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The Oncologist, Vol. 10, No. 3, 183-190, March 2005; doi:10.1634/theoncologist.10-3-183
© 2005 AlphaMed Press

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Original Paper
Gastrointestinal Cancer

Phase II Trial of Oral Rubitecan in Previously Treated Pancreatic Cancer Patients

Howard A. Burris, IIIa, Saul Rivkinb, Robert Reynoldsc, Jules Harrisd, Arnold Waxe, Hal Gersteinf, Karl L. Mettingerg, Arthur Staddonh

a The Sarah Cannon Cancer Center, Nashville, Tennessee, USA; b Swedish Medical Center, Seattle, Washington, USA; c Walt Disney Memorial Hospital, Orlando, Florida, USA; d Rush Presbyterian St. Luke’s Hospital, Chicago, Illinois, USA; e Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; f Cancer Institute of Long Island, Great Neck, New York, USA; g Supergen, Inc., Dublin, California, USA; h Pennsylvania Hospital, Philadelphia, Pennsylvania, USA

Correspondence: Howard A. Burris, III, M.D., The Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 110, Nashville, Tennessee 37203, USA. Telephone: 615-986-4300; Fax: 615-986-0029; e-mail: hburris{at}tnonc.com


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
After completing this course, the reader will be able to:

  1. Describe the current standard of care for the treatment of advanced pancreatic cancer.
  2. State the rationale for treating refractory, advanced pancreatic cancer with the novel oral topoisomerase-I inhibitor rubitecan.
  3. Describe how the phase II trial results of oral rubitecan in pretreated, advanced pancreatic cancer compare with those from prior trials of rubitecan and gemcitabine in advanced pancreatic cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
Background. Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (OrathecinTM; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy.

Methods. Fifty-eight patients with failed or relapsed advanced pancreatic cancer after receiving at least one prior chemotherapy regimen were enrolled to receive eight consecutive weeks of treatment with rubitecan at a dose of 1.5 mg/m2 orally on five consecutive days per week, followed by 2 days off therapy, repeatedly. The primary end point was response rate. Time to progression, overall survival, changes in CA19-9 levels, and the composite measure of clinical benefit response were evaluated as secondary end points.

Results. Among 43 patients with measurable disease, 7% (3/43) achieved partial responses and 16% (7/43) had disease stabilization for an overall response and disease stabilization rate of 23%. All responses were confirmed by independent radiology review. Median survival was longer in responding patients than in the overall study cohort (10 months versus 3 months). Gastrointestinal and hematologic toxicities were the most commonly reported adverse events.

Conclusion. Oral rubitecan produced responses and was well tolerated by heavily pretreated patients with refractory pancreatic cancer. The overall risk-benefit profile of oral rubitecan appears promising, supporting further evaluation in phase III trials in patients with refractory and chemotherapy-naïve pancreatic cancer.

Key Words. Pancreatic neoplasms • 9-nitrocamptothecin • Antineoplastic agents • Rubitecan


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
The annual incidence of pancreatic cancer is nearly equivalent to the annual mortality, estimated to be 31,860 and 31,270, respectively, in the U.S. in 2004 [1]. Patients with locally advanced and metastatic pancreatic cancer have poor prognoses, and diagnosis generally occurs too late for surgery or radiotherapy to be curative. Chemotherapy can provide symptom relief for some patients with advanced pancreatic cancer, but its impact on survival has been modest to date. Historically, 5-fluorouracil (5-FU) was the drug of choice for the systemic treatment of advanced pancreatic cancer, but in single-agent studies conducted in the era of computed tomographic (CT) assessment of tumor response, response rates rarely exceed 20%, with median survival times of 4.2–5.5 months [2]. Compared with 5-FU, first-line treatment with gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) produced a modest median survival advantage (5.7 months versus 4.4 months) and was shown to be more effective for palliation of patients with symptomatic, advanced disease in a randomized clinical trial [2]. In first-line studies, gemcitabine was associated with response rates ranging from 5.4%–14.3%, with median survival times ranging from 5.0–6.3 months [2–7]. Gemcitabine has been used in combination with other agents, including 5-FU, cisplatin (Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), irinotecan (Campostar®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com), and capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com), but no combination regimen has yet shown clear evidence of superiority to single-agent gemcitabine with respect to palliation or survival [8].

