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Phase II Clinical Investigation of Gemcitabine in Advanced Soft Tissue Sarcomas and Window Evaluation of Dose Rate on Gemcitabine Triphosphate Accumulation

From the Departments of Sarcoma Medical Oncology and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to S.R. Patel, MD, Department of Sarcoma Medical Oncology, Box 450, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: spatel{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the efficacy, toxicity, and optimal dose rate of gemcitabine in adult patients with advanced soft tissue sarcomas (STS) by comparing levels of gemcitabine triphosphate (GTP) in peripheral-blood mononuclear cells (PBMCs) of patients receiving two different dose rates.

PATIENTS AND METHODS: Fifty-six assessable patients with STS (17 gastrointestinal [GI] leiomyosarcomas and 39 other histologies) were treated on a two-arm phase II study. Gemcitabine was given at 1 g/m² as a 30-minute infusion weekly for up to 7 weeks followed by 1 week of rest and reassessment of tumor. Subsequent cycles were given at 1 g/m² weekly for 3 weeks followed by 1 week of rest. Nine patients underwent cellular pharmacologic studies at two different dose rates (1 g/m² over a standard 30-minute infusion on week 1 and over pharmacologically based infusion of 150 minutes on week 2) to evaluate GTP levels in PBMCs.

RESULTS: Seven partial responses were noted among 39 patients, for an overall response rate of 18% (95% confidence interval, 7% to 29%). Median duration of response was 3.5 months (range, 2 to 13 months). Four of 10 patients with non-GI leiomyosarcomas achieved a partial response. No objective responses were noted in 17 patients with GI leiomyosarcomas. One patient had a mixed response. Median time to progression for all patients (both arms) was 3 months; median survival was 13.9 months. Treatment was generally well tolerated. Comparison of cellular pharmacology demonstrated a significant 1.4-fold increase in the concentration of GTP with the 150-minute infusion.

CONCLUSION: Given the limited therapeutic armamentarium for STS, the activity of gemcitabine is encouraging. Its potential for combination therapy in the salvage setting should be studied with pharmacologically guided fixed dose-rate infusion.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
SOFT TISSUE SARCOMAS are a heterogeneous group of diseases with an annual incidence of 8,100 new cases for the year 2000.¹ There are distinct biologic differences in certain subtypes of soft tissue sarcomas that need to be taken into account at the time of therapeutic decision making. Gastrointestinal (GI) leiomyosarcomas are notoriously refractory to standard chemotherapeutic agents such as doxorubicin and ifosfamide, whereas uterine or retroperitoneal leiomyosarcomas show some definite sensitivity to these agents; therefore, there is no accepted standard chemotherapy for GI leiomyosarcomas.^2-4 The majority of the other soft tissue sarcoma histologies in the advanced disease setting are treated with a doxorubicin and ifosfamide–based regimen as front-line therapy. Salvage therapy options after failure of front-line therapy are limited; therefore, clinical trials of newer agents are needed to help identify drugs with some activity in this group of diseases.⁵

Gemcitabine is a commercially available pyrimidine antimetabolite with broad-spectrum activity against a variety of malignancies and a generally favorable toxicity profile.⁶ The activity of gemcitabine is dependent on its phosphorylation to its triphosphate, the major intracellular metabolite. Although doses of gemcitabine ranging between 800 and 2,800 mg/m² are generally administered by intravenous infusion over 30 minutes,⁷ there is evidence that this generates plasma gemcitabine concentrations that greatly exceed the levels (15 to 20 µmol/L) that saturate the rate of triphosphate accumulation. Alternatively, gemcitabine infusion at the fixed dose rate of 10 mg/m²/min has been demonstrated to maximize the rate of triphosphate formation.^8,9 In addition, this dose rate may be extended safely for as long as 8 hours, and this results in cellular accumulation of substantially greater triphosphate concentrations.⁹

