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Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma
Annals of Oncology 5: 286-287, 1994. C 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma D. F. Moore, Jr.,1 R. Pazdur,1 J. L. Abbruzzese,1 J. A. Ajani,1 D. W. Dubovsky,2 J. L. Wade m, 3 R. J. Belt,4 C. Mangold,1 B. Bready5 & R. J. Winn1 1
Division of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2Atlanta Regional Community Clinical Oncology Program, Atlanta, GA; 3 Central Illinois Community Clinical Oncology Program, Springfield, IL; * Kansas City Community Clinical Oncology Program, Kansas City, MO;5Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, U.S.A.
Results: Two partial responses were observed. Both of these patients had partial responses which lasted 2 and 3.5 Background: The methotrexate analogue 10-ethyl-10-deaza- months. The median survival for all patients was 3.5 months. aminopterin (10-EdAM, or edatrexate) has shown antitumor Serious (grade 3 or 4) toxic effects were primarily mucosal, activity in preclinical testing and clinical studies of patients hematologic, and dermatologic. Two patients experienced with breast, lung and head and neck carcinomas. A phase II severe pulmonary toxic reactions. study was conducted in patients with advanced pancreatic Conclusion: At the dose and schedule used, edatrexate adenocarcinoma. was poorly tolerated and did not demonstrate significant Patients and methods: Forty patients were enrolled on the antitumor activity. clinical trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for 5 weeks. The treatment course Key words: 10-EdAM, antimetabolite, edatrexate, folate was repeated every 6 weeks. antagonist, methotrexate, pancreatic adenocarcinoma Summary
Introduction
Edatrexate (10-ethyl-lO-deaza-aminopterin, or 10EdAM), a methotrexate analogue, has shown antitumor activity in preclinical and clinical trials, including phase II studies in lung, head and neck, and breast carcinomas [1]. Because of the activity observed against other carcinomas, we conducted a phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma.
doses followed by a week rest period constituted a course of therapy. Patients who had no toxicity after the first course had the weekly dose escalated to 100 mg/m2. If no toxicity was noted at 100 mg/m2, these patients were subsequently treated at 120 mg/m2 for the third course. Weekly doses of edatrexate were withheld in patients who developed grade 2 or greater mucositis or other major organ dysfunction until resolution. Subsequent doses were held at the original level on recovery from grade 2 toxicity and 50% of the original level after recovery from grade 3-4 toxicity. Patients who developed mucositis within 24 hours after receiving edatrexate received calcium leucovorin (15 mg orally every 6 hours x 8 doses).
Results Patients and methods Eligibility criteria included histologic confirmation of pancreatic adenocarcinoma, bidimensionally measurable disease, surgically unresectable or metastatic disease, informed consent, and Zubrod scale <2. Inclusion criteria also required adequate hematologic function (absolute granulocyte count > 1,500/jil, platelet count > 100,000/|il), renal function (serum creatinine level <1.5 mg/dl) and hepatic reserve (total serum bilirubin <1.5 mg/dl, serum glutamic-pyruvic transaminase <2.5 x upper limit of normal). Prior radiotherapy did not preclude eligibility, provided that the radiation field did not include the measurable disease site. Patients with prior chemotherapy or immunotherapy, ascites and/or pleural effusions, or poorly controlled comorbid conditions were excluded. Standard response and toxicity criteria were used [2]. The weekly starting dose for all patients was 80 mg/m2 for five weeks given on days 1, 8, 15, 22, and 29. Five consecutive weekly
Forty patients (20 men, 20 women) were entered and are evaluable. The median age was 66 years (range 3 0 82) and median performance status 1 (range 0-2). Thirty-one patients had liver metastases; nine had exclusively locally advanced, measurable pancreatic carcinoma. Eight patients had prior surgical pancreatic resections and 2 had prior irradiation. No complete responses and only 2 brief partial responses occurred. The duration of the responses were 2 and 3.5 months, with associated survivals of 4.9 and 7.3 months, respectively. The median overall survival for all patients on the study was 3.5 months. Treatment-related toxicities, as depicted in Table 1,
287 Table 1. Toxic effects (Common Toxicity Criteria). Toxic effects
# of patients grade 3 toxicity
Weekly dose (mg/m2)
40
80
100
Dennatologjc reaction Granulocytopenia Anemia Thrombocytopenia Stomatitis Diarrhea Anorexia Malaise Elevated transaminases Pulmonary
1
1 4 1 1 8 1 2
1
3 3
# of patients grade 4 toxicity 120
40
80
1
2 1
1 2 1 1 2
were primarily mucosal and hematologic. Forty patients were treated at weekly doses of 80 mg/m2, 5 were escalated to 100 mg/m2, and 2 to 120 mg/m2. Thirteen patients had the weekly doses reduced to 40 mg/m2 and two of these required further dose reduction to 20 mg/m2. Sixteen patients received calcium leucovorin. One patient died of treatment-associated granulocytopenia caused by polymicrobial sepsis in association with a pelvic abscess. Severe pulmonary toxic effects, including interstitial pneumonitis similar to that described in patients receiving methotrexate, were observed in 2 patients.
