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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 120-126 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.016 Biweekly 72-Hour 9-Aminocamptothecin Infusion As Second-Line Therapy for Ovarian Carcinoma: Phase II Study of the New York Gynecologic Oncology Group and the Eastern Cooperative Oncology GroupFrom the New York University School of Medicine; Roosevelt Hospital; Mt Sinai School of Medicine; and New York-Cornell Hospital Center, New York, NY; and the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD. Address reprint requests to Howard Hochster, MD, New York University School of Medicine, 160 E 32nd St, New York, NY 10016; e-mail: howard.hochster{at}med.nyu.edu
PURPOSE: To determine the antitumor activity of the novel topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given over 72 hours every 2 weeks in patients with ovarian carcinoma previously treated with one platinum-containing regimen. PATIENTS AND METHODS: Patients with ovarian carcinoma who received one prior platinum-containing regimen were eligible. Patients were stratified based on whether their disease was measurable, or nonmeasurable but assessable. 9-AC 35 µg/m2/h was administered by continuous infusion for 72 hours every 2 weeks via ambulatory pump. RESULTS: Sixty patients were entered, 32 with measurable and 28 with nonmeasurable but assessable disease. Ten (16.7%) of 60 patients responded (95% CI, 7.2% to 26.1%), with four complete responses and six partial remissions. The response rate for patients with measurable and nonmeasurable but assessable disease was 22% (95% CI, 7.6% to 36.2%) and 10.7% (95% CI, 2.3% to 28.2%), respectively. None of the responders were platinum-resistant. Nineteen patients (32%) had stable disease. The major toxicities were hematologic, with 25% of patients having grade 3 and 35% having grade 4 neutropenia, including five episodes of febrile neutropenia, 17% having grade 3 to 4 thrombocytopenia, and 27% having grade 3 to 4 anemia. Nonhematologic toxicity included grade 3 to 4 nausea (27%) and grade 3 to 4 vomiting (12%). CONCLUSION: This phase II multicenter trial of biweekly 72 hour 9-AC infusion as second-line therapy for ovarian cancer demonstrates comparable activity to standard approved agents in patients with both measurable and nonmeasurable but assessable disease. Toxicity consists mainly of moderate but controllable myelosuppression. Further studies combining 9-AC with other agents active in ovarian cancer for use as second-line therapy are warranted.
Of the estimated 23,300 women who will be diagnosed with ovarian cancer this year, only 52% can expect to survive beyond 5 years from diagnosis despite optimal cytoreductive surgery and standard first-line chemotherapy [1]. Despite encouraging results with recent platinum-based regimens, up to 75% of women with ovarian cancer eventually experience relapse after first-line therapy and require further treatment [2]. Currently, there is no standard regimen proven most effective for second-line therapy for ovarian cancer, though agents such as topotecan and liposomal doxorubicin have received regulatory approval for this indication. Some reported response rates of the major single agents in second-line therapy include topotecan, with a response rate of 17% to 22% [3-5], liposomal doxorubicin, with a response rate of 20% [5], and gemcitabine, with a response rate of 15% to 19% [6-8]. Despite the regulatory approval of these compounds, the search for novel agents is crucial in the effort to improve overall survival in patients with ovarian cancer. Over the past 10 years, the camptothecins, which include both topotecan and irinotecan, have emerged as a promising family of compounds for the treatment of ovarian and other cancers. This class of antineoplastic agents acts by binding to and inhibiting topoisomerase I, an intranuclear enzyme that normally binds to DNA and facilitates the uncoiling of the supercoiled DNA by inducing single-stranded DNA breakage during S-phase replication and transcription. Once the drug is bound to the nuclear enzyme, the resulting drug-enzyme-DNA complex perpetuates the single-strand DNA breakage and converts topoisomerase I to a cellular poison. Collision of these cleavable DNA–topoisomerase I complexes with the replication fork leads to apoptosis and cytotoxicity [9]. Recent phase II studies of topotecan have shown efficacy in the treatment of recurrent ovarian cancer [3,4,10,11]. 