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Gemcitabine in patients with advanced malignant melanoma or gastric cancer: Phase II studies of the EORTC Early Clinical Trials Group
Annals of Oncology 5: 411—472, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Gemcitabine in patients with advanced malignant melanoma or gastric cancer: Phase II studies of the EORTC Early Clinical Trials Group C. Sessa,1 S. Aamdal, 2 1. Wolff,3 R. Eppelbaum,4 J. F. Smyth,5 A. Sulkes,6 W. Ten Bokkel Huinink,7 J. Vermorken,8 J. Wanders,9 H. Franklin9 & J. Verweij10 1
Department of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland; 2 The Norwegian Radium Hospital, Oslo, Norway; 5 Medizinische Klinik, Niimberg, Germany; iNumbergJ Germany; 5 University of Edinburgh, Edinburgh, U.K.; 6Beilinson Medical Center, Petach Tikva, Israel; 7Netherlands Cancer Institute, Amsterdam; BFree University Hospital, Amsterdam; 9NDDO Free University Hospital, Amsterdam; ^Rotterdam Cancer Institute, Rotterdam, The Netherlands 3
Summary Background: Gemcitabine is a water-soluble analogue of deoxycytidine which has shown significant antitumour activity in a broal panel of slow-growing murine and human carcinomas. Objective responses have been reported in early clinical studies in breast, head and neck, non-small cell lung cancer patients. The weekly schedule was selected for disease-oriented phase II studies because of its better tolerability as compared to daily or twice-weekly schemes. Patients and methods: Gemcitabine (1000 mg/m2) was given as a 30. min. infusion, weekly for three consecutive weeks, followed by one-week rest, every 4 weeks. Twentynine patients with locally advanced/metastatic gastric cancer and 39 patients with metastatic malignant melanoma entered the study. No prior chemotherapy for advanced
Introduction Gemcitabine (LY 188011) is a water-soluble analogue of deoxycytidine, a pirimidine antimetabolite developed by Eli Lilly. The main preclinical features of the compound, which acts through its triphosphate form by inhibiting DNA synthesis, are its antitumour activity, observed in a broad panel of slow-growing murine and human carcinomas, its lack of significant hematological toxic effects, and the report of objective responses it has induced in patients with colon, breast, head and neck, and NSCL cancers treated in early clinical studies [1-3]. Side effects, which included bone marrow suppression with mainly thrombocytopenia, a flu-like syndrome with fever, chills, myalgias and loss of appetite, maculopapular skin rash, appeared to be dose and schedule-dependent, being more pronounced when daily or twice-weekly dosage schemes were used [3,4]. The weekly schedule was selected by the Early Clinical Trials Group (ECTG) of the EORTC for diseaseoriented phase II studies because of the better tolerability and antitumour activity observed in phase I trials. This paper reports the antitumour activity and toxic effects observed in patients with advanced malignant melanoma or gastric cancer. Patients and methods Eligibility criteria common to the 2 studies were histological/cytological diagnosis of malignant melanoma or gastric adenocarcinoma;
disease had been given in all cases. Results: Among 26 evaluable patients with gastric cancer, 1 partial response (PR) of 9 months (4%), 11 no change (NC) and 14 tumour progression (PD) were observed. Of 33 evaluable patients with malignant melanoma, 1 patient achieved a PR for 10 months (3%), 2 had NC and 30 PD. Toxicity was similar in the two groups with moderate myelosuppression, mainly neutropenia, mild to moderate nausea and vomiting in 70% of patients and fatigue grade 1-2 in 50%. Conclusions: At the tested schedule gemcitabine has no relevant antitumour activity in previously untreated patients with advanced malignant melanoma or gastric cancer.
