Chris Feierabend

A phase I study of gemcitabine, 5-fluorouracil and leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors

Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU).Methods: Standard eligibility criteria were required for patients with advanced malignancy to enrol. Gemcitabine was escalated from an initial dose of 800 mg/m2. Gemcitabine was administered prior to leucovorin (25 mg/m2) followed by bolus 5-FU (600 mg/m2) every week for 3 weeks followed by 1 week of rest.Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m2 systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m2, full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m2 was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels.Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m2. Initial evidence of clinical activity was seen in a variety of tumor types.

Phase I Trial of the Polyamine Analog N1,N14-Diethylhomospermine (DEHSPM) in Patients with Advanced Solid Tumors

Background: This phase I study was conducted to determine maximal tolerated dose (MTD) and dose-limiting toxicities (DLT) in patients with advanced solid tumors treated with the polyamine analog N1,N14-diethylhomospermine (DEHSPM). Methods: Patients were treated with DEHSPM administered as a subcutaneous (SC) injection daily for five consecutive days repeated every 4 weeks. Three dose levels were examined starting at 12.5 mg/m2/day, escalating to 37.5 mg/m2/day. Results: A total of 15 patients were enrolled. Dose limiting toxicities (grade 3 or 4) included nausea, vomiting, constipation, ileus, elevations of aspartate aminotransferase (AST) and alkaline phosphatase, hyperbilirubinemia, and ventricular bigeminy. Conclusion: DEHSPM given as a SC injection is overall well tolerated at lower doses, but significant toxicities were observed at the 37.5mg/m2/day dose level. MTD was established at 25 mg/m2/day but further investigation with this study drug is not recommended secondary to the potential for neurotoxicities and hepatic damage as a result of cumulative doses.

Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two-stage trial design for patients with advanced malignancy.

PURPOSE A novel phase I trial design was used to determine the maximum-tolerated dose (MTD) and pharmacokinetics for penclomedine when administered as an intravenous (i.v.) infusion over 1 hour daily for 5 days, repeated every 28 days. This study also tests the feasibility of a novel two-stage design for phase I trials. PATIENTS AND METHODS Twenty-eight patients with advanced malignancy who met standard eligibility criteria were treated with i.v. penclomedine. The initial daily dose was 50 mg/m2. Dose escalations were planned using a modified Fibonacci sequence. One patient was enrolled on each dose level during the first stage of this trial. In the second stage, patients were enrolled in cohorts of three, proceeding in an up-and-down manner based on toxicities observed. MTD was determined by logistic regression analysis. Pharmacokinetic assessment was performed during the first cycle of treatment. RESULTS Dose-limiting toxicities (DLT) observed during this trial were principally neurologic and were self-limited. Although hematologic toxicity was rare, the few patients with significant hematologic changes experienced late nadirs with prolonged time to recovery. The MTD was estimated as 381 mg/m2 (80% CI, 343 to 415 mg/m2). Although there was a long elimination half-life, accumulation of penclomedine over the 5 days of administration was negligible. CONCLUSION The novel trial design used in this study was safe and appeared effective in limiting the numbers of patients treated at lower-dose levels. Reversible neurotoxicity was dose-limiting. Although the estimated MTD was 381 mg/m2, any dose within the CI would be reasonable for phase II study.

Phase I study of eniluracil, oral 5-fluororacil and gemcitabine in patients with advanced malignancy

AbstractPurpose: The objectives of this trial wereto assess the maximal tolerated dose andtoxicity of the combination of oraleniluracil and 5-fluorouracil andintravenous gemcitabine. Patients and methods: Patients withhistologically confirmed, incurablemalignancy (solid tumor or lymphoma)refractory to standard therapy or for whichno standard therapy exists were enrolled. The treatment plan consisted of weeklygemcitabine for three weeks with twicedaily dosing of 5-FU and eniluracil for 21days beginning on day one of gemcitabine. Cycles repeated on an every four weekschedule. The initial cohort receivedgemcitabine 800 mg/m2, oral 5-FU 0.6 mg/m2and eniluracil 6.0 mg/m2. Results: Twenty-six patients were enrolled. Eight patients received less than 2 cyclesof therapy. Hematologic andgastrointestinal toxicity predominated,with 48% of courses resulted in grade oneor two neutropenia. Hematologic toxicitywas dose limiting. One treatment relateddeath occurred. Conclusions: The combination of eniluracil,5-fluorouracil and gemcitabine offers anoral alternative for 5-FU administration.The recommended phase II dose isgemcitabine 1000 mg/m2, 5FU 1.2 mg/m2 andeniluracil 12 mg/m2.

A phase I study of 5-fluorouracil, leucovorin and levamisole

Abstract Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from 30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies.

Phase I study of docetaxel and topotecan in patients with advanced malignancies

Background. Docetaxel and topotecan are drugs with different mechanisms of action and significant activity against various tumour types. Topotecan may influence docetaxel metabolism by inhibiting the CYP3A4 enzyme. We designed a phase I study to evaluate the maximum tolerated dose of this combination and to assess the impact of pharmaco-kinetic interactions of the two drugs on toxicity. Methods. Docetaxel and topotecan were administered intravenously on day 1, and days 1- 5 respectively, using a phase I dose escalation design. Plasma samples were analysed to determine docetaxel and topotecan concentration by HPLC with subsequent pharmacokinetic analysis using NONMEM. Results. Of the 17 patients enrolled in the trial, 11 had grade 3 and 4 neutropenia and 1 had grade 4 thrombocytopenia. Nonhaematological toxicities were less frequent. The maximum tolerated dose for docetaxel and topotecan were 60 mg/m2 on day 1 and 0.75 mg/m2 days 1- 5, respectively. One patient had stable disease. Subjects with grade]3 haematologic toxicity had higher plasma docetaxel or topotecan area under the curve (AUC) (docetaxel 1.0390.11 mg-hr/L versus 0.7390.13 mghr/L; topotecan 65.8914.6 mcg-hr/L versus 41.6913.9 mcg-hr/L). There was no additive effectoftheAUCofthetwodrugsonthe likelihood of grade]3 haematologic toxicity by multiple logistic regression. Conclusion. The dose-limiting toxicity seen with the combination of docetaxel and topotecan was myelosuppression. Future trials will require growth factor support if this combination is pursued.

Gemcitabine, Paclitaxel, and piritrexim: a phase I study.

Piritrexim is a new antifolate that has shown activity in methotrexate-resistant tumors. Gemcitabine is an antimetabolite similar in structure to cytosine arabinoside with early studies demonstrating activity in a variety of cancers. It also has apparent synergistic activity with antifolates from initial work in tumor models. Paclitaxel is an antimicrotubule agent that has a wide spectrum of activity against a variety of solid tumors. The combination of gemcitabine, paclitaxel, and piritrexim was assessed in this phase I trial. Thirty patients were enrolled. The starting doses were piritrexim 25 mg orally twice daily (days 1–4, 15–18), paclitaxel 75 mg/m2 (days 1, 15), and gemcitabine 750 mg/m2 (days 1, 15), which then was escalated in a stepwise fashion. Four patients achieved stable disease while on study, whereas one patient with a poorly differentiated neuroendocrine tumor achieved a partial response. The main toxicity was myelosuppression. The maximum tolerated dose was thought to be piritrexim 25 mg orally three times daily (days 1–4), paclitaxel 150 to 175 mg/m2 (days 1, 15), and gemcitabine 1,000 mg/m2 (days 1, 15). The combination of these new antifolates with paclitaxel and gemcitabine appears safe and should be considered for phase II trials in known responsive tumors such as transitional cell carcinomas.