9-aminocamptothecin (9-AC), a water-insoluble camptothecin, showed excellent preclinical activity in human colon cancer xenografts [12], prompting a series of clinical trials of its activity in colorectal and other cancers. These studies used multiple doses of 9-AC in lipophilic solvents, resulting in prolonged delivery of the agent. Phase I studies have also indicated clinical activity of 9-AC in patients with previously treated ovarian cancer [13]. The active terminal lactone ring of 9-AC is unstable and quickly hydrolyzed to the more water soluble but less active open-ring carboxylate [14]. Because of the transient nature of the 9-AC lactone, prolonged infusion is necessary to achieve adequate plasma levels and effective cytotoxicity [12,15]. Preclinical studies from the National Cancer Institute (NCI, Bethesda, MD) after the initial in vivo studies [12] demonstrated that the 72-hour drug exposure associated with depot administration was essential for activity as compared with rapid intravenous administration. When we initiated this trial, two phase I dose-finding studies had been completed under NCI sponsorship. The first study tested a 72-hour infusion given every 3 weeks [16]. The maximum-tolerated dose on this schedule was 45 µg/m2/h. The dose-limiting toxicity was neutropenia, and nonhematologic toxicities were mild. The second phase I trial examined a 72-hour continuous infusion given every 2 weeks in doses up to 59 µg/m2/h with the use of granulocyte colony-stimulating factor (G-CSF) [13]. The recommended phase II doses using this schedule were 47 µg/m2/h with G-CSF and 35 µg/m2/h without G-CSF. Pharmacokinetic studies also showed linear clearance of the 9-AC lactone, with less than a 5-hour terminal half-life after end of infusion. Less than 10% of the drug administered was found to be in the lactone form [17]. Neutropenia was again the dose-limiting toxicity. Other adverse effects of 9-AC noted in this trial were thrombocytopenia, anemia, nausea, vomiting, fatigue, and alopecia, all of which were more pronounced at the higher dose levels. We report here the results of our phase II trial using the lower dose of 35 µg/m2/h of 9-AC given over 72 hours every 2 weeks.
Patients This study was sponsored by the NCI's Cancer Therapy Evaluation Program and conducted by the New York Gynecologic Oncology Group. The Eastern Cooperative Oncology Group (ECOG) joined the study as an intergroup participant. Eligibility criteria required that patients have a histologic diagnosis of epithelial ovarian cancer with disease either measurable in two dimensions on computed tomography (CT) scan (  2 cm on CT scan or felt to be reproducibly measurable by the reviewing radiologist) or assessable on CT scan with elevated CA-125 levels (> 50 units/mL) on two baseline determinations. Examples of disease that is radiographically assessable but not measurable include fluid collections, small peritoneal implants, and intra-abdominal lymphadenopathy. All patients were required to have been previously treated with one and only one prior platinum-containing regimen for ovarian cancer and no investigational agents. Patients were to have received no therapy within 4 weeks before study entry. All patients were required to have adequate hematologic, renal, and hepatic function at baseline, with an absolute neutrophil count greater than 1,500/µL, serum creatinine  1.5 mg/dL, total bilirubin 1.5 mg/dL, and AST and ALT three times the upper limit of normal. Patients were required to have an ECOG performance status of 0 or 1 and a life expectancy of at least 3 months at study entry [18]. Patients were excluded if they had evidence of a second malignancy, significant infection, significant cardiac disease, intercurrent illness, uncontrolled diabetes, hypothyroidism, hypertension, or asthma. All patients provided written informed consent, as approved by each local institutional review board, before study entry. All patients were required to undergo placement of a central venous catheter for chemotherapy infusion. All patients who were treated are included in the analysis of toxicity and response (including three patients who on review were ineligible: two with performance status of 2 and one with incorrect pathology of carcinosarcoma).
