Pharmacokinetics of very high-dose oral melphalan in cancer patients

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days -6, -5, and -4, followed by BCNU at 300 mg/m2/day i.v. on days -3, -2, and -1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/m2/day p.o. on days -3, -2, and -1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days -7, -5, and -3, followed by melphalan at 157 mg/m2/day p.o. on days -2 and -1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 micrograms/ml (patient 1). Plasma melphalan concentration X time products (C x Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 micrograms.h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C X Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C X T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C X T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.     

Plasma pharmacokinetics of high-dose oral melphalan in patients treated with trialkylator chemotherapy and autologous bone marrow reinfusion

The pharmacokinetics of melphalan following high-dose p.o. administration were determined in 17 patients with various malignancies for the purpose of assessing interpatient and intrapatient pharmacokinetic variability. All patients underwent bone marrow harvest on day -8 (relative to bone marrow reinfusion). On days -7, -6, and -5, melphalan was given p.o. and the dose was escalated on each cohort consisting of at least 3 patients (beginning at 0.75 mg/kg). On days -6, -4, and -2, cyclophosphamide at 2.5 g/m2 and thiotepa at 225 mg/m2 were given i.v. On day -7 the peak melphalan concentration was 1.64 +/- 0.89 (SD) microM with a terminal half-life of 1.56 +/- 0.86 h. The area under the plasma concentration time curve (AUC) and oral clearance were 217.9 +/- 115.1 microM/min and 30.2 +/- 14.2 ml/min/kg. There was only a moderate correlation between the melphalan dose and both the peak concentration (r = 0.50, P less than 0.05) and AUC (r = 0.64, P less than 0.01) over the dosage range of 0.75-2.5 mg/kg. There was a trend towards greater interpatient variability in peak concentration, AUC, and oral clearance observed at the higher doses of melphalan. Analysis of intrapatient pharmacokinetic variability in 8 patients showed a significant difference between the doses given on days -7 and -5 in the peak concentration (2.09 versus 1.07 microM, P = 0.02), AUC (264.9 versus 134.8 microM/min, P = 0.01), and oral clearance (25.1 versus 53.1 ml/min/kg, P = 0.05) but no significant difference in the time to peak and terminal half-life. We conclude that there is marked interpatient and intrapatient variability in melphalan pharmacokinetics following high-dose p.o. administration. The data are consistent with saturable absorptive pathways for melphalan, which might be especially sensitive to concurrent high-dose chemotherapy.     

Oral zidovudine, continuous-infusion fluorouracil, and oral leucovorin calcium: a phase I study

A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.     

Phase I trial of misonidazole (NSC#261037) plus cyclophosphamide in solid tumors

Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.     

Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer.

Nine patients with progressive, metastatic disease from primary carcinoma of the colon were entered into a phase I/II study using continuous intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and high dose melphalan (120 mg m-2). GM-CSF was given alone to six patients during the first part of the study to determine a dose that would produce a peripheral leucocyte count (WCC) greater than or equal to 50 X 10(9) 1(-1) and was initially given at 3 micrograms kg-1 day-1 and escalated to 10 micrograms kg-1 day-1 after 10 days. The infusion was discontinued when the WCC exceeded 50 X 10(9) 1(-1) and after a gap of one week, melphalan was given over 30 min. GM-CSF was recommenced 8 h later and was continued until the neutrophil count had exceeded 0.5 X 10(9) 1(-1) for greater than 1 week. One patient achieved a WCC greater than 50 X 10(9) 1(-1) with GM-CSF 3 micrograms kg-1 day-1, but the other five who entered this phase of the study required dose escalation to 10 micrograms kg-1. No toxicity attributed to GM-CSF was seen. After melphalan, the median times to severe neutropenia (less than 0.5 X 10(9) 1(-1] and thrombocytopenia (greater than 20 X 10(9) 1(-1] were 6 and 9 days respectively. The median durations of neutropenia and thrombocytopenia were 14 and 10 days respectively. All patients required intensive support with a median duration of inpatient stay of 24 days. There was one treatment related death due to renal failure. One complete and two partial remissions (33% response rate) were seen but these were of short duration (median of 10 weeks). This study demonstrates that GM-CSF given by continuous intravenous infusion produces significant increments of peripheral granulocyte counts at 3 and 10 micrograms kg-1 day-1 and is not associated with any toxicity. The duration of neutropenia and thrombocytopenia induced by high-dose melphalan appears to be reduced by the subsequent administration of GM-CSF to times which are at least as short as have been reported in historical series which have used autologous bone marrow rescue.     

