Investigational New Drugs 16: 315–318, 1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands. 315 PALA versus streptozotocin, doxorubicin, and MeCCNU in the treatment of patients with advanced pancreatic carcinoma Robert S. Witte 1 , Louise M. Ryan 2 , Allan J. Schutt 3,∗ , Paul P. Carbone 4 and Paul F. Engstrom 5 1 Gundersen Lutheran, LaCrosse, WI; 2 Dana-Farber Cancer Institute, Boston, MA; 3 Mayo Clinic, Rochester, MN; 4 University of Wisconsin Comprehensive Cancer Center, Madison, WI; 5 Fox Chase Cancer Center, Philadelphia, PA, USA; ∗ currently retired Key words: pancreatic carcinoma, PALA, streptozotocin, doxorubicin, MeCCNU Summary Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were alloc- ated to one of two treatment regimens: 35 received PALA (1250 mg/m 2 daily × 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m 2 IV daily × 5, doxorubicin 45 mg/m 2 IV on day 1 and 22, and methyl CCNU 60 mg/m 2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer. Introduction Pancreatic carcinoma is the fourth leading cause of cancer-related death in North America, surpassed only by carcinoma of the lung, breast, and large bowel [1]. Most patients are not curable even if diagnosed at a surgically resectable stage because of early dissemination both locally and systemically. The need for effective systemic therapy is, clearly, self-evident. At the time of the activation of this protocol those single agents adequately studied to provide valid response rates (all in the 8–20% range) included 5-flourouracil, mitomycin-C, doxorubicin, methyl- CCNU (meCCNU) and streptozotocin [2–6]. Other combinations such as FAM-S (fluorouracil, doxor- ubicin, mitomycin-c, and streptozotocin) and FAM (fluorouracil, doxorubicin, and mitomycin-c) were pu- tatively more active with response rates in the 20–48% range [7, 8]. These trials were, for the most part, single arm phase II studies. These treatment regimens have been subjected to little phase III scrutiny. However, those combinations so tested have not proven more efficacious [9, 11]. There clearly is need to continue the search for more useful systemic therapies for this lethal disease. PALA [N-(phosphonacetyl)-1-aspartic acid, diso- dium salt] is an inhibitor of aspartate transcarbamylase which is a key enzyme in the de novo synthesis of pyrimidines [12]. Pre-clinical data show tight and dur- able binding of PALA to the enzyme in vivo [13]. In a number of transplantable murine tumors treatment with PALA resulted in nearly a doubling of survival, regression of metastatic disease, and no schedule- dependence [14]. Phase I studies utilizing the treat- ment scheme used in this study (1250 mg/m 2 daily for 5 consecutive days) determined that the dose-limiting toxicities were diarrhea and rash [15]. Most patients failing initial chemotherapy treat-