Investigational New Drugs 8: 387-389, 1990. 9 1990 Kluwer Academic Publishers. Printed in the Netherlands.

Brief report

Trimetrexate in locally advanced or metastatic adenocarcinoma of the pancreas A phase II study of the Northern California Oncology Group

Robert W. Carlson 1,4, James H. Doroshow 2, Oluwole O. Odujinrin 2, Marshall S. Flam 3, Mary Malec 4 and Kathleen R. Lamborn 4

1Department of Medicine, Stanford University, Stanford, CA 94305; 2Department of Medical Oncology and TherapeuticsResearch, City of Hope National Medical Center, Duarte, CA 9101O;3San Joaquin Valley Community Clinical Oncology Program, Fresno, CA 93715; 4Northern California Cancer Center, Belmont, CA 94002, USA Key words: trimetrexate, adenocarcinoma, pancreas, phase II Introduction

Trimetrexate is an investigational nonclassical antifol with cellular transport and intracellular accumulation characteristics that differ significantly from methotrexate [1,2]. Preclinical studies demonstrated that trimetrexate has significant antitumor activity, including activity against pancreatic carcinoma [2,3]. In phase I studies, myelosuppression was the dose limiting toxicity. Non-dose limiting toxicities included nausea, vomiting, diarrhea, mucositis, skin rash, liver function abnormalities, and reversible renal dysfunction [4-6]. We report here a phase II study o f trimetrexate in the treatment of pancreatic adenocarcinoma

Methods

This was a phase II trial of the Northern California Oncology Group (NCOG). Patients had measurable locally advanced or metastatic pancreatic adenocarcinoma, life expectancy > 2 months, Karnofsky performance status _ 5 0 % , no prior chemotherapy, no active malignancy within 10 years, no significant concurrent medical problems, and adequate kidney, liver, and bone marrow function. All patients provided signed, informed consent. Trimetrexate glucuronate 12 mg/mZ/d was ad-

ministered intravenously days 1 - 5 o f 21 day cycles. Dose escalation of 25% on each successive cycle was allowed unless the nadir white blood cell count was < 3 , 0 0 0 / m m 3, platelet nadir was < 100,000/ mm 3, or grade 2 or greater non-hematologic toxicity occurred. If the day 22 white blood cell count was < 2 , 5 0 0 / m m 3 or platelet count < 7 5 , 0 0 0 / m m 3, treatment was delayed one week; if the day 29 white blood cell count was still < 2 , 5 0 0 / m m 3 or the platelet count < 7 5 , 0 0 0 / m m 3, treatment was administered at 50% of the prior dose. Standard criteria of response were utilized. Time to progression was measured from date of registration on study to date of first evidence of progressive disease. Survival was measured from date of registration on study until date of death. The study was designed to detect a threshold response rate of 20% or greater with an alpha error of _ 9 5 % .

Results and discussion

Fifteen patients were enrolled: mean age was 61.9 years, 10 (67%) were female, and 14 (93%) had a Karnofsky performance status _>70%. One patient was ineligible for study based upon a second active primary tumor, but received a total of 9 cycles of trimetrexate prior to evidence of disease progression. Thus, 14 patients are considered evaluable for

388

1

Probability

Table 1. Toxicity

a

Toxicity

0.8

0.6

0.4

0.2

n 50

i 150

1o o

I

I

200

250

300

Time (days)

Probability

0.8-

L

1._.

0.6

L. ~

0,4 0.2 0

~ 50

1 O0

150

200

250

300

Time (days) Fig. 1. (a) The median time to progression (b) Median survival

Lowest white blood cell count 3,000-4,400/mm 3 2,000-2,999/mm 3 1,000-1,999/mm 3 < 1,000/mm3 Lowest granulocyte count < 500/mm3 500-1,000/mm 3 > 1,000/mm3 Not available Lowest platelet count 90,000-129,000/mm 3 50,000- 89,000/ram3 25,000- 49,000/ram3 < 25,000/mm3 Stomatitis Faint enanthema Patchy mucositis Confluent mucositis Nausea and vomiting Nausea Mild nausea and vomiting Diarrhea, minimal Pruritus Minimal hair loss

N of patients with toxicity (070) 0 5 (33) 0 2 (13) 2 (13) 3 (20) 8 (53) 2 (13) 2 (13) 2 (13) 1 (7) 1 (7) 2 (13) 1 (7) 1 (7) 1 (7) 3 (20) 3 (20) 1 (7) 1 (7)

time.