We conducted a two-arm phase II trial of gemcitabine in patients with GI leiomyosarcomas and other soft tissue sarcomas. The first objective of the investigation was to define the activity and toxicity profile of this agent, keeping in mind the potential for combination with DNA-damaging agents in the future. The second objective was to compare accumulation of gemcitabine triphosphate in peripheral-blood mononuclear cells (PBMCs) as a surrogate to evaluating the infusion rate that maximizes triphosphate formation. For this purpose, in select consenting patients, we compared the accumulation of gemcitabine triphosphate after infusion of gemcitabine at two different dose rates, either a standard 30-minute infusion or a pharmacologically based prolonged (150 minutes) infusion in the same individuals to permit each patient to serve as their own control.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients with a histologically confirmed diagnosis of soft tissue sarcoma, advanced/metastatic measurable or nonmeasurable but assessable disease, adequate organ function (defined as absolute granulocyte count of 1,500/µL, platelet count of 100,000/µL, total bilirubin 1.5 mg/dL, ALT < 1.5 x normal, and serum creatinine 2.0 mg/dL), and an anticipated life expectancy of at least 12 weeks were eligible. Patients with active infections or significant heart disease and pregnant or lactating women were excluded. Patients with GI leiomyosarcoma were eligible regardless of prior chemotherapy exposure. Patients with other soft tissue sarcomas were required to have received, refused, or not be eligible for standard chemotherapy including doxorubicin and ifosfamide. No other concurrent chemotherapy or immunotherapy was allowed. All patients gave signed, informed consent. Nine patients consented for pharmacologic investigations on PBMCs involving withdrawal of blood samples.

Treatment Plan
Gemcitabine was administered at a dose of 1,000 mg/m² as a 30-minute infusion weekly for up to 7 weeks followed by 1 week of rest and re-evaluation of tumor for response assessment. In patients with stable or responding disease, therapy was continued on a weekly basis for 3 weeks followed by 1 week of rest, and tumor response assessments were made every 8 weeks. No dose escalations were allowed for the first 7 weeks of treatment. Subsequent cycles not complicated by any grade 3 or 4 nonhematologic toxicities qualified for dose escalations to 1,100 (level 1) and 1,200 mg/m² (level 2) weekly for 3 weeks. There were no planned dose reductions. Instead, subsequent therapy was withheld until complete recovery as defined in the eligibility criteria. Treatment was continued until maximum response, tolerance, or progression. Surgical resection of residual disease where feasible was permitted.

Pharmacology Investigations
Nine patients who consented to optional pharmacologic studies were given the first week of gemcitabine at 1 g/m² over 30 minutes (dose rate, 33 mg/m²/min) and the second week on a window therapy at 1 g/m² over 150 minutes (dose rate, 6.66 mg/m²/min). This infusion duration was selected based on previous phase I studies with a fixed dose rate of gemcitabine that recommended a 150-minute infusion.^10,11 For these 2 weeks, peripheral-blood samples (10 to 20 mL) were drawn before therapy and at 30, 60, 90, 120, and 150 minutes after start of gemcitabine infusion. Blood samples were collected and processed to extract nucleotides and gemcitabine triphosphate as described previously.¹² These triphosphates were separated on a 10-SAX Partisil anion exchange column (Whatman, Clifton, NJ) using Waters high-pressure liquid chromatography system (Waters Corporation, Milford, MA) as described previously.¹³

Evaluations Before and During treatment
Before enrollment, patients had a standard history and physical examination. Laboratory studies included a complete blood cell (CBC) count with differential and platelet count, electrolytes, magnesium, and serum chemistries. A chest x-ray, computed tomography scan, or magnetic resonance imaging to image sites of tumor for baseline measurements were obtained. During treatment, ALT and CBC count with differential and platelets were monitored weekly or more frequently as necessary. A CBC count, chemistries with electrolytes, and a chest x-ray were performed before each cycle. Tumor imaging was obtained every two cycles.

Response Criteria
Complete response was defined as the disappearance of all clinical evidence of tumor. Pathologic complete response was defined as no viable tumor in the resected specimen representing the residual radiologic abnormality. Partial response (PR) was defined as a 50% reduction in the sum of the products of the biperpendicular diameters of measurable lesions without the appearance of new lesions for at least 3 weeks. Minor response was defined as a decrease in tumor size between 25% and 49%. Stable disease was defined as a less than 25% change in the dimensions of the tumor, and progressive disease was defined as a 25% increase in the sum of the products of the biperpendicular diameters or appearance of new lesions.

Statistics
The study was conducted using the optimal two-stage design as proposed by Simon.¹⁴ Alpha and beta errors were set at 10%. A response rate of more than 15% was considered to be of interest, and so 17 patients were entered in the first stage in each of two arms. If no responses were noted in the first stage, that arm would be terminated. Otherwise, if one or more responses were noted, an additional 22 patients needed to be accrued for a total of 39 patients in each of two arms. Nonparametric Wilcoxon signed-rank two-tailed test was used to determine the significance of differences between paired measurements of gemcitabine triphosphate values. The rate of gemcitabine triphosphate accumulation (150-minute infusion) was determined by linear regression analysis.