Discussion Edatrexate is a methotrexate analogue that competitively inhibits the folate binding site of the target enzyme dihydrofolate reductase and indirectly blocks nucleotide synthesis. Preclinical data suggested rapid influx and prolonged retention of edatrexate in tumor cells, both exceeding those of methotrexate [3,4]. Edatrexate is active in various cell lines (L1210, Ehrlich, S-180), murine ascites tumors (L1210, S-180) and preclinical animal models (e.g., human tumor xenografts in mice) [1, 3, 4]. Edatrexate is more active than methotrexate in some preclinical models and demonstrates activity in methotrexate-resistant tumor systems [4,5]. The toxicity of edatrexate in humans is well characterized and resembles that of methotrexate. A phase I study (in which 120-1080 mg/m2 of edatrexate was given weekly for 3 weeks) and a phase II study (80 mg/ m2 given weekly for 5 weeks) reported mucositis as the dose-limiting toxic effect [1, 6]. Other toxicities included leukopenia, thrombocytopenia, malaise, elevated liver function tests, skin rash, diarrhea, and pleurisy [1, 6]. As a result of phase I and II trial data, dose schedules of 100 mg/m2 (3-week schedule) and 80 mg/m2
(5-week schedule) have been recommended [1]. Phase II trials of edatrexate have reported single-agent activity in non-small cell lung carcinoma, head and neck carcinomas, and breast carcinoma [1]. In contrast with the responses observed in other carcinomas, our phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma produced only 2 partial responses. A phase II trial at Memorial Sloan-Kettering Cancer Center found no activity for edatrexate against advanced pancreatic adenocarcinoma [7]. In summary, edatrexate, at the dose and schedule described, was associated with significant toxicity. Edatrexate did not demonstrate significant activity against advanced pancreatic adenocarcinoma. Acknowledgement This work was supported in part by a grant from the National Cancer Institute, Bethesda Maryland U.SA. (NCI contract N01-CM-07310) References 1. Grant SC, Kris MG, Young CW et al. Edatrexate, an antifolate with antitumor activity: A review. Cancer Invest 1993; 11: 3645. 2. Ajani JA, Welch SR, Raber MN et al. Comprehensive criteria for survival in therapy-induced toxicity. Cancer Invest 1990; 8: 141-53. 3. Sirotnak FM, DeGraw JI, Schmid FA et al. New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid tumor murine models. Cancer Chemother Pharmacol 1984; 12: 26-30. 4. Fry DW, Jackson RC. Biological and biochemical properties of new anticancer folate antagonists. Cancer Metastasis Rev 1987; 5:251-70. 5. Lee JS, Libshitz HI, Murphy WK et al. Phase U study of 10ethyl-deaza-aminopterin (10-EDAM;CGP 30 694) for stage HTB or IV non-small cell lung cancer. Invest New Drugs 1990; 8: 299-304. 6. Kris MG, Kinahan JJ, Gralla RJ et al. Phase I trial and clinical pharmacological evaluation of 10-ethyl-deaza-aminopterin in adult patients with advanced cancer. Cancer Res 1988; 48: 5573-4. 7. Casper ES, Schwartz GK, Johnson B et al. Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma. Invest New Drugs 1992; 10: 313-6. Received 29 October 1993; accepted 15 December 1993. Correspondence to: Richard Pazdur, MD Division of Medicine Box 92 The University of Texas M. D. Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA.