Rubitecan (9-nitro-20(S)-camptothecin; OrathecinTM; SuperGen Inc., Dublin, CA, http://www.supergen.com), a water insoluble camptothecin derivative, is a topoisomerase-I inhibitor with broad antitumor activity in human xenograft models [9]. Topoisomerase-I facilitates DNA replication by forming a complex with DNA to induce single-strand breaks that are necessary for DNA relaxation, with subsequent repair [10]. Like other topoisomerase-I inhibitors, rubitecan acts to inhibit DNA religation by stabilizing the topoisomerase-I–DNA complex. In human tumor xenograft models, the antitumor activity of rubitecan has been shown to be superior to those of topotecan (Hycamtin®; GlaxoSmithKline, Philadelphia, PA, http://www.gsk.com) and irinotecan [11, 12]. In a pancreatic tumor xenograft model, the administration of rubitecan for 5 days per week for 4 weeks to mice inoculated with human pancreatic CFPAC-1 carcinoma resulted in a dose-dependent decrease in mean tumor volume out to 64 days, with no tumor regrowth seen at the highest dose (2.0 mg/kg/day) [13].

Because rubitecan is water insoluble, it has been formulated as an oral agent, which may be a convenient, cost-effective option for the management of advanced pancreatic cancer. In addition, the antitumor activity of rubitecan depends on delivery of the molecule in its intact lactone form. When hydrolyzed to the carboxylate form under neutral or basic conditions, rubitecan has little antitumor activity [14]. When administered orally with an acidic beverage, rubitecan has shown activity in clinical trials. In a phase I study of rubitecan at doses of 1.0, 1.5, and 2.0 mg/m2/day in 28 patients with metastatic refractory cancer, five responses (one complete response [CR] and four partial responses [PRs]) were observed [14]. In another phase I study, which evaluated similar dose cohorts of rubitecan in 29 evaluable patients with refractory solid tumors, six responses were observed (five PRs and one CR in a patient with pancreatic cancer) [15, 16]. In previous phase II studies conducted in patients with pancreatic carcinoma, rubitecan was initiated at a dose of 1.5 mg/m2/day for 5 days per week, with dose adjustments based on patient response [17, 18]. In the European trial, 4 of 14 evaluable patients (29%) had objective responses (World Health Organization [WHO] criteria) and 93% had subjective responses as measured by pain relief and reduced analgesic use [18]. Among 60 evaluable patients in the U.S. study (receiving >8 weeks of treatment and a follow-up scan), nine (15%) had PRs (WHO criteria) and 19 (32%) responded, either by improvement on CT scan, decreased CA19-9 level, improved quality of life, or increased survival [17]. Responding patients had a median survival time of 18.6 months. The most common toxicities were hematologic, gastrointestinal, and genitourinary. Of note, in early clinical trials of rubitecan, cystitis (hemorrhagic/interstitial) occurred in 20%–22% of patients; however, hydration was not routinely administered [14, 17]. Patients were able to resume rubitecan, without consequence, by increasing their daily fluid intake to a minimum of 3 liters/day [14].

The current clinical trial was designed as an open-label, multicenter, phase II trial to evaluate the safety and efficacy of rubitecan at a dose of 1.5 mg/m2/day given orally for 5 consecutive days per week to patients with locally advanced or metastatic pancreatic cancer who had failed previous chemotherapy. The trial also sought to determine if increased hydration would minimize the incidence of cystitis, thus improving patient comfort and compliance.


   PATIENTS AND METHODS
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 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 Additional Reading
 
Patient Population
Adult patients with histologically or cytologically confirmed pancreatic cancer were eligible for the trial if they had failed or relapsed disease after receiving at least one prior chemotherapy regimen (other than gemcitabine alone). Patients who had received rubitecan or other camptothecin analogues in the past or who had received gemcitabine alone as the only previous chemotherapy treatment were not eligible. Prior chemotherapy had to have been completed at least 3 weeks prior to enrolling in this study, and there had to be sufficient recovery from the effects of any prior surgery, chemotherapy, radiotherapy, or immunotherapy. A Karnofsky Performance Status (KPS) score of 50 or better was required. Patients were required to have adequate baseline bone marrow, hepatic, and renal function, as demonstrated by granulocytes ≥1.5 x 109/l, hemoglobin ≥10 g/dl, platelets ≥100 x 109/l, serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase ≤3x the normal limits, serum bilirubin ≤2.0 mg/dl, and serum creatinine ≤2.0 mg/dl. Patients with tumor involvement of the liver were eligible if liver transaminase(s) were ≤5x the normal range. Patients scheduled for surgery within 8 weeks of treatment initiation and pregnant or nursing females were not eligible.