High-dose combination cyclophosphamide,cisplatin, and melphalan with autologous bone marrow support

Summary A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m², respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (C_max) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.Supported in part by grant 5-PO1-CA32672 from the National Cancer Institute     

A phase I study of the hypoxic cell radiosensitizer Ro-03-8799

The 2-nitroimidazole hypoxic cell radiosensitizer Ro-03-8799 has been suggested to have possible advantages over misonidazole with regard both to radiosensitization and toxicity on the basis of reported experimental work. The present work reports a Phase I escalating dose toxicity study of the drug. This has shown severe acute central neurotoxicity at high dose levels (greater than 1 g/m2). Initial results of a multiple-dose toxicity study indicate that 1 g/m2 is likely to be the maximum dose which may be given repeatedly. The plasma and tumor pharmacokinetics of the drug have been measured. The mean t 1/2 for 9 patients was 5.8 +/- 1.5 hr. Peak plasma concentration is linearly related to dose and at 1 g/m2 is 12.1 +/- 2.3 micrograms/ml (n = 6). Human tumor drug concentrations have been measured after single doses of 1 g/m2 given to 8 patients with a variety of tumors. Peak tumor concentrations of drug of 11.7-81.6 micrograms/g were found. Because of acute, dose-limiting toxicity related to individual doses it may not be possible to achieve, in human tumors, concentrations of drug that offer significant advantage over misonidazole in terms of radiosensitizing efficiency. No evidence of chronic cumulative toxicity was observed at the doses employed.     

Etoposide induction of tumor immunity in Lewis lung cancer

PURPOSE: The purpose of these sequential phase I studies was to evaluate the antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. METHODS: A total of 52 patients with advanced cancer were treated in two sequential phase I studies utilizing high-dose prochlorperazine. In study 1, designed to investigate the antiemetic effects of dose-intensive prochlorperazine, various cisplatin-based multiagent chemotherapeutic regimens were administered in combination with escalating doses of prochlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m2) was administered over 24 h as a continuous intravenous infusion in combination with infusional high-dose prochlorperazine. Antiemetic efficacy in the first trial was assessed in terms of the number of episodes of nausea, retching, and/or emesis during the 24 h following cisplatin administration. The pharmacokinetics of high-dose prochlorperazine were evaluated in eight patients treated in study 2 at the two dose levels below those at which dose-limiting toxicity was noted. RESULTS: The maximally tolerated dose of prochlorperazine in combination with cisplatin (60 mg/m2 administered as a continuous infusion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitation and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regimen in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level was 1.1 microM, a concentration previously reported to be consistent with the reversal of the multidrug resistance phenotype. Two partial responses were observed in study 2. CONCLUSIONS: We conclude that the antiemetic efficacy of high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels consistent with those required in vitro for drug resistance reversal are attainable within the dose range having a tolerable toxicity profile.     

Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of docetaxel infused over 1 hour when given in combination with oral zosuquidar to patients with resistant solid tumors. EXPERIMENTAL DESIGN: In cycle 1, patients received docetaxel alone. In subsequent cycles, zosuquidar was administered with docetaxel, which was escalated from 75 to 100 mg/m2. Zosuquidar was escalated from 100 to 300 mg/m2 every 8 hours on days 1 to 3 for a total of 7 doses, or from 400 to 500 mg every 12 hours for 2 doses administered 2 hours before docetaxel. The pharmacokinetics of docetaxel with and without zosuquidar administration were obtained. RESULTS: Thirty-six of 41 patients completed at least one cycle of docetaxel and zosuquidar. The maximum tolerated dose was docetaxel 100 mg/m2 and zosuquidar 500 mg every 12 hours for 2 doses. The most common toxicity was neutropenia. In 35 patients, zosuquidar produced minimal increases in the docetaxel peak plasma concentrations and area under the curve. Dosing over 3 days with zosuquidar (7 doses) did not show benefit over the 1-day dosing. Of the 36 patients, one patient had a partial response, and 14 patients had disease stabilization. CONCLUSIONS: Docetaxel at 75 or 100 mg/m2 and zosuquidar 500 mg 2 hours before docetaxel and 12 hours later is well tolerated. Zosuquidar minimally alters the pharmacokinetics of docetaxel, allowing full dose docetaxel to be given with this P-glycoprotein modulator. A Phase II study with this combination in advanced breast carcinoma is underway.     

Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion.

Regional chemotherapy allows further exploitation of the steep dose response curve of most chemotherapeutic agents, while systemic toxicity remains tolerable. We investigated the difference in maximally tolerated dose, pharmacokinetics and antitumour effect comparing administration of melphalan as a bolus in isolated liver perfusion (ILP) or via hepatic artery infusion (HAI). For these in vivo studies an experimental model for liver metastases in male WAG/Ola rats is obtained by subcapsular inoculation of CC531 rat colon carcinoma cells. In this system, ILP allowed administration of a two times higher dose than HAI (12 mg kg-1 vs 6 mg kg-1). In both treatment modalities systemic toxicity (leukopenia) was dose limiting. No hepatic toxicity was observed. Bolus administration of the maximally tolerated doses of melphalan in HAI (6 mg kg-1) and ILP (12 mg kg-1) resulted in four times higher concentrations in both liver and tumour tissue of the ILP treated rats. However, the ratio of mean drug concentration in liver vs tumour tissue appeared to be 1.5 times that found for HAI. In the range of the in tumour tissue measured melphalan concentrations the CC531 cells showed a steep dose response relationship in vitro. Whereas HAI resulted in significant tumour growth delay, complete remissions were observed in 90% of the rats treated with ILP. This study shows that with 12 mg kg-1 melphalan in ILP highly effective drug concentrations are achieved in CC531 tumour tissue; although the melphalan concentration in liver tissue shows an even higher increase than in tumour tissue, hepatic toxicity is negligible in this dose range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human alpha-lymphoblastoid interferon. A phase I study including pharmacokinetics and effects on hematologic stem cells (CFU-GMs)

Human alpha lymphoblastoid interferon (Wellferon) was administered to 33 patients in a phase I study. Patients received Wellferon intramuscularly every 12 hours for 14 doses in nine dosage levels ranging from 0.75 X 10(6) units to 50.0 X 10(6) units. Toxicity tended to be dose dependent and included fever/chills, malaise, hematologic toxicity, and digestive tract toxicity. Thirty X 10(6) u q 12 h was felt to be the maximum tolerated dose. Three partial responses (renal cell carcinoma, diffuse histiocytic lymphoma, Hodgkin's disease) were achieved. Interferon rapidly (2 to 3 hours after the initial injection) reached peak serum levels which varied generally with dose and exceeded 500 u/ml at the 30 and 50 X 10(6) u dosages. Multiple doses of interferon resulted in cumulative peak levels substantially higher than first dose levels (greater than 500 u/ml at dosages greater than 3 X 10(6) u/ml and greater than 1,500 u/ml at dosages greater than or equal to 18 X 10(6) u). Interferon given at high dosages persisted up to 10 days beyond the final injection. Despite hematologic toxicity, inhibition of CFU-GM was not seen.     