Key words: gemcitabine, phase II study, advanced gastric cancer, melanoma
performance status (WHO scale) <2; life expectancy >3 months; age >18 and <75 years; WBC and platelet count, serum creatinine and bilirubin values within normal limits; documented progression of disease within 2 months prior to the study; informed consent. Previous chemotherapy for metastatic disease was not allowed. In patients with malignant melanoma immunotherapy was not a criterion of exclusion, while previous adjuvant chemotherapy was allowed only if it was local (extracorporal circulation) and given more than 6 months before entry into the study. Previous adjuvant chemotherapy in patients with gastric cancer was allowed only if completed > 12 months before the start of gemcitabine. Only patients with bidimensionally measurable disease could enter the melanoma study, while unidimensionally measurable lesions were also accepted as tumour parameters in patients with gastric cancer. The drug was provided by Lilly as lyophilized powder in vials containing either 100 mg or 500 mg of gemcitabine as the hydrochloride salt, mannitol and sodium acetate. Vials were reconstituted with 5 ml and 25 ml, respectively, of normal saline to make a solution of 20 mg/ml. The appropriate amount of drug was then diluted with 250 ml of normal saline and administered as a 30 min. infusion. Gemcitabine was given at 1000 mg/m2 on a weekly basis for three consecutive weeks followed by a one-week rest. A treatment course consisted of 4 weeks. Half of the dose was given in instances of grade 2 hematological or skin toxicity on the day of retreatment, while treatment was omitted in instances of gTade > 2 hematological or grade 3 non-hematological toxicity. The dose could be increased by 25% during the subsequent course if there had been grade < 1 hematological/non-hematological toxicity in the preceding one. Patients were evaluable for response after 2 courses of therapy; treatment was discontinued in instances of progressive disease while its continuation was left to the discretion of the investigator when there was no significant change in tumour size. Patients in response remained on study until disease progression or excessive toxicity. Early progressive disease was defined as progression occurring before 8 weeks. The WHO criteria for response and toxicity were applied [5].
472
Results Gastric cancer Twenty-two men and seven women, with a median age of 64 years (range: 22-70) and a median PS of 1, entered the study between May 1991 and July 1992 (Table 1). Two patients were found ineligible (one of them with elevated bilirubin and the other with an elevated serum creatinine level) and a third was not evaluable because treatment with gemcitabine was stopped after the first administration due to rumour-related early death. Fourteen out of 26 evaluable patients showed disease progression, which occurred between 4 and 8 weeks after the start of treatment in three of them; eleven had stable disease, and one patient with unresected primary tumour and regional nodes as tumour lesions, achieved a partial response of 9 months. Twenty-nine patients and a total of 117 courses of therapy were evaluable for toxicity. Doses were reduced because of toxicity in 2.5% of courses. Treatment had to be delayed because of drug-related toxicity in 5% of courses. Neutropenia was associated with 42% of courses (grade 2-3: 28%) and thrombocytopenia with 6%. Nausea and vomiting occurred in 76% of patients (grade 3: 7%), fatigue grade 1-2 in 52% and fever grade 1-2 in 55%. Fifteen patients (52%), fourteen of them with liver metastases, showed an elevation of liver function tests (LFTs) (of grade 3 in 5 cases) during the study. Melanoma Thirty-nine patients, 20 men and 19 women, with a median age of 48 years (range: 26-74 years) and a median PS of 1, entered the study between December 1990 and September 1991 (Table 1). One patient was not eligible because radiotherapy had been given within the 4 weeks prior to the study. Five patients were not evalu-
able for response because of an erroneous starting dose of 800 mg/m2, which was not increased during the subsequent courses. Of 33 evaluable patients, one patient, with lung metastases as dominant site of disease, achieved a partial response for 10 months. Two patients had stable disease and thirty showed tumour progression, in 13 cases within 4 to 8 weeks. Thirty-nine patients and a total of 85 courses of therapy were evaluable for toxicity. Doses were reduced because of toxicity in 14% of courses. Drugrelated delays were not reported. Neutropenia occurred after 40% of courses (of grade 2-4 in 20%) and thrombocytopenia after 5%. Seventy-nine percent of patients presented nausea and vomiting (grade 3: 23%), 56% fatigue grade 1-2 and 31% fever grade 1-2. Twenty-four patients (61%), seven of them with liver metastases at the start of treatment, showed an elevation of LFTS (of grade 3 in four patients) during the study. Discussion The results of these studies, with a 4% and 3% objective response in patients with gastric cancer and malignant melanoma, respectively, suggest that at the tested schedule of 1000 mg/m2, weekly for 3 consecutive weeks, gemcitabine has no relevant antitumour activity in these tumour types. A similar pattern of toxicity was observed in the two groups of patients with moderate myelosuppression, mainly neutropenia, and gastro-intestinal toxicity. These results confirm the phase I data showing good tolerability of this schedule and suggest that, at least in unpretreated patients, doses higher than 1000 mg/m2 could be safely and, perhaps, more successfully, investigated. References
Table 1. Patient characteristics.