	RESULTS

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Patient Characteristics
Fifty-six assessable patients were treated on the study between January 1998 and March 2000. The median age was 54 years (range, 28 to 76 years). The majority of the patients (92%) had a Zubrod performance status of 0 to 1 and the remainder (8%) had a Zubrod performance status of 2 (Table 1). There were 29 female and 27 male patients. The histologic types are outlined in Table 1. Seventeen patients had GI leiomyosarcoma. The other arm included 10 patients with non-GI leiomyosarcomas, nine with unclassified sarcomas, seven with malignant fibrous histiocytoma or high-grade spindle cell sarcomas, four with liposarcomas, and nine with other miscellaneous histologies. Five of the 17 patients with GI leiomyosarcomas had received prior chemotherapy. Thirty-six of the 39 other soft tissue sarcomas had prior exposure to standard chemotherapy, with a median of one prior regimen (range, one to three regimens).

View larger version (122K): [in this window] [in a new window]   Fig 1. Responses to gemcitabine. (A and B) Partial response: at baseline (left), and with chemotherapy (right).

View larger version (33K): [in this window] [in a new window]   Fig 2. Time to progression in months (all patients).

View larger version (39K): [in this window] [in a new window]   Fig 3. Overall survival in months (all patients).

Hematologic toxicities. The median absolute granulocyte count nadir was 1.1/µL (range, 0.1 to 4.5/µL), without any episodes of febrile neutropenia or associated morbidity. The median platelet nadir was 154/µL (range, 13 to 340/µL) and was not associated with any bleeding complications. Six patients experienced grade 3 to 4 neutropenia and five patients experienced grade 3 to 4 thrombocytopenia. Two patients experienced grade 3 anemia. As expected, patients who were heavily pretreated encountered myelosuppression (mostly thrombocytopenia) that led to delays in their scheduled treatments.

Nonhematologic toxicities. Self-limiting grade 3 elevation of ALT was seen in two patients in two cycles. Two patients experienced grade 3 myalgias, two patients encountered bilateral lower-extremity edema with an erythematous rash, and one patient complained of grade 3 anorexia. Grade 1 to 2 fatigue was reported by 11 patients.

Cellular Pharmacology
Cellular pharmacology studies demonstrated that the concentration of gemcitabine triphosphate varied between 50 and 310 µmol/L in the PBMCs of the nine patients (Table 3) after a 30-minute infusion of gemcitabine (1 g/m²). For illustrative and comparative purposes, data from two representative patients are presented in Fig 4A and4B.After a 30-minute infusion, gemcitabine triphosphate reached a plateau at the end of infusion in one patient (Fig 4A) or after 60 minutes in the second patient (Fig 4B). This is consistent with the interpretation that gemcitabine triphosphate is maximized by the plasma gemcitabine concentrations achieved during the infusion. The levels were generally maintained for 150 minutes, suggesting slow elimination of the triphosphate as observed before.^9,15,16 In the same patients, when gemcitabine (1 g/m²) was infused over 150 minutes, the triphosphate accumulation was linear for the entire duration of infusion (r² = 0.95 and 0.93; Fig 4). Most likely this reflects the ability of cells to maintain the rate of triphosphate accumulation constant as a result of the sustained presence of optimal gemcitabine concentrations in plasma. This linear rate resulted in a peak concentration of gemcitabine triphosphate at the end of the infusion, ie, 150 minutes, which was higher than the plateau levels achieved after the 30-minute infusion in the same patient. Comparison of the paired triphosphate values in seven assessable patients demonstrated the concentration of gemcitabine triphosphate at 30 minutes after each infusion was not significantly different (P = .30). However, a median 1.4-fold increase in the maximum gemcitabine triphosphate concentration (range, 1.0 to 2.6-fold, P = .016) was obtained when gemcitabine was infused over 150 minutes compared with the 30-minute infusion (Table 3). Problems with either the drug infusion pump or with high-pressure liquid chromatography analyses precluded triphosphate analyses during week 2 in two patients.