A phase I trial of intravenous melphalan, paclitaxel, and cisplatin plus granulocyte-colony stimulating factor in patients with suboptimal advanced epithelial ovarian carcinoma or peritoneal carcinoma

BACKGROUND: The primary purpose of this study was to establish the maximum tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma. METHODS: Patients with suboptimal (>2 cm residual tumor) Stage III or Stage IV epithelial ovarian carcinoma or peritoneal carcinoma were eligible for this Phase I study. In the first stage of the study, the doses of paclitaxel and cisplatin were fixed at 135 mg/m(2) and 75 mg/ m(2), respectively, and the dose of intravenous melphalan was escalated in consecutive cohorts of 3-6 patients depending on toxicity. The planned dose escalation levels of melphalan were 6 mg/m(2), 10 mg/m(2), and 14 mg/m(2). In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m(2) and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m(2), 175 mg/m(2), 200 mg/m(2), 225 mg/m(2), and 250 mg/m(2). G-CSF was administered for 12-19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS: Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m(2), with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m(2) with a toxicity rate of < 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS: The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted.     

CB 1954 revisited

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.     

Motexafin gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a Children's Oncology Group phase I study

The purpose of this study was to determine the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and intratumor and brain distribution of motexafin gadolinium (MGd) with involved field radiation therapy in children with newly diagnosed intrinsic pontine gliomas. MGd was administered as a 5-min intravenous bolus 2-5 h prior to standard radiation. The starting dose was 1.7 mg/kg. After first establishing that 5 doses/week for 6 weeks was tolerable, the dose of MGd was escalated until dose-limiting toxicity was reached. Radiation therapy was administered to 54 Gy in 30 once-daily fractions. Forty-four children received MGd at doses of 1.7 to 9.2 mg/kg daily prior to radiation therapy for 6 weeks. The maximum tolerated dose was 4.4 mg/kg. The primary dose-limiting toxicities were grade 3 and 4 hypertension and elevations in serum transaminases. Median elimination half-life and clearance values were 6.6 h and 25.4 ml/kg/h, respectively. The estimated median survival was 313 days (95% confidence interval, 248-389 days). The maximum tolerated dose of MGd and the recommended phase II dose was 4.4 mg/kg when administered as a daily intravenous bolus in conjunction with 6 weeks of involved field radiation therapy for pediatric intrinsic pontine gliomas.     

Oral melphalan pharmacokinetics--relation to dose in patients with multiple myeloma

The pharmacokinetics of melphalan have been studied after oral doses of 5, 10 and 20 mg, and 10 mg i.v. Seven patients with multiple myeloma received the drug on 4 consecutive days and the concentration of melphalan was determined by liquid chromatography. Melphalan was rapidly absorbed after p.o. administration. Absorption lag-time was less than 1 h. The median time for attaining the peak concentration was 1.12 h (97% confidence interval: 0.68-1.55), 1.21 h (0.85-1.43) and 1.08 h (0.84-1.29) after doses of 5, 10 and 20 mg. The bioavailability showed large interindividual variations, and was not significantly affected by the dose given. There was a significant decrease in bioavailability during the treatment course (P less than 0.05). Absorption of melphalan obeys first-order kinetics in the dose interval studied. The results indicate that it might be of benefit to administrate oral melphalan for fewer days than the usually used 4 day regimen, in an attempt to achieve a higher bioavailability.     

The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: results of a phase 1 study.

PURPOSE: Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on beta-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics. EXPERIMENTAL DESIGN: ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urine ABT-751 and metabolite pharmacokinetics were determined. RESULTS: The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1 were abdominal pain, constipation, and fatigue. The MTD on the b.i.d. schedule was 150 mg. Cycle 1 of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean T(max) of about 2 hours. The pharmacokinetics of ABT-751 were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 microg/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months. CONCLUSIONS: The MTD and recommended phase 2 doses for ABT-751 were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing. Toxicities were abdominal pain, constipation, and neuropathy.     