Toxicity and Response Response to treatment was the primary end point of this study. For patients with measurable disease or radiographically assessable disease, response to therapy was determined by CT scan measurement graded by independent radiologists. Response was classified as complete, partial, stable, progressive, or nonassessable. A complete response to therapy required that all measurable and nonmeasurable but assessable disease resolve by CT scan and that CA-125 levels normalize. A partial response required that the sum products of all disease measurements decrease to less than 50% of baseline for patients with measurable disease. For patients with nonmeasurable but assessable disease, CA-125 levels were required to be reduced by at least 50% from baseline on two sequential measurements and remain decreased for at least 28 days. Patients with no significant change in measurable or nonmeasurable but assessable disease during a period of 4 weeks or more were considered to have stable disease. The development of new lesions or an increase in the size of baseline lesions by 25% or more constituted disease progression, and patients were subsequently withdrawn from the study.
Drug Treatment Anticipated side effects included leukopenia, thrombocytopenia, anemia, diarrhea, nausea, vomiting, alopecia, mucositis, and fatigue. Antiemetics were used as necessary. Treatment doses were held in patients with neutropenia or thrombocytopenia until their absolute neutrophil count returned to 1,500/µL or greater and their platelet count returned to 75,000/µL. Patients experiencing neutropenia with an absolute neutrophil count less than 500/µL, thrombocytopenia with a platelet count less than 25,000/µL, any grade 3 nonhematologic toxicity, or patients who had treatment held for two consecutive cycles secondary to toxicity were restarted at a decreased dose of 9-AC. Doses were decreased first to 700 µg/m2/d (29.1 µg/m2/h), then if toxicity persisted, to 600 µg/m2/d (25 µg/m2/h), and then to 435 µg/m2/d (18.1 µg/m2/h). Patients with grade 4 nonhematologic toxicities were restarted at doses reduced by 25%. Patients were treated until their disease progressed, responded completely, or until they were unable to tolerate therapy secondary to toxicity.
Statistical Methods
Patient Characteristics Sixty patients from 26 institutions were entered onto the study between December 5, 1995, and October 11, 2000. All 60 were assessed for response and toxicity. Patient characteristics are summarized in Table 1. The median age for the group was 62 years and ranged from 36 to 82 years. Thirty-two patients were enrolled in the measurable disease arm of the study, and 28 in the nonmeasurable but assessable disease arm. The most common tumor histologies were papillary serous (28 patients) and adenocarcinoma (20 patients). Twenty-eight patients had an ECOG performance status of 0, and 30 patients had an ECOG performance status of 1. Slightly more than half the patients had platinum-sensitive ( > 12 months) relapse, with platinum-resistant and -refractory patients also enrolled. Although eligibility criteria stated that each patient was to have ECOG performance status of 1 or less, two patients were enrolled and treated in our study and then later reported to have had performance status of 2 at study entry. Similarly, one patient was found after study enrollment to have a histologic diagnosis of carcinosarcoma and was thus considered ineligible. These three patients received study drug and are therefore included in our intention-to-treat analysis and assessed for toxicity and for response.
Treatment and Dosing A total of 471 bi-weekly cycles of 9-AC were administered to 60 patients. The median number of cycles per patient was five and ranged from one to 32, with 42 patients (70%) receiving three or more cycles. Twenty-five patients (42%) required treatment delays secondary to toxicity. Of the 49 cycles that were delayed because of toxicity, the majority (80%) resulted from delayed hematologic recovery, either for neutrophil or platelet count. Sixteen cycles were delayed at the patient's request, at the discretion of the treating physician, or secondary to logistical and scheduling difficulties. Overall, 86% of cycles were administered on schedule. Twenty patients (33%) required dose reductions secondary to toxicity. Three of these patients had their dose reduced twice. Ten dose reductions (17%) were for neutropenia, one was for thrombocytopenia, and nine (15%) were for grade 3 or 4 gastrointestinal toxicity (nausea, vomiting, or diarrhea). These results are summarized in Table 2. Five patients went off study because of toxicity, 38 patients went off study because of disease progression, six patients were removed from the study at the discretion of their treating physician, and 10 patients requested no further treatment. Only one patient died of progressive disease while on study.