All patients gave written informed consent before enrolling in the trial, and the study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Treatment
Treatment was initiated in patients who successfully achieved pain stabilization after a 2- to 7-day run-in period. Rubitecan was supplied as hard gelatin capsules containing 0.5 or 1.25 mg. Eligible patients received treatment with rubitecan at a dose of 1.5 mg/m2 orally, rounded up to the nearest 0.25 mg increment, for 5 days each week, followed by 2 days off therapy, repeatedly, for 8 weeks. Doses were to be taken at the same time each morning. Patients were instructed to take the medication with orange juice, cola, or another acidic pH beverage and to increase their oral hydration to at least 3 liters/day.

The starting dose was chosen based on results of a phase I dose-escalation study and a phase II trial conducted in patients with pancreatic cancer [14, 17]. Four dose levels for rubitecan were predetermined for the study (Table 1Go). The dose was raised or lowered incrementally, based on each individual patient’s weekly blood count and assessment of toxicity. Treatment was planned to last for 8 weeks, but responding patients and those with stable disease could continue to receive additional courses of therapy until they met criteria for discontinuation.


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  		Table 1. Rubitecan dose schedules
 
The rubitecan dose level was modified for toxicity. Patients with no drug-related toxicity and a granulocyte and platelet nadir that never dropped below 2 x 109/l and 150 x 109/l, respectively, during the first 4 weeks of therapy had their daily dose increased to 2.0 mg/m2/day. Patients with a granulocyte nadir of 0.5–1 x 109/l or a platelet nadir of 50–100 x 109/l had treatment held and their dose decreased by one level. Patients with a granulocyte count <0.5 x 109/l or a platelet nadir <50 x 109/l had their dose held and decreased by two levels. For any degree of hematologic toxicity, treatment was held until platelet recovery to >100 x 109/l and granulocyte recovery to ≥1.5 x 109/l. G-CSF could be used in the event of neutropenia (≤0.5 x 109/l) or for the treatment of febrile neutropenia; however, it was not to be given concomitantly with rubitecan.

Dose modifications for nonhematologic toxicities, except for alopecia or emesis, were made according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC). No changes were made for CTC grade 0–2 toxicities. For grade 3 toxicities, the dose could be held or the dose level decreased by one step, at the investigator’s discretion. For grade 4 toxicities, treatment was held until recovery and resumed at two dose levels lower. Any patient with hematologic or nonhematologic toxicities that resulted in a chemotherapy delay for more than 2 weeks was to have a dose reduction by one level. Any patient with a dose delay greater than 6 weeks was removed from study.

Efficacy Evaluation
The primary end point of the study was objective tumor response rate. Antitumor efficacy was evaluated for all patients with bidimensionally measurable disease. A CT scan was performed at baseline in all patients, with follow-up scans performed every 56 days during the study. Images were digitized, and the product of the maximal length and width was used to calculate a two-dimensional area. If several measurable tumors were present, tumor size was represented by the sum of the areas.

For patients with measurable disease, objective tumor responses were determined using modified WHO criteria [19]. CR was defined as the complete disappearance of evident disease on CT scan and a normal CA19-9 level for at least 4 weeks. PR was defined by a >50% shrinkage of measurable disease for at least 4 weeks, with no new or progressive lesion(s). Stable disease (SD) was defined as a change in measurable disease too small to meet the requirement for PR or progression, with no new lesions for a period of at least 4 weeks. Progressive disease (PD) was defined as an unequivocal increase of at least 50% in the size of any measurable lesion, clear worsening of evaluable disease sites, the appearance of new lesions, the reappearance of any lesion that had disappeared, or significant deterioration in symptoms, weight, or performance status (unless the deterioration was clearly unrelated to the cancer). Patients with PD were removed from protocol treatment, but follow-up assessments were continued. Symptomatic progression was defined by worsening of symptoms, such as the development of ascites that required paracentesis in a patient with no clinical evidence of ascites at baseline, development of partial or complete bowel obstruction, significant deterioration in symptoms or weight, or a decrease in KPS score of 20 or more points.

