A phase I study of an oral simulated FOLFOX with high dose capecitabine.

BACKGROUND: A phase I study of high-dose capecitabine given over 2 days, along with oxaliplatin, bolus 5FU and leucovorin (LV), was designed to simulate FOLFOX6 without the need for infusional 5FU. METHODS: Schedule A included oxaliplatin 100 mg/m(2), 5FU 400 mg/m(2), and LV 20 mg/m(2) (all given IV on days 1 and 15, 28 day cycle). Capecitabine was administered orally every 8 h x 6 doses, days 1 and 15. Schedule B excluded 5FU and LV, maintaining oxaliplatin and capecitabine. Pharmacokinetics were performed for capecitabine for 6 patients on each schedule. RESULTS: 36 patients were treated. The dose-limiting toxicities seen included nausea, dehydration, fatigue, hypotension and confusion. Minimal palmar-plantar erythrodysesthesia was seen. Myelosuppression was common, but not a dose limiting toxicity. The pharmacokinetic parameters for capecitabine were unaltered. CONCLUSION: Using capecitabine to mimic FOLFOX6 is feasible and well tolerated with a toxicity profile that differs from standard 14-day capecitabine dosing, with less palmar-plantar erythrodysesthesia. The phase II dose for capecitabine in combination with oxaliplatin, 5FU, and LV is 1,500 mg/m(2)/dose or 2,250 mg/m(2)/dose in the absence of bolus 5FU/LV.

Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan.

BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a phase I study of BSO administered with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2). This treatment also produced consistent, profound glutathione depletion (<10% of pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.

Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer.

PURPOSE: We conducted a phase I trial of a 3-hour infusion of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) to identify the maximum-tolerated dose of Taxol as a 3-hour infusion with and without granulocyte colony-stimulating factor (G-CSF) support. MATERIALS AND METHODS: Thirty-five patients with advanced, untreatable malignancies were treated with a 3-hour infusion of Taxol once every 3 weeks. Groups of three patients were entered at escalating dose levels of Taxol in a traditional phase I design in each of two parallel arms: arm A, without G-CSF, and arm B, with G-CSF. Patients assigned to the G-CSF arm received G-CSF 5 micrograms/kg/d subcutaneously starting on day 2 for 9 to 14 days. All patients were pretreated with dexamethasone, diphenhydramine, and ranitidine, and were monitored continuously for cardiac arrhythmias during the first treatment. RESULTS: Dose-limiting myelosuppression with Taxol without G-CSF was observed at the 250-mg/m2 dose level. The dose-limiting toxicity for Taxol with G-CSF was peripheral neuropathy at the 300-mg/m2 dose level. One of 35 patients (2.8%) had a grade 3 anaphylactic reaction at 250 mg/m2. No clinically significant cardiac arrhythmias were documented. Twenty-seven of 111 courses (24%) were associated with grade 3 arthralgias or myalgias requiring narcotics for pain control. Taxol plasma concentrations declined in a triexponential fashion, with a final elimination half-life of 10 to 12 hours. The peak Taxol plasma concentrations and total area under the curve (AUC) increased with increasing doses of Taxol, although this increase appeared to be somewhat nonlinear. CONCLUSION: The maximum dose of Taxol recommended for phase II and III studies, when administered as a 3-hour infusion alone and with G-CSF support, is 210 mg/m2 and 250 mg/m2, respectively. No increased incidence of hypersensitivity reactions or other side effects were observed, with the possible exception of arthralgias and myalgias. If ongoing trials demonstrate that a 3-hour infusion is as efficacious as a 24-hour infusion, we conclude that with proper monitoring and premedication, high-dose Taxol can be safely administered in the outpatient setting.

Phase I clinical and pharmacokinetic study of oral carboxyamidotriazole, a signal transduction inhibitor.