Toxicity All 60 patients were assessable for toxicity. Toxicities are reported as the worst grade per patient according to NCI Common Toxicity Criteria [19] and are summarized in Table 3. Myelosuppression was the most common toxicity and the one predominantly responsible for treatment delays and dose reductions. Sixty percent of patients experienced neutropenia of grade 3 or worse. Gastrointestinal toxicity was also significant, with 27% of patients experiencing nausea of grade 3 or worse, and 20% experiencing vomiting of grade 3 or worse. Five patients died within 30 days of their last treatment. In all five cases, the cause of death was progressive disease. Two of these five patients were subsequently found to have had performance statuses of 2 at study entry, which violated entry criteria. The blood counts of all five patients had recovered to normal levels before their demise.
Additional unusual adverse events were reported in this study, including new-onset suicidal ideation with an attempted suicide after receiving her first dose of 9-AC and pulmonary fibrosis on day 17 of cycle one. Three patients experienced electrolyte abnormalities that may have been related to treatment with 9-AC or its vehicle; two had hypocalcemia (one grade 3, one grade 4), and the third patient had grade 3 hypocalcemia, hypokalemia, and hyponatremia.
Response
Four patients had a complete response to therapy, three with measurable disease and one with nonmeasurable but assessable disease. The patient with assessable disease showed complete resolution of baseline para-aortic adenopathy by CT scan as well as sustained normalization of her CA-125 levels; she remained disease-free for 25 months. Two of the patients with measurable disease showed complete resolution of their peritoneal metastases by CT scan accompanied by normalization of their CA-125 levels and remained disease-free for 18 and 24 months. The fourth patient was initially diagnosed with papillary serous ovarian carcinoma in 1991, experienced relapse in late 1995, and was enrolled in our study at that time. Baseline CT measurements described a 5-cm pelvic mass. After her fourth cycle of chemotherapy, CT scans showed a complete resolution of the pelvic mass, although her CA-125 level remained close to baseline. She refused further therapy after cycle 7. Remarkably, this patient has remained clinically and radiographically disease-free since discontinuing 9-AC therapy without further chemotherapy or surgery. At the time of this report she remains disease-free, with a progression-free survival of 78 months. For all responders, the median duration of response was 12.1 months (range, 4.6 to 78 months). Response data stratified by platinum sensitivity are summarized in Table 5. Only seven patients enrolled had platinum-refractory relapse, occurring within 6 months of completing prior therapy, and none of these patients responded to 9-AC. Nineteen patients had platinum-resistant relapse (between 6 and 12 months after last therapy), and two of these patients had partial remissions (11%). Of the remaining 34 patients with platinum-sensitive relapse, eight responders were observed (24%), including four complete and four partial remissions. These response rates are statistically equivalent given the small sample size.
Eighteen patients (30%) had stabilization of their disease while on study (95% CI, 18.4% to 41.6%), with a median duration of stable disease of 4.4 months (range, 0.2 to 15.6 months). All but one patient eventually experienced progression of their disease. The median progression-free survival for all 60 patients was 4 months, and the median overall survival from on-study was 15.6 months.