Age (yrs) Median Range Men/women Performance status 0 1 2 Sites of disease Primary tumour Nodes Lung Liver Previous treatment Surgery Radiotherapy Lmmunotherapy Chemotherapy None
1. Hertel LW, Boder GB, Kroin JS et al. Evaluation of the antitumour activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res 1990; 50: 4417-22. 2. Abbruzzese JL, Grunewald R, Weeks EA et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491-8. 3. Tanis B, Clavel M, Guastalla J et al. Phase I study of gemcitabine (difluorodeoxycytidine; dFdC; LY 188011) administered in a two-weekly schedule. Proc Am Assoc Cancer Res 1990; 31: 207. 4. Brown T, O'Rourke T, Bums H et al. A phase I trial of gemcitabine (LY 188011) administered intravenously every two weeks. Proc Am Soc Clin Oncol 1991; 10: 115. 5. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment Cancer 1981; 47: 207-14.
Gastric cancer (N - 29)
Melanoma (N - 39)
64 22-70 22/7
48 26-74 20/19
8 16 5
16 21 2
21 7 6 14
6 15 23 13
Received 25 January 1994; accepted 27 January 1994.
22 1 0 0 6
36 10 16 6 2
Correspondence to: Dr. Cristiana Sessa Department of Oncology Ospedale San Giovanni CH - 6500 Bellinzona, Switzerland
Short report Gemcitabine in patients with advanced malignant melanoma or gastric cancer: Phase II studies of the EORTC Early Clinical Trials Group C. Sessa,1 S. Aamdal, 2 1. Wolff,3 R. Eppelbaum,4 J. F. Smyth,5 A. Sulkes,6 W. Ten Bokkel Huinink,7 J. Vermorken,8 J. Wanders,9 H. Franklin9 & J. Verweij10 1
Department of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland; 2 The Norwegian Radium Hospital, Oslo, Norway; 5 Medizinische Klinik, Niimberg, Germany; iNumbergJ Germany; 5 University of Edinburgh, Edinburgh, U.K.; 6Beilinson Medical Center, Petach Tikva, Israel; 7Netherlands Cancer Institute, Amsterdam; BFree University Hospital, Amsterdam; 9NDDO Free University Hospital, Amsterdam; ^Rotterdam Cancer Institute, Rotterdam, The Netherlands 3
Summary Background: Gemcitabine is a water-soluble analogue of deoxycytidine which has shown significant antitumour activity in a broal panel of slow-growing murine and human carcinomas. Objective responses have been reported in early clinical studies in breast, head and neck, non-small cell lung cancer patients. The weekly schedule was selected for disease-oriented phase II studies because of its better tolerability as compared to daily or twice-weekly schemes. Patients and methods: Gemcitabine (1000 mg/m2) was given as a 30. min. infusion, weekly for three consecutive weeks, followed by one-week rest, every 4 weeks. Twentynine patients with locally advanced/metastatic gastric cancer and 39 patients with metastatic malignant melanoma entered the study. No prior chemotherapy for advanced
Introduction Gemcitabine (LY 188011) is a water-soluble analogue of deoxycytidine, a pirimidine antimetabolite developed by Eli Lilly. The main preclinical features of the compound, which acts through its triphosphate form by inhibiting DNA synthesis, are its antitumour activity, observed in a broad panel of slow-growing murine and human carcinomas, its lack of significant hematological toxic effects, and the report of objective responses it has induced in patients with colon, breast, head and neck, and NSCL cancers treated in early clinical studies [1-3]. Side effects, which included bone marrow suppression with mainly thrombocytopenia, a flu-like syndrome with fever, chills, myalgias and loss of appetite, maculopapular skin rash, appeared to be dose and schedule-dependent, being more pronounced when daily or twice-weekly dosage schemes were used [3,4]. The weekly schedule was selected by the Early Clinical Trials Group (ECTG) of the EORTC for diseaseoriented phase II studies because of the better tolerability and antitumour activity observed in phase I trials. This paper reports the antitumour activity and toxic effects observed in patients with advanced malignant melanoma or gastric cancer. Patients and methods Eligibility criteria common to the 2 studies were histological/cytological diagnosis of malignant melanoma or gastric adenocarcinoma;