Time to progression (TTP), overall survival, CA19-9 level, and clinical benefit response (CBR) were secondary end points. TTP was measured as progression-free survival and defined as the median time to radiological or symptomatic progression or death; overall survival was measured as the median time to death from registration on study. A CA19-9 CR was defined as CA19-9 values decreasing to normal (<37 U/ml) for at least 4 weeks, while a CA19-9 PR was defined as a >50% decrease in CA19-9 value, but not below 37 U/ml, for at least 4 weeks. CA19-9 SD was defined as a CA19-9 level increase or decrease of <25% for at least 4 weeks, and CA19-9 PD was defined as a 100% increase over the lowest elevated CA19-9 value recorded on study or any abnormal value if the patient had a normal level at baseline.

A patient was considered a clinical benefit responder if either: the patient demonstrated a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption or a 20-point or greater improvement in KPS score for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters, or the patient was stable on all of the aforementioned parameters and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation. Sustained worsening was defined as four consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in KPS score occurring during the first 12 weeks of therapy.

Patients were followed until disease progression and death. The date and cause of death of each patient enrolled in this study were recorded, including deaths of patients withdrawn from protocol treatment, if details were known.

Safety Evaluation
Patients were evaluated by weekly hematology and urinalysis and monthly physical exams, blood chemistry, and CBR assessment. Safety was assessed by evaluating adverse events and laboratory analyses. Adverse events were coded using the CTC criteria, when applicable, and investigator assessments of severity in other cases. The CTC criteria were used for laboratory analyses, when available.

Statistical Methods
All patients who received at least one dose of rubitecan were included in the safety and efficacy analyses. Kaplan-Meier life-table analyses were used to determine TTP and survival. TTP was defined as the time from first treatment day to objective or symptomatic progression or death. Survival was calculated from the day of first treatment to death. CBR was examined by a repeated-measures analysis, with an examination of interactive variables.

A sample size of 50 patients was judged to be sufficient to allow an estimation of response rate, given that most patients were unlikely to have measurable disease and the expected response rate was less than 20%.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 Additional Reading
 
A total of 58 patients was enrolled in the trial between September 1998 and March 1999. Patient demographics are shown in Table 2Go. Most patients had stage IV disease. The pancreas was the most frequent site of tumor involvement, followed by the liver, ascitic fluid, and the lungs. More than half the patients had multiple sites of disease. Forty-three (74%) patients had received two or more prior chemotherapy regimens. One patient had not received prior chemotherapy, and seven had received gemcitabine alone as their only chemotherapy as exceptions from the inclusion criteria. Those eight patients are included in the analyses, as they were registered in the study; however, none obtained an objective response to treatment and all but one died within 1 year of treatment.


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  		Table 2. Baseline characteristics of enrolled patients
 
Most patients (69%) received 8 weeks of treatment or less. Approximately 60% received at least 6 weeks of treatment, while 31% received at least 8 weeks and 17% received at least 16 weeks. Weeks on therapy ranged from <1 to 64, with five patients continuing treatment for 28–64 weeks. Disease progression (n = 30) and symptomatic progression (n = 13) were the most common reasons for discontinuing treatment. Nine patients were withdrawn due to early death from disease progression. Only three patients (5%) discontinued the drug due to adverse events as the primary reason.

Objective Tumor Response
Forty-three patients (74%) had bidimensionally measurable disease and could be evaluated for tumor response (Table 3Go). No patient met the criteria for a CR, although three patients met the criteria of a PR as assessed by the investigator and four patients met this criteria as assessed by the sponsor. Seven patients (16%) met the criteria for SD. In evaluable patients who remained on study/treatment for at least one follow-up scan (n = 30), the overall response rate was 10%; disease stabilization was seen in seven patients (23%).


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  		Table 3. Independently verified best tumor response in patients with measurable disease
 
The radiographic images of the 15 patients who received at least 8 weeks of treatment and/or had scans available indicating responsive or stable disease were subsequently reviewed by an independent group (WorldCare Clinical Inc., Cambridge, MA) who determined the best response according to WHO criteria and protocol criteria. Independent radiologic review (IRR) confirmed PRs in three patients and minor responses or disease stabilization in seven patients.

