Panel Recommends Hycamtin Approval for Ovarian Cancer

May 1, 1996

BETHESDA, Md--The FDA's Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval of SmithKline Beecham's Hycamtin (topotecan HCl) for the treatment of patients with metastatic ovarian cancer after failure of initial or subsequent chemotherapy.

BETHESDA, Md--The FDA's Oncologic Drugs Advisory Committee (ODAC)has unanimously recommended approval of SmithKline Beecham's Hycamtin(topotecan HCl) for the treatment of patients with metastaticovarian cancer after failure of initial or subsequent chemotherapy.

Hycamtin is the first topoisomerase I inhibitor to be recommendedfor approval in the United States. This new class of drugs killscancer cells by inhibiting the enzyme toposiomerase I, which isessential in the replication of DNA.

At the ODAC hearing, Colin Broom, MD, of SmithKline Beecham, saidthat ovarian cancer is diagnosed in an estimated 26,700 womeneach year in the United States, and about 14,800 US women dieannually from the disease. About 30% to 50% of women treated forovarian cancer will relapse, with the recurring cancer often resistantto the original chemotherapy. Second-line drugs are then neededto treat the recurrence.

Dr. Eric Rowinsky, of Johns Hopkins Oncology Center, describedthree phase I trials examining safety and pharmacology. He saidthat the major toxicity of Hycamtin is hematological, particularlyneutropenia. He noted that, based on these studies, a phase IIdose was recommended and consistently used in all the trials.

Maurie Markman, MD, of the Cleveland Clinic Cancer Center, speakingin support of the new drug application (NDA), summarized the resultsof the phase I trial (039), an open, randomized, multicenter studythat compared Hycamtin with Taxol (paclitaxel) in 226 women withrecurrent ovarian cancer after first-line platinum therapy.

Patients were randomized to either a 30-minute IV infusion ofHycamtin, 1.5 mg/m²/day for 5 days, or to a 3-hour infusionof paclitaxel, 175 mg/m², every 21 days.

The objective response rate (complete response plus partial response)was 20.5% for Hycamtin vs 13.2% for paclitaxel, with a medianduration of response of 32.1 weeks for Hycamtin vs 19.7 weeksfor paclitaxel. The median time to progression was 23.1 weeksfor Hycamtin vs 14 weeks for paclitaxel (P = .0021). Median survivalwas 61.3 weeks for Hycamtin vs 42.6 weeks for paclitaxel (P =.5153).

Dr. Markman said that the difference in time to progression betweenHycamtin and paclitaxel was significant. A comparison of the qualityof life of patients on the two drugs showed little difference,and there was no statistical difference in the rate of survivalbetween patients on Hycamtin and those on paclitaxel.

He concluded that Hycamtin "is active in ovarian cancer andis comparable to paclitaxel in its activity."

Side Effects

Dr. Broom described trial 034, a noncomparative study in 111 womenwith recurrent ovarian cancer after first-line platinum therapy,carried out for the purpose of obtaining safety and toxicity data.The study to date has shown that toxicity, in the form of neutropenia,is "predictable, noncumulative, reversible, and manageable,"he said.

In the combined ovarian cancer studies, 80% of 445 patients receivingHycamtin experienced grade 4 neutro-penia, but only 18 patients(4%) withdrew from the study due to such hematologic and/or infectivecomplications, Dr. Broom said.

There were three deaths (0.7%) secondary to neutropenia. The mostfrequently reported nonhematologic side effects were gastrointestinal,including nausea and vomiting.

Steven Hirschfeld, MD, PhD, representing the FDA, also summarizedtrials 034 and 039. He said that the results of the two trialsin his analysis were comparable to the results SmithKline Beechamdescribed.

Hycamtin had a similar modest response rate to that of paclitaxel,but with significantly greater hematologic toxicity. He concludedby saying that Hycamtin represents an alternative to current salvagetherapies for women with ovarian cancer.

The ODAC Vote

The FDA panel then voted on four points. On point one, they votedunanimously that study 039 was adequate and well-controlled, andsupports the company's NDA.

On point two, they voted 7 to 1 that study 034 was adequate andwell-controlled, and supports the NDA. Richard Gelber, PhD, professorof pediatrics (biostatistics), Dana-Farber Cancer Institute, votedagainst this point, stating that study 034 could not stand aloneas a valid study and was only helpful when combined with study039.

Other panel members pointed out that the group of patients whodid respond in study 034 were from a hard-core, non-responsivegroup, and thus the results were valid.

The panel voted unanimously for point three, that the toxicityof Hycamtin is acceptable for patients with recurrent ovariancancer.

On the final point, the panel eliminated a clause that would havelimited the indication only to women who had specifically undergoneplatinum therapy, and voted unanimously to recommend that Hycamtinbe approved "for treatment of patients with metastatic carcinomaof the ovary after failure of initial or subsequent chemotherapy."