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Phase II Study of Troxacitabine (BCH-4556) in Patients With Advanced and/or Metastatic Renal Cell Carcinoma: A Trial of the National Cancer Institute of Canada-Clinical Trials Group

From the Princess Margaret Hospital, University Health Network, Toronto; BCCA-Vancouver Cancer Centre; Tom Baker Cancer Centre, Calgary; CHUM-Pavillon Notre-Dame, Montreal; Toronto-Sunnybrook Regional Cancer Centre, Toronto; Ottawa Regional Cancer Centre; Shire Pharmaceuticals Development Inc; National Cancer Institute of Canada-Clinical Trials Group.

Address reprint requests to Malcolm J. Moore, MD, Department of Medical Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9 Canada; email: malcolm.moore{at}uhn.on.ca.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: A multi-institution phase II study was undertaken by National Cancer Institute of Canada–Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma.

Patients and Methods: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m² intravenously, once every 3 weeks.

Results: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically.

Conclusion: Troxacitabine given at a dose of 10 mg/m² once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

	INTRODUCTION

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RENAL CELL carcinoma (RCC) is a common urologic malignancy, accounting for 95,000 deaths worldwide.¹ In North America, it is estimated that there will be 34,000 new cases of RCC in the year 2001 and 13,500 people will die of their disease.^2,3 At the time of diagnosis, approximately one third to one half of patients with RCC will have incurable or unresectable disease, and 60% of patients’ will develop metastasis within 10 years postcurative nephrectomy.^4,5 Although there have been some improvements in the effectiveness of surgery and immunotherapy, most of the patients who develop metastatic or advanced RCC will still die within 1 year of disease development.⁶

RCC has been highly resistant to chemotherapy and radiation therapy. Progestational agents were previously thought to have some benefit; however, recent studies have not shown them to be of value.⁷ Biologic response modifiers, such as interleukin 2 (IL-2) and interferon alfa-2a (IFN-2a), are currently thought to be the most active agents for the systemic treatment of metastatic RCC. IL-2 and IFN produce response rates ranging from 15% to 30% in phase II studies; lower rates are observed in phase III studies. Phase III studies have demonstrated some improvement in survival from the use of IFN; the benefit in terms of quality of life is less clear because of the toxicity.⁸ Combinations of interferon with retinoids, fluoropyrimidines, and other cytokines have recently been the subjects of intense investigation.⁹ No clear benefit to these combinations has been demonstrated, and there is no standard therapy for patients who experience treatment failure or who do not respond to IL-2-based and/or interferon-based immunotherapy.¹⁰ These observations demonstrate the importance of novel treatment approaches for metastatic renal cell carcinoma.

Troxacitabine (BCH-4556; (-)-2'-deoxy-3'-oxacytidine, Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada) is a stereochemically nonnatural nucleoside analog that is a potent inhibitor and chain terminator for cellular DNA polymerases in vitro. It has shown to be efficient against RCC cell lines both in vivo and in vitro. Good responses were found in animals bearing CAKI-1, A498, and RXF-393 RCC tumors. Complete regression was observed in most of the animals tested.¹¹ It also previously has been shown to have potent antitumor activity in human prostate, pancreatic, and hepatocellular xenograft tumor models.^12–14

Three phase I studies of troxacitabine have been performed in patients with solid tumors using schedules of administration every 3 weeks, weekly, and daily for 5 days, respectively. In a study by National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG), troxacitabine was given as a 30-minute infusion every 3 weeks to a total of 45 patients in doses ranging from 0.025 to 12.5 mg/m². Two patients at the dose of 12.5 mg/m² experienced dose-limiting granulocytopenia (grade 4), and 10 mg/m² was chosen as the recommended dose for the initial phase II studies.¹⁵ A second study administered troxacitabine as a 30-minute intravenous infusion daily for 5 days every 3 weeks. Thirty-nine patients were treated at escalating doses ranging from 0.12 to 1.8 mg/m²/d. At troxacitabine doses 1.2 mg/m²/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to every 4 weeks. The recommended dose from this study for phase II studies of troxacitabine given as a 30-minute infusion daily for 5 days every 4 weeks was 1.2 mg/m²/d for heavily pretreated patients and 1.5 mg/m²/d for lightly pretreated patients.¹⁶ A third study gave the drug as a 30-minute infusion weekly for 3 weeks. No patient experienced skin rash, although myelosuppression prevented redosing at 4.27 mg/m², and the recommended dose for this schedule was defined as 3.2 mg/m² weekly for 3 weeks every 4 weeks.¹⁷ Overall, the dose-intensity and toxicity were similar for all three schedules; these results differ from those observed with other nucleoside analogs.

