. Jean Maroun, MD, head of medical oncology, Ottawa Regional Cancer Center, said that the trial aims to establish the maximum tolerated dose in preparation for a phase II trial.

Thus far, 18 patients have been enrolled. In addition to the standard inclusion criteria, participants must have adequate renal function, because raltitrexed is excreted through the kidneys, he said. Prior treatment with a thymidylate synthase inhibitor is permitted.

Irinotecan is administered as an IV infusion over 90 minutes. After a 15-minute break, raltitrexed is given as a 15-minute infusion. The cycle is repeated every 3 weeks. Irinotecan doses were escalated from 300 to 350 mg/m² and raltitrexed doses from 2.5 to 3.5 mg/m².

Although clinical benefit was not the primary study objective, Dr, Maroun said that stable disease has been observed in 53% of participants, with disease progression in only four (24%). Time to disease progression has ranged from 5 to 30 weeks. Dose-limiting toxicities have included febrile neutropenia, grade 3 fatigue, and diarrhea.

Dr. Bertino concluded the discussion on an optimistic note, observing that these three studies of raltitrexed in combination with a drug shown to be active in colorectal cancer “give hope for future progress. Each combination deserves further study.”