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Purpose: The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors., Methods: This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.5-mg/kg dose was given before the first dose in the 3-mg/kg cohort to determine pharmacokinetics (PK) and pharmacodynamics under unsaturated conditions. After completion of dose escalation in the QW cohorts, patients were enrolled in two additional cohorts and received MEDI-575 25 or 35 mg/kg every 3 weeks (Q3W). Secondary measures included assessments of PK, immunogenicity, and antitumor activity., Results: A total of 35 patients received MEDI-575 QW (n = 23) or Q3W (n = 12). Most treatment-related adverse events were grade 1 or 2 in severity across all dose levels, with fatigue (n = 12) and nausea (n = 8) being reported most frequently. With no reports of dose-limiting toxicities (DLTs), the MTD was not reached. MEDI-575 exhibited a nonlinear PK profile and increased plasma platelet-derived growth factor-AA levels in a dose-dependent manner with limited immunogenicity. Stable disease was reported as the best tumor response in 9 of 29 evaluable patients; however, no objective responses were reported., Conclusion: Administration of MEDI-575 QW or Q3W resulted in a favorable safety profile, including a lack of DLTs, but without evidence of antitumor activity in patients with refractory solid tumors.

In previous phase I reports of short bolus infusion of rhizoxin, problems in assay sensitivity prevented the description of pharmacokinetic-pharmacodynamic relationships, and a pharmacologically guided approach to dose escalation was deemed not feasible. In this report, we describe a mathematical model, which explains the schedule-dependent interpatient pharmacodynamic variability of rhizoxin administered on a continuous infusion schedule. Using patient demographic and toxicity data from 45 patients treated in a phase I dose and duration escalation study of rhizoxin, we sought to model the nadir neutrophil count. We hypothesized that a surrogate derived variable based on dose and duration would reflect a pharmacokinetic parameter that would be a significant covariate. Multiple linear regression analysis was carried out to determine the other significant covariates. Dose/m2 x Log(DUR/ALB) was significantly correlated with the LogANCnadir (Log10 neutrophil nadir; r = 0.56, P < 0.001). Other significant covariates included baseline performance status (PS), baseline serum bilirubin (BIL), and Log10 baseline neutrophil count (LogANCbaseline). Model bias and precision were assessed using the mean prediction error (MPE) and the root mean square error (RMSE) of the ANCnadir, respectively. We constructed 1-4 covariate models. The variability of ANCnadir was modeled with good precision and accuracy with a 4-covariate model (MPE and RMSE 0.113 +/- 0.182 x 10(3) cells/microl and 1.22 x 10(3) cells/microl, respectively). This model should be validated and improved on with further clinical data. We believe that such pharmacodynamic modeling should be explored further to determine its performance and clinical relevance compared with modeling using pharmacokinetic parameters.

Purpose: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule., Methods: Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and/or response: I UFT 300 mg/day, JM-216 5 mg/day (three patients), II UFT 300 mg/day, JM-216 10 mg/day (four patients), III UFT 300 mg/day, JM-216 20 mg/day (ten patients)., Results: All 17 evaluable patients were evaluable for toxicity. At dose level III dose-limiting nausea and emesis were observed in one patient despite maximal antiemetic support. Importantly, neurotoxicity and nephrotoxicity were not observed at the JM-216 dose levels examined in this study. This observation is consistent with results seen with single agent JM-216., Conclusion: For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities. These doses are considerably below the maximally tolerated doses of single agent JM-216 and UFT. Shorter administration schedules should be explored in an attempt to increase the dose intensity and minimize the toxicity of this combination oral regimen.

Unlabelled: A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs., Purpose: To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types., Methods: Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily., Results: A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary., Conclusions: The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Depletion of the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT) increases the sensitivity of cells in culture and of human tumor xenografts to chloroethylnitrosoureas such as carmustine (BCNU). We have previously demonstrated that dacarbazine (DTIC) can deplete AGT activity in cells in culture and in human tumor xenografts. A phase I trial of DTIC followed immediately by BCNU was conducted to determine the DTIC dose resulting in maximal depletion of AGT in the peripheral blood mononuclear cells (PBMC) of cancer patients and to determine the maximally tolerated dose of DTIC given as a 4-h infusion immediately prior to a fixed dose of BCNU. A 4-h infusion of DTIC followed by a 2-h infusion of BCNU was given to 42 patients with refractory solid tumors. Complete depletion of AGT activity was not achieved at DTIC doses of up to 750 mg/m2. The dose-limiting toxicity was hematologic, although at higher doses of BCNU (> or = 100 mg/m2) we observed significant nonhematologic toxicity. Our recommended phase II doses are 1,000 mg/m2 DTIC followed by 75 mg/m2 BCNU. AGT activity in PBMC of the 28 patients studied decreased to a mean of 62% +/- 11% (SE) of the baseline value at 4 h after initiation of the DTIC infusion. At 24 h after initiation of the DTIC infusion, AGT activity in PBMC was depleted to a mean of 65% +/- 14% of the baseline value. There was no direct correlation between the DTIC dose and the extent of AGT depletion. Baseline PBMC AGT levels varied widely among patients.