Acknowledgements response and 15 patients are evaluable for toxicity. A total of 47 (mean 3.1; range 1 - 9 ) cycles of trimetrexate was administered. No patient achieved a partial or complete response. Five patients had stable disease at the completion of 2 cycles while the other 9 patients had evidence o f progression. The median time to progression was 43 days (Fig. 1) and median survival was 109 days. The toxicity experience is outlined on Table 1. Two patients experienced white cell nadirs of < l , 0 0 0 / m m 3 and 2 patients platelet counts < 25,000/mm 3. The only grade 3 or 4 non-hematologic toxicity was confluent mucositis in a single patient. We conclude that trimetrexate at this dose and schedule has acceptable toxicity but no significant activity against adenocarcinoma of the pancreas.

Support for the study described was provided by grants CA21744, CA39098, CA25838, CA35016, and CA35283 f r o m the National Cancer Institute, N I H , D H H S , to the Northern California Cancer Center and its member institutions, and grant CA 33572 to the City of H o p e National Medical Center, Duarte, CA. Dr. Carlson is the recipient of an American Cancer Society ClinicalOncology Career Development Award. The following N C O G institutions, with their respective principal investigators, accrued patients to this study: Bay Area Military Hospitals, H o w a r d Wold; City of H o p e National Medical Center, James H. Doroshow; University of California, Davis Medical Center, Frederick J. Meyers; Bay Area T u m o r Institute/East Bay Oncology Group, Michael Cassidy; Northern Nevada Cancer Council, John Shields, F. Roy MacKintosh; Sacramento

389 CCOP,

V i n c e n t C a g g i a n o ; San J o a q u i n Valley

C C O P , Phyllis J o y c e A g e r . W e also wish to t h a n k Ms. P a t A c o r d f o r assistance in d a t a analysis a n d Mrs. C l a r a R o m a n o f or secretarial assistance.

References 1. Kamen BA, Eibl B, Cashmore AR, Bertino JR: Uptake and efficacy of trimetrexate (TMQ, 2,4-diamino-5-methyl-6(3,4,5-trimethoxyanilino) methyl] quinazoline), a nonclassical antifolate in methotrexate-resistant leukemia cells in vitro. Biochem Pharmacol 33:1697-1699, 1984 2. Jackson RC, Leopold WR, Hamelehle KL, Fry DW: Preclinical studies with trimetrexate: A review of conclusions and unanswered questions. Semin Oncol 15 (2 Suppl 2):1-7, 1988

3. Lathan B, Von Hoff DD, Elslager E: Use of a human tumor cloning system to evaluate analogs of methotrexate and mitoxantrone. Cancer Treat Rep 68:733-738, 1984 4. Steward JA, McCormack J J, Tong W, DeLap RJ, GrilloLopez AJ: A phase I study of trimetrexate. (Abstract) Proc Am Assoc Cancer Res 26:159, 1985 5. Rosen M, Ohnuma T, Zimet A, Coffey V, Zhang N, Holland JF: Phase I study of trimetrexate (trimetrexate, TMQ, JB-11) glucuronate in a 5 day infusion schedule. (Abstract) Proc Am Assoc Cancer Res 27:172, 1986 6. Stewart JA: Safety and tolerance of trimetrexate: Results of a phase II multicenter study in patients with metastatic cancer refractory to conventional therapy or for which no conventional therapy exists. Semin Oncol 15 (2 Suppl 2): 10-16, 1988

Address for offprints: R.W. Carlson, Division of Medical Oncology, Stanford University Medical Center, M211, Stanford, CA 94305, USA