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The experimental drug canfosfamide failed to achieve survival end points in two phase III trials in patients with platinum-refractory or -resistant ovarian cancer.
One study compared canfosfamide (TLK286, Telcyta) and carboplatin with pegylated liposomal doxorubicin (Doxil) as second-line treatment in 247 patients recruited at 66 sites. Dr. Peter G. Rose said progression-free survival was 3.5 months in both arms of the trial.
A subgroup of 38 patients (19 in each arm) characterized by a drug-free period of 6 months or longer responded more favorably to the combination, with an overall response rate of 31.6%. Drug-free period was defined as the time from last treatment with platinum-based chemotherapy to initiation of first study treatment.
The second trial compared single-agent canfosfamide to topotecan (Hycamtin) or pegylated liposomal doxorubicin in 461 women with disease progression following second-line treatment with doxorubicin or topotecan. Dr. Ignace Vergote, University Leuven (Belgium), said median overall survival was 8.5 months for canfosfamide, 10.8 months with topotecan and 14.2 months with doxorubicin (P = .0001).
Telik Inc. sponsored both studies.
Dr. Rose's group randomized 123 women to receive intravenous canfosfamide (750 mg/m²) in combination with carboplatin (AUC = 5) monthly, while 124 women received doxorubicin at 50 mg/m² monthly. Though more frequent in the combination arm, hematologic toxicity was well managed with growth factor support or dose reductions, according to the investigators. Grade 3/4 thrombocytopenia occurred in 33% of the women on canfosfamide and carboplatin. About 20% of both arms had grade 3/4 neutropenia.
The combination's failure to meet end points "may in part be due to the challenges of radiologic imaging interpretation in ovarian cancer as well as to the complex biology involved in platinum resistance and resensitization," said Dr. Rose, a professor of reproductive biology and oncology at Case Western Reserve University, Cleveland. According to the independent radiology review, about one-fourth of patients may have been prematurely discontinued from study involvement, confounding the analysis.
Discussant Dr. Carol Aghajanian of Memorial Sloan Kettering Cancer Center said, "It's unfortunate that the response rate is not reported—the authors explaining that response rate varied too much between clinician assessments and radiology review assessments—and it's disappointing that the trial's final results could not be analyzed."
In the trial reported by Dr. Vergote, 232 patients received canfosfamide at 1,000 mg/m² intravenously every 3 weeks, while 229 patients received either topotecan at 1.5 mg/m² daily for 5 days once every 3 weeks, or doxorubicin at 50 mg/m² once monthly.
In addition to worse overall survival, median progression-free survival was 2.3 months for canfosfamide and 4.3 months for topotecan or doxorubicin (P = .0001). The overall response rate was 11% for topotecan or doxorubicin and 4% for canfosfamide.
"This study showed us that, as a single agent, canfosfamide doesn't have a lot of cytostatic effects, but other studies suggest that we may get better results by using this drug in combination," he said.
Vergote I. et al. Single agent, canfosfamide (C, TLK286) vs. pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P)-refractory or resistant ovarian cancer (OC): Phase 3 study results. Abstract LBA5528.
Rose P. et al. Phase 3 Study: Canfosfamide (C, TLK286) plus carboplatin (P) vs. liposomal doxorubicin (D) as 2nd-line therapy of platinum (P)-resistant ovarian cancer (OC). Abstract LBA 5529.
Commentary |
Rose et al. evaluated the new agent canfosfamide (TLK-286 or Telcyta) in combination with carboplatin vs. pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant disease. The rationale was the postulated mechanism of action for canfosfamide, which includes potentially reversing resistance to the platinum compounds. Further interest came from a phase II trial of canfosfamide plus cisplatin in patients with platinum-resistant disease, which produced an astoundingly high 56% response rate. The new study unfortunately showed no significant difference in overall efficacy between canfosfamide/carboplatin and PLD. It illustrates the difficulty of managing platinum-resistant ovarian carcinoma patients and the importance of evaluating efficacy in large, randomized phase III trials rather than smaller phase II studies, which can provide important clues to potential activity but also can be misleading because of small numbers of patients and the lack of a control arm. — J. Tate Thigpen, M.D.
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