disease had been given in all cases. Results: Among 26 evaluable patients with gastric cancer, 1 partial response (PR) of 9 months (4%), 11 no change (NC) and 14 tumour progression (PD) were observed. Of 33 evaluable patients with malignant melanoma, 1 patient achieved a PR for 10 months (3%), 2 had NC and 30 PD. Toxicity was similar in the two groups with moderate myelosuppression, mainly neutropenia, mild to moderate nausea and vomiting in 70% of patients and fatigue grade 1-2 in 50%. Conclusions: At the tested schedule gemcitabine has no relevant antitumour activity in previously untreated patients with advanced malignant melanoma or gastric cancer.
Key words: gemcitabine, phase II study, advanced gastric cancer, melanoma
performance status (WHO scale) <2; life expectancy >3 months; age >18 and <75 years; WBC and platelet count, serum creatinine and bilirubin values within normal limits; documented progression of disease within 2 months prior to the study; informed consent. Previous chemotherapy for metastatic disease was not allowed. In patients with malignant melanoma immunotherapy was not a criterion of exclusion, while previous adjuvant chemotherapy was allowed only if it was local (extracorporal circulation) and given more than 6 months before entry into the study. Previous adjuvant chemotherapy in patients with gastric cancer was allowed only if completed > 12 months before the start of gemcitabine. Only patients with bidimensionally measurable disease could enter the melanoma study, while unidimensionally measurable lesions were also accepted as tumour parameters in patients with gastric cancer. The drug was provided by Lilly as lyophilized powder in vials containing either 100 mg or 500 mg of gemcitabine as the hydrochloride salt, mannitol and sodium acetate. Vials were reconstituted with 5 ml and 25 ml, respectively, of normal saline to make a solution of 20 mg/ml. The appropriate amount of drug was then diluted with 250 ml of normal saline and administered as a 30 min. infusion. Gemcitabine was given at 1000 mg/m2 on a weekly basis for three consecutive weeks followed by a one-week rest. A treatment course consisted of 4 weeks. Half of the dose was given in instances of grade 2 hematological or skin toxicity on the day of retreatment, while treatment was omitted in instances of gTade > 2 hematological or grade 3 non-hematological toxicity. The dose could be increased by 25% during the subsequent course if there had been grade < 1 hematological/non-hematological toxicity in the preceding one. Patients were evaluable for response after 2 courses of therapy; treatment was discontinued in instances of progressive disease while its continuation was left to the discretion of the investigator when there was no significant change in tumour size. Patients in response remained on study until disease progression or excessive toxicity. Early progressive disease was defined as progression occurring before 8 weeks. The WHO criteria for response and toxicity were applied [5].