PURPOSE: We conducted a phase I trial of carboxyamidotriazole (CAI, NSC 609974), designed to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetic characteristics of CAI gelatin capsule (gelcap) formulation administered daily as a single oral dose. PATIENTS AND METHODS: Twenty-nine patients with advanced malignancy who met standard eligibility criteria were treated with once-daily CAI given in cycles of 28 days. Pharmacokinetic sampling was performed on days 1 and 29 and trough plasma CAI levels were assessed weekly. RESULTS: Patients were entered at dose levels of 50, 75, and 100 mg/m2. All three patients at the 100-mg/m2 level experienced dose-limiting neurocerebellar toxicity. Other neurotoxicities were mild. Gastrointestinal side effects were common, but generally mild, with 23 patients experiencing nausea and/or vomiting of any grade. Fatigue was a frequent complaint, with 19 patients experiencing mild to moderate symptoms. Six patients with nausea and vomiting and five with fatigue experienced relief of symptoms with a change to nocturnal administration of CAI. Peak plasma concentrations (Cp) occurred at 2.4 +/- 1.5 hours after administration of the oral gelcap dose. Patients approached steady-state trough plasma concentrations (Css) by days 8 to 15 and maintained a relatively constant Css throughout the course of treatment. For all patients, the mean variation in weekly CAI Cp was 12.4% +/- 5.3%. CONCLUSION: The MTD for the gelcap formulation was 75 mg/m2 with dose-limiting neurocerebellar toxicity (ataxia) seen at 100 mg/m2. Other prominent side effects, including nausea, vomiting, and fatigue, were partially alleviated through altering the administration schedule to nighttime dosing.

Phase I clinical trial of carboplatin and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes in a phase I clinical trial. PATIENTS AND METHODS: Thirty assessable patients with cancer refractory to conventional therapy were treated. During induction therapy, patients received WBH alone in week 1, WBH plus carboplatin in week 2, and carboplatin alone in week 5. Carboplatin dose was escalated (three patients per group) as follows: 100, 150, 200, 250, 300, 350, 400, 480, and 575 mg/m2; three additional patients were entered at 480 mg/m2. Carboplatin was administered at target temperature. RESULTS: Comparisons of the mean/median WBC and platelet nadirs for carboplatin alone and carboplatin plus WBH demonstrated no enhancing effect by WBH. Toxicities including nausea and/or vomiting, as well as myelosuppression, were within acceptable limits, allowing for escalation to a dose of 575 mg/m2; three of three patients at this dose level experienced grade 4 myelosuppression with no associated infection or bleeding. No renal toxicity was observed. Analysis of platinum in plasma ultrafiltrate and urine showed only slight effects of WBH on the pharmacokinetics and renal excretion of platinum. Responses included the following: lung--minor response (200 mg/m2); gastrointestinal neuroendocrine--complete response (CR) (400 mg/m2); pancreatic--partial response (PR) (480 mg/m2); small bowel--PR (575 mg/m2); ovarian--CR, two patients (575 mg/m2), with marker data suggesting WBH enhancement of carboplatin cytotoxicity. Another three patients experienced clinical improvement after WBH plus carboplatin, but progression with carboplatin alone (lung, 400 mg/m2; gastrointestinal neuroendocrine, 480 mg/m2; melanoma, 480 mg/m2). CONCLUSION: We conclude that carboplatin with WBH is well tolerated even at conventional carboplatin doses. Clinical results are consistent with preclinical predictions of an increased therapeutic index for this combination, which encourages future clinical studies.

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 trial of intravenous thymidine and carboplatin in patients with advanced cancer.

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m(2) in a phase I trial. PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m(2) (n = 3); 300 mg/m(2) (n = 7); 350 mg/m(2) (n = 4); 400 mg/m(2) (n = 3); 480 mg/m(2) (n = 10); and 576 mg/m(2) (n = 5). At the maximum-tolerated dose (480 mg/m(2)), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy. RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m(2)-dose level, and disease stabilization (7 months) at the 400-mg/m(2-dose) level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m(2)-dose level. CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.

Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes. PATIENTS AND METHODS: Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY). RESULTS: Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail. CONCLUSION: We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.

Leucovorin modulation of 5-iododeoxyuridine radiosensitization: a phase I study.

Evidence for clinically significant radiosensitization by the halogenated pyrimidine 5-iododeoxyuridine (IdUrd) continues to accumulate. In vitro radiosensitization has been demonstrated in human colon tumor cell lines following exposure to 1-10 micrometer. Coadministration of leucovorin (LV) increases radiosensitization, which correlates directly with increased IdUrd DNA incorporation. Clinical data regarding proliferation rates and thymidine kinase levels in tumors versus normal tissues suggest selective incorporation of IdUrd into gastrointestinal tumors may occur. The objectives of this Phase I study were: (a) to assess the feasibility of LV modulation of IdUrd radiosensitization by determining the maximum tolerated dose (MTD) of IdUrd plus LV; and (b) to perform correlative laboratory studies to investigate the potential of IdUrd plus LV to increase radiosensitization in vivo. Seventeen patients with unresectable or recurrent gastrointestinal adenocarcinomas received a 14-day course of continuous i.v. infusion of IdUrd prior to initiation of radiotherapy. Two additional 14-day infusions of IdUrd with LV were given during the course of radiotherapy (60 Gy in 6 weeks). The initial dose of IdUrd was 250 mg/m2/day and was escalated in subsequent patients to 400 and 600 mg/m2/day. The LV dose remained fixed at 250 mg/m2/day. Leukopenia was the dose-limiting toxicity, and 400 mg/m2/day was the MTD for this trial. At the MTD, the mean +/- SD steady-state plasma concentration of IdUrd during the infusion, measured by high-performance liquid chromatography, was 0.66 +/- 0.23 micrometer. There was no significant influence of LV on IdUrd DNA incorporation in peripheral blood granulocytes as measured by high-performance liquid chromatography. Based on toxicity data and correlative laboratory studies, a meaningful increase in radiosensitization would not be achieved with the IdUrd infusion schedule and dose of LV investigated compared with IdUrd alone.

Phase I clinical trial of perillyl alcohol administered daily.

Perillyl alcohol (POH; NSC-641066), a naturally occurring monoterpene, has shown antitumor and preventive activity in preclinical studies in rodent models. Drug-related activities that have been observed include the induction of apoptosis, cell cycle arrest, the inhibition of posttranslational modification of proteins that are involved in signal transduction, and differential gene regulation. We treated 18 patients who had advanced malignancies with POH, which was given on a continuous three-times-a-day schedule at the following doses: (a) level 1 (L1), 800 mg/m2/dose; (b) level 2 (L2), 1600 mg/m2/dose; and (c) level 3 (L3), 2400 mg/m2/dose. The main toxicity, which seemed to be dose related, was gastrointestinal and included nausea and vomiting, anorexia, unpleasant taste, satiety, and eructation. Two heavily pretreated ovarian cancer patients experienced reversible > or =grade 3 granulocytopenia. Grade 1-2 fatigue was also noted. The parent drug was not detectable in the plasma. The mean peak plasma levels of the two main metabolites on days 1 and 29 were 175 and 139 microM (L1), 472 and 311 microM (L2), and 456 and 257 microM (L3) for perillic acid (PA) and 7.1 and 9.8 microM (L1), 34.2 and 34.0 microM (L2), and 26.2 and 23.4 microM (L3) for dihydroperillic acid (DHPA). Peak levels were noted 2-3 h postingestion for PA and 3-5 h postingestion for DHPA. Metabolite half-lives measured about 2 h for each. POH, PA, and DHPA were detectable in the urine of all patients at L3. About 9% of the total dose was recovered in the first 24 h. The majority was recovered as PA; less than 1% was recovered as POH. Disease stabilization for > or =6 months was seen, although no objective tumor responses were noted. Further study of POH continues with a more frequent dosing schedule.