There have been limited phase II data reported with troxacitabine to date. NCIC-CTG performed a phase II study of troxacitabine in patients with non–small-cell lung cancer. The most common toxicity was skin rash (82% of patients).¹⁸ A phase I/II study of troxacitabine was performed in patients with advanced refractory leukemias starting at a dose of 0.72 mg/m²/d for 5 days every 28 days. The dose-limiting toxicities in this study were stomatitis and hand-foot syndrome (HFS). The recommended dose for this schedule and patient population was defined as 8 mg/m²/d.¹⁹ In phase II studies, a greater than 50% stable disease rate was observed in non–small-cell lung cancer¹⁸ and responses were observed in acute myelogenous leukemia.²⁰

Given the preclinical activity in renal cell cancer, the responses seen in early studies, and the urgent need for better therapies in this disease, a phase II trial of troxacitabine in advanced RCC was initiated by the NCIC-CTG.

	PATIENTS AND METHODS

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Patient Eligibility
Patients with histologically or cytologically confirmed advanced and/or metastatic RCC who were not eligible for curative radiotherapy or surgery were eligible for this study. The study protocol was approved by the institutional review boards at all participating sites, and patients were entered onto the trial after written informed consent was obtained. Other eligibility criteria included age 18 years, Eastern Cooperative Oncology Group performance score of 2 (ambulatory and capable of all self-care), and at least one site of bidimensionally measurable disease. To be considered measurable, a lesion must have been clearly defined by computed tomography (CT) scan, x-ray, or physical examination in at least two dimensions and must have measured at least 2 x 2 cm for CT scan and at least 1 x 1 cm for chest x-ray or physical exam. Bone lesions were not considered to be bidimensionally measurable. No previous chemotherapy for advanced or localized disease was permitted. Prior radiation was permitted, but patients had to have recovered from any acute toxic effects of the radiation before registration, and at least 4 weeks must have elapsed since the last dose of radiation. In addition, if the sole site of measurable disease was in a radiation field, there must have been documented progression at that site for the patient to be eligible. Previous treatment with IFN (with or without low-dose IL-2) was permitted if at least 4 weeks had elapsed since the last dose. No other immunotherapy or gene therapy was permitted.

Requirements for organ function included absolute granulocytes 1.5 x 10⁹/L, platelets 100 x 10⁹/L, serum creatinine within normal limits or creatinine clearance 60 mL/min, bilirubin within normal limits and AST or ALT 3 times the upper limit of normal or 5 times the upper limit of normal if liver metastases were documented. Women of childbearing potential must have had a negative urine pregnancy test and must have taken adequate precautions to prevent pregnancy during treatment. Patients were excluded if they had any prior malignancy, unless it was a superficial malignancy that was definitively treated at least 5 years previously, with no evidence of recurrence. Patients with documented brain metastases or any serious medical condition or illness that would not permit the patient to be managed according to the protocol were excluded. Any patients experiencing signs or symptoms of CNS metastatic disease must have had a computed tomography scan of the brain, with contrast, before enrolling. Pregnant or lactating women were excluded from the study.

Study Design and Treatment
This was a multi-institutional study conducted by the NCIC-CTG at six participating centers (Princess Margaret Hospital, University Health Network; Toronto–Sunnybrook Regional Cancer Centre; Ottawa Regional Cancer Centre, Toronto, Ontario; BCCA–Vancouver Cancer Centre, Vancouver, British Columbia; Tom Baker Cancer Centre, Calgary, Alberta; and CHUM–Pavillon Notre-Dame, Montreal, Quebec, Canada). Shire Pharmaceuticals supplied troxacitabine. Treatment was given on an outpatient basis unless the patient was in the hospital for other reasons. Troxacitabine was delivered at a dose of 10 mg/m² intravenously (IV) over 30 minutes once every 3 weeks. Hematology was examined weekly on days 1, 8, and 15 of each cycle. Biochemistry was evaluated on day 1 of each cycle. Radiology was evaluated on the last day of every even-numbered cycle. Toxicity was assessed and graded using National Cancer Institute Common Toxicity Criteria version 2.