Short report Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma D. F. Moore, Jr.,1 R. Pazdur,1 J. L. Abbruzzese,1 J. A. Ajani,1 D. W. Dubovsky,2 J. L. Wade m, 3 R. J. Belt,4 C. Mangold,1 B. Bready5 & R. J. Winn1 1
Division of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2Atlanta Regional Community Clinical Oncology Program, Atlanta, GA; 3 Central Illinois Community Clinical Oncology Program, Springfield, IL; * Kansas City Community Clinical Oncology Program, Kansas City, MO;5Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, U.S.A.
Results: Two partial responses were observed. Both of these patients had partial responses which lasted 2 and 3.5 Background: The methotrexate analogue 10-ethyl-10-deaza- months. The median survival for all patients was 3.5 months. aminopterin (10-EdAM, or edatrexate) has shown antitumor Serious (grade 3 or 4) toxic effects were primarily mucosal, activity in preclinical testing and clinical studies of patients hematologic, and dermatologic. Two patients experienced with breast, lung and head and neck carcinomas. A phase II severe pulmonary toxic reactions. study was conducted in patients with advanced pancreatic Conclusion: At the dose and schedule used, edatrexate adenocarcinoma. was poorly tolerated and did not demonstrate significant Patients and methods: Forty patients were enrolled on the antitumor activity. clinical trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for 5 weeks. The treatment course Key words: 10-EdAM, antimetabolite, edatrexate, folate was repeated every 6 weeks. antagonist, methotrexate, pancreatic adenocarcinoma Summary
Introduction
Edatrexate (10-ethyl-lO-deaza-aminopterin, or 10EdAM), a methotrexate analogue, has shown antitumor activity in preclinical and clinical trials, including phase II studies in lung, head and neck, and breast carcinomas [1]. Because of the activity observed against other carcinomas, we conducted a phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma.
doses followed by a week rest period constituted a course of therapy. Patients who had no toxicity after the first course had the weekly dose escalated to 100 mg/m2. If no toxicity was noted at 100 mg/m2, these patients were subsequently treated at 120 mg/m2 for the third course. Weekly doses of edatrexate were withheld in patients who developed grade 2 or greater mucositis or other major organ dysfunction until resolution. Subsequent doses were held at the original level on recovery from grade 2 toxicity and 50% of the original level after recovery from grade 3-4 toxicity. Patients who developed mucositis within 24 hours after receiving edatrexate received calcium leucovorin (15 mg orally every 6 hours x 8 doses).
Results Patients and methods Eligibility criteria included histologic confirmation of pancreatic adenocarcinoma, bidimensionally measurable disease, surgically unresectable or metastatic disease, informed consent, and Zubrod scale <2. Inclusion criteria also required adequate hematologic function (absolute granulocyte count > 1,500/jil, platelet count > 100,000/|il), renal function (serum creatinine level <1.5 mg/dl) and hepatic reserve (total serum bilirubin <1.5 mg/dl, serum glutamic-pyruvic transaminase <2.5 x upper limit of normal). Prior radiotherapy did not preclude eligibility, provided that the radiation field did not include the measurable disease site. Patients with prior chemotherapy or immunotherapy, ascites and/or pleural effusions, or poorly controlled comorbid conditions were excluded. Standard response and toxicity criteria were used [2]. The weekly starting dose for all patients was 80 mg/m2 for five weeks given on days 1, 8, 15, 22, and 29. Five consecutive weekly
Forty patients (20 men, 20 women) were entered and are evaluable. The median age was 66 years (range 3 0 82) and median performance status 1 (range 0-2). Thirty-one patients had liver metastases; nine had exclusively locally advanced, measurable pancreatic carcinoma. Eight patients had prior surgical pancreatic resections and 2 had prior irradiation. No complete responses and only 2 brief partial responses occurred. The duration of the responses were 2 and 3.5 months, with associated survivals of 4.9 and 7.3 months, respectively. The median overall survival for all patients on the study was 3.5 months. Treatment-related toxicities, as depicted in Table 1,
287 Table 1. Toxic effects (Common Toxicity Criteria). Toxic effects
# of patients grade 3 toxicity
Weekly dose (mg/m2)
40
80
100
Dennatologjc reaction Granulocytopenia Anemia Thrombocytopenia Stomatitis Diarrhea Anorexia Malaise Elevated transaminases Pulmonary
1
1 4 1 1 8 1 2
1
3 3
# of patients grade 4 toxicity 120
40
80
1
2 1
1 2 1 1 2
were primarily mucosal and hematologic. Forty patients were treated at weekly doses of 80 mg/m2, 5 were escalated to 100 mg/m2, and 2 to 120 mg/m2. Thirteen patients had the weekly doses reduced to 40 mg/m2 and two of these required further dose reduction to 20 mg/m2. Sixteen patients received calcium leucovorin. One patient died of treatment-associated granulocytopenia caused by polymicrobial sepsis in association with a pelvic abscess. Severe pulmonary toxic effects, including interstitial pneumonitis similar to that described in patients receiving methotrexate, were observed in 2 patients.