Verapamil with mitoxantrone for advanced ovarian cancer: a negative phase II trial

Fourteen patients with advanced epithelial ovarian cancer were treated with oral verapamil 240 to 480 mg daily for 3 days and intravenous mitoxantrone 12 to 14 mg/m2 on the second days of verapamil administration. Courses were repeated at 21 day intervals to a maximum of 4 courses. Most patients had cancers refractory to prior cisplatin or carboplatin, or had cancers which recurred quickly after such treatments. This poor prognostic profile of patients probably accounted for the lack of objective responses to verapamil plus mitoxantrone. Despite maximally tolerated daily oral verapamil doses (480 mg daily) our inability to achieve in vivo levels of verapamil that in vitro have an optimum cytotoxic potentiating effect mitigate against further clinical exploration of verapamil as a sole enhancing agent.     

Five-day infusional fluorodeoxyuridine with oral leucovorin and escalating doses of interferon alpha-2b: a phase I study

In a previous phase I study we identified the maximally tolerated dose (MTD) of a continuous intravenous infusion of fluorodeoxyuridine (FUdR) to be 0.3 mg/kg daily for 5 days when combined with oral leucovorin (LV) given at 100 mg q4h. In an attempt to modulate FUdR further, we added escalating doses of interferon alpha-2b (IFN) to FUdR/LV in a phase I cohort study. A total of 36 patients with refractory solid tumors were treated at two dose levels of FUdR and five dose levels of IFN. Although the initial patient cohort was treated with a dose of FUdR lower than that previously identified as the MTD [FUdR at 0.2 mg/kg daily with LV at 100 mg q4h and IFN at 2 million units (MU)/m² daily], three of six patients developed grade 3 mucositis, indicating that the toxicity of FUdR/LV was increased in the presence of low doses of IFN. After decreasing the FUdR dose to 0.1 mg/kg daily, we could increase the dose of IFN from 2 to 30 MU/m² daily in five additional cohorts of patients. With increasing IFN doses, no increase in mucositis or dermatitis was observed, indicating no further potentiation of FUdR/LV toxicity with higher IFN doses. However, known toxicities of IFN, including transient myelosuppression and hepatic transaminase elevation, were observed more frequently at IFN doses of 15 and 30 MU/m² daily, where they became dose-limiting. We conclude that IFN modulates FUdR/LV at low doses, resulting in increased FUdR toxicity. When the dose of IFN is increased, this FUdR/LV toxicity does not appear to be potentiated further and IFN-related toxicities become dose-limiting.This study was supported in part by a gift from Schering-Plough Pharmaccuticals and an American Cancer Society Clinical Oncology Career Development Award (to M.J.R.). We thank Burroughs-Wellcome for supplying the leucovorin tablets.     

A Phase II trial of high-dose intravenous interferon alpha-2 in advanced colorectal cancer

Twenty-one patients with metastatic colorectal cancer were treated with high-dose intravenous interferon alpha-2 (30-50 X 10(6) units/m2) administered daily for 5 consecutive days. Courses of therapy were repeated every 2 to 3 weeks. No tumor responses were seen among 15 evaluable patients. In two subjects, disease remained stable for 3 and 7 months, respectively. Toxicity was substantial and a de-escalation of dose was frequently required. Fevers, gastrointestinal symptoms, fatigue, leukopenia, and elevated serum transaminases were common. High-dose interferon was found to be ineffective in the treatment of metastatic colorectal cancer. A daily dose of 50 X 10(6) units/m2 was greater than the maximum tolerated dose in this group of patients.     

High-dose intravenous zidovudine with 5-fluorouracil and leucovorin. A phase I trial.

BACKGROUND. The inhibition of pyrimidine metabolism by 5-fluorouracil (5-FU) enhances the anti-cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine-induced DNA damage correlates with cytotoxicity. METHODS. A Phase I trial of high-dose continuous-infusion intravenous zidovudine therapy in combination with 5-FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous-infusion 5-FU (800 mg/M2/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5-FU and leucovorin, for 48 hours, and terminating with the end of the 5-FU infusion. Zidovudine plasma levels and zidovudine-induced DNA damage were assessed. RESULTS. Zidovudine administered in doses of 2-20 g/M2/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5-FU and leucovorin but resulted in a dose-dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M2/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population. CONCLUSIONS. Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) are required for increased anti-cancer activity with 5-FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.