View larger version (20K): [in this window] [in a new window]   Fig 4. Pharmacokinetics of gemcitabine triphosphate in PBMCs of two representative patients. PBMCs were collected either after 30-minute infusion (•) or 150-minute infusion () for patient no. 6 (A) and patient no. 9 (B).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Three prior studies of gemcitabine in patients with advanced sarcomas have been reported. Two used the conventional 30-minute infusions. In the first of these, 26 assessable patients were treated with gemcitabine at a dose of 1,250 mg/m² intravenously over 30 minutes every week for 3 weeks followed by 1 week of rest.¹ Only one PR was noted in a patient with uterine leiomyosarcoma. The median time to progression was 2.1 months.¹⁷ Differences between this trial and our study that may explain the discrepancy in outcome, to a certain extent, are the different histologic distribution and inclusion of GI leiomyosarcomas, with some possible contribution from the relatively high proportion (26%) of low-grade tumors. As has been outlined above, GI leiomyosarcomas and occasional abdominal/mesenteric sarcomas resembling GI stromal tumors are known to be resistant to all standard chemotherapy drugs. As noted in our trial, these tumors are also insensitive to gemcitabine. In another study, 18 patients with heavily pretreated sarcomas of bone and soft tissue were treated with gemcitabine at a dose of 1,000 mg/m² infused over 30 minutes weekly for 7 weeks followed by 1 week of rest and a re-evaluation for response.¹⁸ One PR in a patient with a leiomyosarcoma and a minor response in a patient with an angiosarcoma were noted. The median time to progression was 27 weeks. The final published report used a more prolonged infusion of a lesser gemcitabine dose.¹⁹ Eighteen patients with pretreated advanced soft tissue sarcomas were treated with 200 mg/m² infused over 6 hours on days 1, 8, and 15 of a 28-day cycle in a phase II trial. Two patients achieved PRs lasting 5 and 6 months. One other patient with disease that had been progressive on ifosfamide and doxorubicin had an objective response of greater than 50% confined to the lungs and stable local recurrence for 6 months. This body of data taken with our present trial clearly demonstrates the biologic activity of gemcitabine in previously treated patients with soft tissue sarcomas. The activity in patients with leiomyosarcomas of non-GI origin is interesting, especially in light of the lack of any activity in the subset of patients with GI leiomyosarcomas.

A secondary objective of this investigation was to evaluate which of two gemcitabine dose rates generated greater gemcitabine triphosphate accumulation. The standard infusion duration of gemcitabine is 30 minutes⁷ for doses that vary between 800 mg/m² and 2,800 mg/m². Previous preclinical,^8,13 biochemical,²⁰ and clinical⁹ investigations have strongly suggested that the rate of gemcitabine triphosphate accumulation is saturated at 10 to 20 µmol/L of gemcitabine in plasma or medium. This concentration of gemcitabine is achieved in plasma when gemcitabine is infused at a dose rate of 6 to 10 mg/m²/min.^9,15 Our data presented in Fig 4 and Table 3 demonstrate a pharmacologic advantage of a 150-minute infusion of gemcitabine (dose rate of 6.66 mg/m²/min) over a standard 30-minute infusion (dose rate of 33 mg/m²/min). Although at present data in the target tumor tissue are lacking for such comparisons, the data in surrogate PBMCs strongly suggest the benefit of the pharmacologically based gemcitabine infusion rate. Clinical benefits obtained in patients with pancreatic carcinomas with 150-minute infusion relative to 30-minute infusion²¹ provide further support for use of a prolonged infusion at a fixed dose rate of gemcitabine.

The options for patients who have had prior exposure to full therapeutic doses of doxorubicin and ifosfamide are very limited. Several agents, including dacarbazine, etoposide, or cisplatin, have marginal activity in this disease. Therefore, it is important to evaluate new drugs with different mechanisms of action to define their clinical activity and toxicity profiles. Additionally, all of the currently used agents for sarcoma damage DNA, and as a response it would be expected that they initiate incision DNA repair processes. Gemcitabine, by its actions on deoxynucleotides^22,23 and its incorporation into DNA,²⁴ has been shown to inhibit such DNA repair processes.²⁵ This feature, along with its favorable toxicity profile, suggests combination therapies that consider interacting mechanisms of action. Future studies should incorporate pharmacologic studies, preferably in tumor cells, to better define the optimal schedule of gemcitabine administration.

	ACKNOWLEDGMENTS

 
Supported in part by a clinical grant from Eli Lilly Inc, Indianapolis, IN, and by grant nos. CA 32839 and CA 57629 from the National Cancer Institute, United States Department of Health and Human Services, Bethesda, MD.

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Submitted January 26, 2001; accepted April 25, 2001.

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