Discussion Edatrexate is a methotrexate analogue that competitively inhibits the folate binding site of the target enzyme dihydrofolate reductase and indirectly blocks nucleotide synthesis. Preclinical data suggested rapid influx and prolonged retention of edatrexate in tumor cells, both exceeding those of methotrexate [3,4]. Edatrexate is active in various cell lines (L1210, Ehrlich, S-180), murine ascites tumors (L1210, S-180) and preclinical animal models (e.g., human tumor xenografts in mice) [1, 3, 4]. Edatrexate is more active than methotrexate in some preclinical models and demonstrates activity in methotrexate-resistant tumor systems [4,5]. The toxicity of edatrexate in humans is well characterized and resembles that of methotrexate. A phase I study (in which 120-1080 mg/m2 of edatrexate was given weekly for 3 weeks) and a phase II study (80 mg/ m2 given weekly for 5 weeks) reported mucositis as the dose-limiting toxic effect [1, 6]. Other toxicities included leukopenia, thrombocytopenia, malaise, elevated liver function tests, skin rash, diarrhea, and pleurisy [1, 6]. As a result of phase I and II trial data, dose schedules of 100 mg/m2 (3-week schedule) and 80 mg/m2
(5-week schedule) have been recommended [1]. Phase II trials of edatrexate have reported single-agent activity in non-small cell lung carcinoma, head and neck carcinomas, and breast carcinoma [1]. In contrast with the responses observed in other carcinomas, our phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma produced only 2 partial responses. A phase II trial at Memorial Sloan-Kettering Cancer Center found no activity for edatrexate against advanced pancreatic adenocarcinoma [7]. In summary, edatrexate, at the dose and schedule described, was associated with significant toxicity. Edatrexate did not demonstrate significant activity against advanced pancreatic adenocarcinoma. Acknowledgement This work was supported in part by a grant from the National Cancer Institute, Bethesda Maryland U.SA. (NCI contract N01-CM-07310) References 1. Grant SC, Kris MG, Young CW et al. Edatrexate, an antifolate with antitumor activity: A review. Cancer Invest 1993; 11: 3645. 2. Ajani JA, Welch SR, Raber MN et al. Comprehensive criteria for survival in therapy-induced toxicity. Cancer Invest 1990; 8: 141-53. 3. Sirotnak FM, DeGraw JI, Schmid FA et al. New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid tumor murine models. Cancer Chemother Pharmacol 1984; 12: 26-30. 4. Fry DW, Jackson RC. Biological and biochemical properties of new anticancer folate antagonists. Cancer Metastasis Rev 1987; 5:251-70. 5. Lee JS, Libshitz HI, Murphy WK et al. Phase U study of 10ethyl-deaza-aminopterin (10-EDAM;CGP 30 694) for stage HTB or IV non-small cell lung cancer. Invest New Drugs 1990; 8: 299-304. 6. Kris MG, Kinahan JJ, Gralla RJ et al. Phase I trial and clinical pharmacological evaluation of 10-ethyl-deaza-aminopterin in adult patients with advanced cancer. Cancer Res 1988; 48: 5573-4. 7. Casper ES, Schwartz GK, Johnson B et al. Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma. Invest New Drugs 1992; 10: 313-6. Received 29 October 1993; accepted 15 December 1993. Correspondence to: Richard Pazdur, MD Division of Medicine Box 92 The University of Texas M. D. Anderson Cancer Center 1515 Holcombe Boulevard Houston TX 77030 USA.