Time to Event
The median time to disease progression for the 58 enrolled patients was 59 days (95% confidence interval [CI], 53–65 days), with a range of 6–456 days. The 6-month and 1-year survival rates were 17% and 9%, respectively. Median survival was 92 days (95% CI, 76–124 days), with a range of 8–1,749+ days. Among the patients treated for more than 8 weeks, the median survival was 170 days (range 75–1,208+ days). Three long-term survivors were censored at 703, 887, and 956 days. The median survival time for the 10 patients with verified disease response or stabilization by IRR was 309 days (range, 128–1,208).

CA19-9
CA19-9 values were available at baseline for 42 patients. Eighteen of those patients either had no follow-up measurement taken or were unevaluable as they had a follow-up within 1 month of the baseline measurement. One patient had normal CA19-9 values throughout treatment and was, therefore, not included in the analysis. Of the 23 evaluable patients, two (8%) had CRs and one (4%) had a PR (defined as a >50% decline from baseline in tumor marker level).

Clinical Benefit
Sufficient follow-up data to assess CBR were available for 35 patients, and three patients had evidence of clinical benefit. One patient experienced a sustained 20-point improvement in KPS score, concurrent with a partial tumor response and stabilization of CA19-9 level. One patient with disease stabilization experienced a sustained reduction in pain intensity along with a weight gain and a 10-point improvement in KPS score. A third patient with a partial tumor response had fluctuations in KPS score during the study, but ultimately achieved a 20-point improvement in the fourth month, with further improvements in the next 2 months.

Toxicity
All 58 patients received at least one dose of rubitecan and were included in the safety analysis. Treatment with oral rubitecan was generally well tolerated. Only three patients (5%) discontinued treatment due to toxicity as the primary reason. More than half the patients (55%) remained on their initial rubitecan dose of 1.5 mg/m2 throughout the study, and 11% had a dose increase to 2.0 mg/m2. Temporary dose delays of one or several days were necessary for 23 patients (40%). Among those patients, three had their dose decreased to 1.0 mg/m2, one patient had their dose decreased to 1.0 mg/m2 then to 0.75 mg/m2, and 19 patients required a change in the schedule to 4 days on and 3 days off (some of these patients returned to the previous dose schedule). The most common reasons for dose delay or reduction were hematologic or gastrointestinal toxicities.

The most commonly reported nonhematologic adverse events were asthenia, alopecia, diarrhea, anorexia, abdominal pain, and nausea and vomiting (Table 4Go). Over half the patients experienced nausea and/or vomiting, although in most cases, these events were of grade 1 or 2 severity. The rates of grade 3 nausea and vomiting were 12% and 14%, respectively, and no patient had a grade 4 event. Diarrhea was reported in 40% of patients and was severe (grade 3) in 9% of patients. With increased hydration in this protocol, only one patient (2%) experienced cystitis.


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  		Table 4. Nonhematologic adverse events reported
 
Hematologic toxicities were also frequently reported (Table 5Go); however, many of these patients had grade 1–2 hematologic toxicities at baseline. Fifteen patients (26%) developed grade 3 or 4 leukopenia, 12 (21%) had grade 3 or 4 neutropenia, six (10%) had grade 3 or 4 thrombocytopenia, and seven (12%) had grade 3 anemia during the study. Of four cases in which a diagnosis of sepsis was reported or considered, two had confirmed bacteriemia and recovered on i.v. antibiotics, one case was consistent with febrile neutropenia, and one case had a white blood cell (WBC) count of 3 x 109/l. There were nine patient deaths during the study, and an additional 18 patients died within 30 days of receiving the last dose of rubitecan. All deaths were related to disease progression, although, for one patient whose death was attributed to disease progression, dehydration and kidney failure categorized as probably related to the study drug may have been contributing factors.