On the basis of prior studies that demonstrated the sensitivity of ovarian carcinoma to 9-AC and other camptothecins, we set out to determine this drug's efficacy as a second-line agent in patients pretreated with a single platinum-containing regimen. To date, phase II studies of 9-AC in other malignancies have been disappointing, showing minimal antitumor effect in colorectal, non–small-cell lung, and cutaneous T-cell lymphoma [20-23]. This has been attributed to a relative lack of lactone-ring formation for the 9-AC compound compared with topotecan and irinotecan. However, the equilibrium of lactone and carboxylate form is a pH-dependent phenomenon and may reflect the solvent system used for 9-AC administration as compared with physiologic or intracellular pH. In general, these nonresponsive tumors are those in which topotecan also has minimal activity. However, the topoisomerase I inhibitor topotecan followed the taxanes as a more recent, active agent for the treatment of ovarian cancer. Although topotecan may be administered by multiple daily 30-minute infusions, prolonged infusion has shown activity and less toxicity in ovarian cancer [4]. Infusional therapy of topoisomerase I inhibitors involves added logistic difficulties and costs related to use of pumps and central lines. In the case of 9-AC, preclinical studies demonstrated that intravenous bolus dosing of soluble drug was far less active than depot administration [14]. In this study, 9-AC had modest activity in pretreated ovarian cancer patients. Among our patients, 16.7% responded to 9-AC at this dose level, with 22% of patients with measurable disease responding. Furthermore, among those with measurable disease, three patients (9.4%) achieved complete response. All four complete responders had platinum-sensitive relapse, whereas among the six partial responders, four had platinum-sensitive, and two had platinum-resistant relapses. These response rates are well within the range of those reported for other second-line agents currently used to treat ovarian carcinoma, including paclitaxel (13.2% to 25%), topotecan (17% to 21.6%), and pegylated liposomal doxorubicin (19.7%) [2,3,5,24,25]. In addition, a more recent report of a single-institution phase II trial including 31 patients treated with the topoisomerase I inhibitor irinotecan reported a 17% response rate, with somewhat shorter time to progression and survival than reported here [26]. Neutropenia was the most common toxicity, with 60% of patients experiencing absolute neutrophil counts less than 1,000/µL. In addition, 27% of patients had nausea or vomiting of grade 3 or 4 in severity. Overall these toxicities were controllable with the usual supportive measures and reversible. Both hematologic and nonhematologic toxicities were slightly more severe than anticipated based on prior studies of 9-AC at this dose level [13,16,20,27]. However, trials using higher dose levels showed similar toxicity profiles, including frequent and marked myelosuppression [21-23]. One explanation for such increased toxicity in our study population is that our sample size of 60 patients is considerably larger than that of the previously cited trials, for which sample sizes ranged from 11 to 17 patients. Therefore, the CIs for toxicity of these reported studies overlap, and the toxicity rates observed here may be more representative of the true values. Another explanation involves the nature of the patient population. All patients in our study were previously treated, which may predispose to greater toxicity. Pazdur et al [20]conducted their trial of 9-AC in a previously untreated cohort of 17 patients with colorectal cancer. These patients may have been less prone to nausea, vomiting, and myelosuppression than those enrolled in our trial. In summary, 9-AC, when given as a 72-hour continuous infusion [16], resulted in a significant rate of response in patients with previously treated ovarian carcinoma. Toxicities were moderate, though somewhat more severe than expected based on prior studies at this dose level. However, with appropriate dose reductions and supportive care, all toxicities were both reversible and manageable, and the toxicity profile for this program is less than that reported in pivotal trials of topotecan and irinotecan [3,10,11,26]. The efficacy of 9-AC should be further evaluated, particularly in combination with other active agents and in patients resistant to topotecan. Further studies may clarify the issue of cross-resistance for various topoisomerase I inhibitors, particularly given the uniquely lipophilic and insoluble nature of 9-AC.
The authors indicated no potential conflicts of interest.
We thank the New York University Clinical Trials office personnel, including Peggy Nixdorf, Zoë Doran, RN, Anne Hamilton, MD, and Heather Wasserstrom, for their assistance in data management, and the personnel at the collaborating New York Gynecologic Oncology Group and ECOG sites for their assistance and faithful data submission.
This study was conducted in conjunction with the Eastern Cooperative Oncology Group and supported in part by Public Health Service grant No. CA21115 and grant Nos. CA16087, CA76642, CA21115(-27), N01-CM-07003-74S from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services, Bethesda, MD. Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