502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m2. No significant hematologic, gastrointestinal, or neurologic toxicity was observed. At doses of 2,000 mg/m2 and higher, prolongation of the corrected QT interval on ECG was evident in most patients but was completely reversible, was not associated with arrhythmias, and was not dose-limiting. Dose-limiting pulmonary toxicity characterized by acute onset of dyspnea, severe hypoxemia, interstitial pulmonary edema, and death occurred in three patients treated at the highest dose levels. Plasma concentrations of 502U83 and its metabolites were measured by high-performance liquid chromatography. The 502U83 maximal concentration (Cmax) and area under the concentration-time curve (AUC) were proportional to the delivered dose; however, substantial interpatient variability in total body clearance was noted at all dose levels. Significant conversion of 502U83 to two glucuronide metabolites was detected. Metabolite concentrations were highest in the three patients who succumbed to pulmonary toxicity, although the precise contribution of these metabolites to the observed toxic effects is unknown. In view of the unfavorable clinical profile of QTc prolongation and pulmonary toxicity produced by 502U83, further clinical development of this agent has been suspended.

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 tumor 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.

A total of 25 patients with metastatic renal cancer were treated on a phase II protocol with 5 days of continuous-infusion fluorodeoxyuridine (FUDR), (0.1 mg/kg daily) together with high-dose oral leucovorin (100 mg 4 h) and daily x6 high-dose interferon-alpha 2b (30 x 10(6) IU/m2). Despite the good performance status of the patients and the inclusion of 14 previously untreated patients in the cohort, no response was observed among the 20 evaluable patients. Toxicities included high fever, moderate anemia, transient leukopenia, transient and mild elevations of transaminases, and moderate to severe nausea, vomiting, diarrhea, and mucositis. There were also two episodes each of confusion, fluid retention, and pancreatitis and one episode of increased creatinine levels. During the study three deaths occurred, two of which were possibly therapy-related. Despite previous reports of activity of FUDR in metastatic renal cancer, the present regimen cannot be recommended.

Fluorodeoxyuridine (FUdR) interferes with cellular metabolism by inhibiting thymidylate synthase. Therefore, we sought to modulate its activity with leucovorin (LV) and to identify the maximally tolerated dose given as a 5-day continuous intravenous infusion in combination with oral administration of LV at a dose of 100 mg every hour for four doses immediately preceding the start of the FUdR infusion and then every 4 h for the entire duration of FUdR treatment. Patients were evaluated at six FUdR dose levels ranging from 0.1 to 0.375 mg/kg per day. Severe or life-threatening mucositis was first observed in two of six patients treated at 0.25 mg/kg daily. Further escalation of the dose to 0.3 mg/kg per day resulted in grade 2 mucositis in four of six patients and in grade 3 mucositis in two cases. A dose of 0.375 mg/kg daily resulted in grade 3 toxicity in all three patients treated. Other types of toxicities included skin rash and hand-foot syndrome, but no hematologic toxicities were observed. Stable disease was observed in 11 of 24 evaluable patients, including 3 subjects with renal cell carcinoma. Our recommended dose for phase II trials is 0.3 mg/kg FUdR per day.

Carboplatin (400 mg/m2) was given at 28-day intervals to 41 patients with malignant mesothelioma. In all, 40 patients were eligible and evaluable for response. Partial responses were seen in 2 cases (5%); regression of evaluable disease, in 1 patient (2%); and stable disease, in 19 subjects (48%). A median of two doses of carboplatin per patient resulted in mild toxicity. Leukopenia (less than or equal to 2,000 cells/microliters) and thrombocytopenia (less than 100,000 cells/microliters) were seen in only 6% and 20% of the patients, respectively. Median survival from study entry was estimated at 7.1 months, with a 1-year survival of 25% +/- 7%. Carboplatin given at a dose of 400 mg/m2 at 28-day intervals shows minor activity against malignant mesothelioma.

Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of 5 patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumors. In 3 of the cases no evidence of tumor was found at autopsy. Both an acute and a long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional 16 collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.