Therapy was continued until the patient met withdrawal criteria or had progressive disease. Any patient who experienced grade 3 or 4 toxicity attributable to the therapy and not the underlying disease had therapy discontinued until toxicity resolved to less than grade 1. If toxicity took longer than 2 weeks to resolve, the patient was removed from the study. Patients with grade 3 or 4 skin rash or HFS, nadir granulocyte counts of less than 0.5 x 10⁹/L, or nadir platelet counts of less than 50 x 10⁹/L had their dose decreased by 25%. Patients who required more than two dose reductions were removed from the study. Patients were also removed from study for the following reasons: disease progression, intolerable adverse effects that were judged by the investigator to be either physically or psychologically detrimental to the patient, intercurrent illness interfering with protocol treatment and/or assessment, patient request to discontinue treatment, or investigator discretion.

Response Assessment
All patients who received at least one cycle of therapy were considered evaluable for response, and all patients were evaluable for toxicity from the time of their first treatment with troxacitabine. A complete response was defined as complete disappearance of all evidence of disease, as well as no new lesions or disease-related symptoms determined by two observations not less than 4 weeks apart. A partial response (PR) was defined as a 50% decrease from baseline in the sum of the greatest perpendicular diameters of all measurable lesions, with no new lesions and no increase in lesions determined by two observations at least 4 weeks apart. Progressive disease was defined as an increase of 25% in the sum of the products of measurable lesions, reappearance of any lesion that had previously disappeared, or the appearance of any new lesion. Stable disease was defined as not meeting the criteria for complete response, PR, or progression. Duration of response was measured from the time that measurement criteria were first met until disease progression was objectively documented. Overall survival was measured from the time of registration to the date of death resulting from any cause. Patients were seen at 4-week intervals while receiving treatment and at a minimum of 3-month intervals until progression and/or death after completion of protocol therapy.

Statistical Considerations
The purpose of this phase II study was to assess the antitumor activity of troxacitabine in a population of patients with metastatic RCC. A two-stage design was used to minimize the expected number of patients treated in the event that the regimen proved to be disappointing or successful. The regimen was to be rejected if the estimated true response rate was less than 5% and would be accepted as active if the true response rate was greater than 20%. The first stage was designed to accrue 15 patients. If no patients responded, the study would be closed and the regimen rejected as inactive. If one or more patients responded, an additional 15 patients would be accrued. In the final set of 30 evaluable patients, if three or fewer responses were observed the conclusion would be that the regimen is inactive. If four or more responses were observed the conclusion would be that the regimen is promising. An alpha error of 0.05 and a beta error of 0.10 were used, meaning that the null hypothesis is being tested such that the true response rate is 5% versus the alternative hypothesis that the true response rate is 20%. With this design, the probability of rejecting the null hypothesis when it is true is 0.058 and the power is 0.865 when the response probability is 20%. Treatment toxicity and Kaplan-Meier estimates of time to progression and overall survival were also determined.

	RESULTS

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Patient Characteristics
The study was centrally activated in June of 1999. After 15 patients were entered onto the study, accrual was held pending assessment of response in this first cohort. After documentation of a PR in one patient, the trial was reopened for the second stage of accrual in February 2000. The trial was closed in March of 2000 after the accrual of 35 patients at six different institutions. Table 1 lists patient demographics and clinical characteristics. All patients entered onto the study had measurable disease.

Response to Treatment
All 35 patients entered onto the study are evaluable for toxicity, and 33 patients are evaluable for response (two patients had only one cycle of treatment and did not have their disease reassessed). These patients are included in the intent-to-treat analysis in determining response rates and survival. Out of 33 patients, there were two confirmed PRs (6.1%). The duration of response for the two patients with PRs was 2.3 and 17+ months, respectively. Twenty-one patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. There are 11 patients with stable disease for 4 months or greater (of whom four patients have subsequently progressed) and eight patients with stable disease for greater than 6 months (of whom two patients have subsequently progressed; Fig 1). Of the two patients with a PR, one patient (a 45-year-old man with lung lesions) progressed after 2.3 months and the other patient (a 62-year-old woman with lung lesions) continues to have a near-complete response after 17 months. Including the two patients who were not evaluable, the results of the intent-to-treat statistics showed a response rate of 5.7% (95% confidence interval [CI], 0.7% to 19.2%).

View larger version (22K): [in this window] [in a new window]   Fig 1. Time to progression curve for NCIC-CTG trial I.119; (——), all patients. Summary statistics: median for all patients, 2.96; 95% confidence interval, 2.04 to 5.16.

