Beth Bready

Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma.

PURPOSE To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.

PHASE I TRIALS OF URACIL-TEGAFUR (UFT) USING 5 AND 28 DAY ADMINISTRATION SCHEDULES : DEMONSTRATION OF SCHEDULE-DEPENDENT TOXICITIES

We conducted two consecutive phase I clinical trials to identify the qualitative and quantitative toxic effects of uracil-tegafur (UFT) [Taiho Pharmaceutical Co. Ltd, Tokyo, Japan; (BMS-200604) Bristol-Myers Squibb, Princeton, NJ] administered either on a 5 or 28 day schedule and to determine the phase II trial starting doses for both schedules. Nineteen patients were entered on the 5 day schedule and 23 patients were entered on the 28 day schedule; a minimum of three patients were entered at each dose level studied. In both phase I trials, the daily UFT dose was divided into three doses administered every 8 h. Dose levels examined with the 5 day schedule were 360, 720, 900 and subsequent de-escalation to 800 mg/m2/day. Dose levels studied with the 28 day schedule were 180, 360, 450 and subsequent de-escalation to 400 mg/m2/day. With the 5 day schedule, the dose-limiting toxicity (DLT) was granulo-cytopenia, with four of five patients experiencing grade 4 granulocytopenia at the 900 mg/m2/day dose level. With the 28 day schedule, the DLT was diarrhea, which was noted in three of eight patients treated at 400 mg/m2/day and in three of six patients treated at 450 mg/m2/day. At these dose levels, four of these patients required prolonged hospitalizations for their diarrhea. The toxic effects of UFT are schedule dependent, with marked differences in the toxic effect profile (neutropenia versus diarrhea). With the 5 day schedule, the phase II UFT starting dose is 800 mg/m2/day. On the 28 day schedule, the suggested phase II UFT starting dose is 360 mg/m2/day. Future clinical trials examining the combination of UFT plus oral folinic acid are being conducted to develop oral regimens of therapy for advanced colorectal carcinoma and adjuvant therapy for colon carcinoma.

Pilot phase II trial of 13-cis-retinoic acid and interferon-α combination therapy for advanced pancreatic adenocarcinoma

The combination of interferons (IFNs) and retinoids in antineoplastic therapy is based upon preclinical, in vitro, and in vivo observations. Retinoid-IFN combinations have shown significant antitumor activity against advanced cutaneous and cervical squamous cell carcinoma (SCC), and the toxic effects do not appear to overlap. Based on in vitro evidence of synergy and observed clinical activity, we conducted a pilot phase II trial of 13-cis-retinoic acid (1 mg/kg/day) and IFN alpha (6 million units/day) in patients with advanced pancreatic adenocarcinoma. No objective responses occurred among six evaluable patients. The toxicities were mild and reversible, and grade 3 fatigue occurred in only one patient. No objective antitumor activity was noted against pancreatic adenocarcinomas at the dose and schedule utilized. Further exploration of this this purely biological approach is not warranted for pancreatic adenocarcinomas.

Phase II evaluation of recombinant alpha-2a-interferon and continuous infusion fluorouracil in previously untreated metastatic colorectal adenocarcinoma

Background. Thirty‐nine patients with advanced measurable metastatic colorectal carcinoma were entered in a clinical trial of recombinant alpha‐2a‐interferon (rα‐2a‐IFN) and continuous‐infusion 5‐fluorouracil (5‐FU). Patients had not been treated previously with chemotherapy and had bidimensionally measurable disease.

Sequential biochemical modulation of fluorouracil with folinic acid, N-phosphonacetyl-L-aspartic acid, and interferon alfa-2a in advanced colorectal cancer.

PURPOSE Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFNalpha-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m(2) followed by 5-FU 425 mg/m(2) on days 1 to 5; (cycle 2) PALA 250 mg/m(2) on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m(2) as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFNalpha-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m(2) on days 57 to 61, and then weekly bolus of 5-FU 750 mg/m(2)/wk on days 71, 78, and 85. Response was determined after cycle 3. RESULTS All patients had a Zubrod performance status >/= 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue. CONCLUSION This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA.

Phase II trial of piroxantrone in metastatic gastric adenocarcinoma

SummaryPiroxantrone, a synthetic intercalating agent, was studied in patients with advanced, measurable gastric adenocarcinoma who had not received prior chemotherapy. The starting piroxantrone dose was 150 mg/m2 given intravenously over 1 hour on day 1 and repeated every 21 days. Response and toxicity could be evaluated in 15 patients. No complete, partial, or minor responses were observed. Toxic effects included granulocytopenia, anemia, vomiting, nausea, anorexia, fatigue, stomatitis, alopecia, hyperbilirubinemia, and increased alkaline phosphatase levels. At the stated dose and schedule, piroxantrone does not possess significant activity against advanced gastric cancer.

Phase II trial of isotretinoin and recombinant interferon alfa-2a in metastatic colorectal carcinoma

Phase II trials of the novel biologic combination isotretinoin (13-cis-retinoic acid) plus recombinant interferon alfa-2a have demonstrated this combinations major activity against advanced squamous cell carcinomas of the skin and cervix. Because this combination has had limited study in other tumors, we initiated a phase II trial of this regimen in patients with metastatic colorectal adenocarcinoma. Sixteen patients with measurable metastatic colon carcinoma who had received no previous chemotherapy were entered on the trial. Patients received recombinant interferon alfa-2a, 6 million units a day subcutaneously, and isotretinoin, 1 mg/kg per day orally in two divided doses. Patients were evaluated for response after 8 weeks of treatment and then continued on therapy until progressive disease was documented. We did not observe complete or partial responses. Two patients experienced minor responses in measurable pulmonary metastases lasting 12 and 8 weeks. Grade 3–4 toxic reactions included fatigue (5 patients), granulocytopenia (6 patients), neurotoxicity (2 patients), and elevated serum triglyceride levels (2 patients). Although this combination has demonstrated significant activity in squamous cell carcinomas of the skin and cervix, our results suggest that it has little therapeutic activity against advanced colorectal adenocarcinomas.