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  		Table 5. Highest CTC grade hematologic toxicity during study
 

   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 Additional Reading
 
The current study was designed as a phase II, open-label study to explore the activity of oral rubitecan in heavily pretreated patients with locally advanced or metastatic refractory pancreatic cancer. The majority of patients enrolled in this trial had stage IV disease and most (72%) had received 2–5 prior chemotherapy regimens. Despite these characteristics, treatment with oral rubitecan was feasible in most patients, and more than half the patients were able to continue treatment beyond 6 weeks. A third of the patients continued treatment beyond 8 weeks, and five patients continued treatment for 6 or more months. In these heavily pretreated, poor-prognosis patients, tumor growth control was achieved in 23% (7% PR rate, 16% SD rate), as confirmed by IRR. Most notably, evaluable patients who remained on study for at least one follow-up scan had an objective response rate of 10% and an SD rate of 23%. Median survival was longer in patients with PRs or SD than in the overall study population (10 months versus 3 months, respectively). Four of these patients lived for more than 1 year, two lived for more than 2 years, and one lived for more than 3 years. These results are encouraging and warrant further evaluation of oral rubitecan in refractory patients as well as in the first-line setting, where it might be even more effective.

The response rates reported in this trial compare favorably with previous results with rubitecan and gemcitabine in patients with pancreatic cancer [2, 3, 17, 20, 21]. In the previous phase II single-center study of rubitecan, an investigator-assessed response rate of 7% (per WHO criteria) was reported [17]. In first-line gemcitabine studies, response rates for patients with measurable disease ranged from 3%–12% [2, 3, 20, 21]. In the pivotal first-line, randomized gemcitabine trial, despite a tumor response rate for gemcitabine of only 5% and no responses confirmed by blinded radiology review, there were statistically significant improvements in survival and CBR compared with patients who received 5-FU. This finding highlights the difficulty in assessing changes in measurable disease, which can be compromised by fibrosis and local inflammation, and suggests that, in addition to complete and partial responses, disease stabilization may be an important end point to evaluate in pancreatic cancer.

Small reductions in tumor size classified as stable disease may often cause major improvements in pain symptoms [22]. Thus, stable disease, as well as objective tumor responses, may be an index of tumor growth control and a predictor of clinical benefit and has been suggested as a primary goal of palliative treatment for advanced pancreatic cancer [22].

Treatment with oral rubitecan was generally well tolerated in this heavily pretreated patient population, and only three patients discontinued treatment due to toxicity as the primary reason for study withdrawal. Gastrointestinal events were the most commonly reported adverse events. Grade 3–4 nausea and vomiting were reported by 12%–14% of the patients in this study, and 9% experienced grade 3–4 diarrhea. The incidence of grade 3–4 neutropenia was 19%. Although WBCs fell suddenly in some patients, checking blood counts weekly according to the study protocol identified patients quickly, and clinical sequelae were negligible. Furthermore, while dose delays or dose reductions were relatively common, they were generally easy to manage with an oral formulation.

An additional purpose of the study was to evaluate the impact of increased oral hydration on the rate of cystitis. Patients in the current trial were advised to drink a minimum of 3 liters of fluid per day during treatment. With this recommendation, only one patient (2%) developed cystitis in this trial, compared with 20%–22% in previous studies [14, 17]. Thus, hydration appears to be effective and feasible in this patient population.

The results of this study demonstrate that oral rubitecan has activity in refractory, advanced pancreatic cancer, with an acceptable safety profile. Taken together with the results of a previous phase II trial in pancreatic cancer, the data support the evaluation of oral rubitecan in refractory patients, as well as in the first-line setting.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
Supported by a grant from SuperGen, Inc.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
Additional Reading
 

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  18. Konstadoulakis MM, Antonakis PT, Tsibloulis BG et al. A phase II study of 9-nitrocamptothecin in patients with advanced pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2001;48:417–420.[CrossRef][Medline]
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  20. Rothenberg ML, Moore MJ, Cripps MC et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996;7:347–353.[Abstract/Free Full Text]
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   ADDITIONAL READING
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
    Heinemann V. Present and future treatment of pancreatic cancer. Semin Oncol 2002;29(suppl 9):23–31.

    Von Hoff DD, Bearss D. New drugs for patients with pancreatic cancer. Curr Opin Oncol 2002;14:621–627.[CrossRef][Medline]

    Ulukan H, Swaan PW. Camptothecins: a review of their chemotherapeutic potential. Drugs 2002;62:2039–2057.

    Pantazis P, Han ZY, Chatterjee D et al. 9-Nitrocamptothecin. Drugs Future 1999;24:1311–1323.[CrossRef]

Received October 27, 2004; accepted for publication December 9, 2004.




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