The most common hematologic toxicity was granulocytopenia, with four episodes of febrile neutropenia. Biochemical toxicity was minimal. One patient had grade 2 elevation in bilirubin (normal baseline), and two patients had grade 2 hyperglycemia (normal baseline glucose). One patient, with grade 2 hyperglycemia at baseline, experienced grade 4 hyperglycemia while on study.

There were eight serious events assessed to be related to treatment. Four patients were hospitalized for febrile neutropenia and one was hospitalized for pancytopenia; all events were believed to be secondary to therapy. In addition, three patients were hospitalized for events believed possibly to be related to therapy: one patient for hyponatremia, one patient for skin rash, and one patient for diarrhea and colitis. There were no treatment-related deaths.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study demonstrates that troxacitabine may have modest activity against renal cell cancer. There were two confirmed responses, one of which is a durable near-complete remission. There were 21 patients who demonstrated stable disease, of whom eight patients remained stable for 6 months or longer. The toxicity of this drug in this intermittent schedule was manageable; hematologic and cutaneous toxicities were the most frequent events observed.

Although we did not achieve the number of responses that were predetermined to categorize this drug as worthy of further study, we did observe prolonged stability in 30% of patients. To what degree this is the result of the activity of the drug as opposed to the indolent and unpredictable nature of this disease is less clear. Although disease stabilization does occur as a part of the natural history of metastatic RCC,²¹ many phase II studies have shown relatively low rates or even lack of any stable disease.^22–25 This study has shown a moderate rate of stable disease, indicating that there may be some effect of the drug on the course of the disease. The results are similar to those seen with a similar nucleoside analog, gemcitabine, in a previous NCIC study.²⁶ There are certainly other areas of oncology in which drugs with low response rates and stable disease rates of 40% to 60% have been shown to improve survival, such as gemcitabine in advanced pancreatic cancer and irinotecan and docetaxel as second-line therapies in colorectal and lung cancers, respectively.

A true measure of the benefits of troxacitabine in advanced RCC can only come from a phase III study comparing a troxacitabine-based regimen to the current standard of care with survival and quality of life as the critical end points. This will be a challenge given the differing opinions about what currently constitutes standard therapy for advanced disease. In Canada, immunotherapy is not in widespread use, whereas in the United States, the use of IFN and IL-2 is more frequent. The toxicity of this drug is manageable on the 3-week schedule. Given the similarity in monthly dose administered and toxicity from all the phase I studies of troxacitabine, it is unlikely that the therapeutic ratio could be increased by using an alternate dosing or administration schedule. It will be up to the clinical research community involved in RCC trials to consider whether it is worthwhile to develop further trials with troxacitabine. A recent phase II study of thalidomide in advanced renal cancer showed a lack of responses and a stable disease rate of 16 of 25 patients (64%); these results are similar to those obtained by our group with troxacitabine. On the basis of the phase II data with thalidomide, the Eastern Cooperative Oncology Group has planned a randomized phase III trial.²⁷

A study by Motzer et al²¹ showed that there are five prognostic factors useful in predicting survival for RCC patients and that they can be used to categorize patients into three risk groups, for which the median survival times are separated by 6 months or more. Unfavorable risk factors include absence of a prior nephrectomy, low Karnofsky performance status (< 80%), high lactate dehydrogenase (> 1.5 times the upper limit of normal), low serum hemoglobin (less than the lower limit of normal), and high corrected serum calcium (> 10 mg/dL). This model reported three distinct groups with survival times of 20, 10, and 4 months for favorable-risk, intermediate-risk, and poor-risk patients, respectively. When our study data were examined for those risk factors, we were able to perform the analysis on 32 patients, although lactate dehydrogenase levels were missing for 12 patients.

The results of lactate dehydrogenase being assumed to be abnormal if it is missing can be found in Table 3. The results of lactate dehydrogenase being assumed to be normal if it is missing can be found in Table 4.

There remains an urgent need to develop new therapies for advanced renal cancer. The results with chemotherapy have been quite disappointing, and there is greater interest in novel agents such as signal transduction inhibitors, antiangiogenesis agents, or targeted immunotherapy. Some of these targeted therapies may be likely to produce disease stability, rather than tumor response. Thus, interpreting phase II studies in renal cancer to decide what therapies are worthy of study in larger (and more expensive and difficult) phase III studies will remain problematic. It may be useful to use data generated from previous phase II and III studies to define expected progression and progression-free rates that could then be used to define agents of interest in phase II studies.

Our current study indicates that the nucleoside analog troxacitabine may have modest activity against RCC; however, larger studies would be required to confirm this result.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 11, 2002; accepted January 22, 2003.

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