472
Results Gastric cancer Twenty-two men and seven women, with a median age of 64 years (range: 22-70) and a median PS of 1, entered the study between May 1991 and July 1992 (Table 1). Two patients were found ineligible (one of them with elevated bilirubin and the other with an elevated serum creatinine level) and a third was not evaluable because treatment with gemcitabine was stopped after the first administration due to rumour-related early death. Fourteen out of 26 evaluable patients showed disease progression, which occurred between 4 and 8 weeks after the start of treatment in three of them; eleven had stable disease, and one patient with unresected primary tumour and regional nodes as tumour lesions, achieved a partial response of 9 months. Twenty-nine patients and a total of 117 courses of therapy were evaluable for toxicity. Doses were reduced because of toxicity in 2.5% of courses. Treatment had to be delayed because of drug-related toxicity in 5% of courses. Neutropenia was associated with 42% of courses (grade 2-3: 28%) and thrombocytopenia with 6%. Nausea and vomiting occurred in 76% of patients (grade 3: 7%), fatigue grade 1-2 in 52% and fever grade 1-2 in 55%. Fifteen patients (52%), fourteen of them with liver metastases, showed an elevation of liver function tests (LFTs) (of grade 3 in 5 cases) during the study. Melanoma Thirty-nine patients, 20 men and 19 women, with a median age of 48 years (range: 26-74 years) and a median PS of 1, entered the study between December 1990 and September 1991 (Table 1). One patient was not eligible because radiotherapy had been given within the 4 weeks prior to the study. Five patients were not evalu-
able for response because of an erroneous starting dose of 800 mg/m2, which was not increased during the subsequent courses. Of 33 evaluable patients, one patient, with lung metastases as dominant site of disease, achieved a partial response for 10 months. Two patients had stable disease and thirty showed tumour progression, in 13 cases within 4 to 8 weeks. Thirty-nine patients and a total of 85 courses of therapy were evaluable for toxicity. Doses were reduced because of toxicity in 14% of courses. Drugrelated delays were not reported. Neutropenia occurred after 40% of courses (of grade 2-4 in 20%) and thrombocytopenia after 5%. Seventy-nine percent of patients presented nausea and vomiting (grade 3: 23%), 56% fatigue grade 1-2 and 31% fever grade 1-2. Twenty-four patients (61%), seven of them with liver metastases at the start of treatment, showed an elevation of LFTS (of grade 3 in four patients) during the study. Discussion The results of these studies, with a 4% and 3% objective response in patients with gastric cancer and malignant melanoma, respectively, suggest that at the tested schedule of 1000 mg/m2, weekly for 3 consecutive weeks, gemcitabine has no relevant antitumour activity in these tumour types. A similar pattern of toxicity was observed in the two groups of patients with moderate myelosuppression, mainly neutropenia, and gastro-intestinal toxicity. These results confirm the phase I data showing good tolerability of this schedule and suggest that, at least in unpretreated patients, doses higher than 1000 mg/m2 could be safely and, perhaps, more successfully, investigated. References
Table 1. Patient characteristics.
Age (yrs) Median Range Men/women Performance status 0 1 2 Sites of disease Primary tumour Nodes Lung Liver Previous treatment Surgery Radiotherapy Lmmunotherapy Chemotherapy None
1. Hertel LW, Boder GB, Kroin JS et al. Evaluation of the antitumour activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res 1990; 50: 4417-22. 2. Abbruzzese JL, Grunewald R, Weeks EA et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491-8. 3. Tanis B, Clavel M, Guastalla J et al. Phase I study of gemcitabine (difluorodeoxycytidine; dFdC; LY 188011) administered in a two-weekly schedule. Proc Am Assoc Cancer Res 1990; 31: 207. 4. Brown T, O'Rourke T, Bums H et al. A phase I trial of gemcitabine (LY 188011) administered intravenously every two weeks. Proc Am Soc Clin Oncol 1991; 10: 115. 5. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment Cancer 1981; 47: 207-14.
Gastric cancer (N - 29)
Melanoma (N - 39)
64 22-70 22/7
48 26-74 20/19
8 16 5
16 21 2
21 7 6 14
6 15 23 13
Received 25 January 1994; accepted 27 January 1994.
22 1 0 0 6
36 10 16 6 2
Correspondence to: Dr. Cristiana Sessa Department of Oncology Ospedale San Giovanni CH - 6500 Bellinzona, Switzerland