The in vivo immunomodulatory effects of recombinant interferon gamma plus recombinant tumor necrosis factor-alfa

We conducted a phase I study in which an intramuscular injection of interferon gamma (IFN gamma) at 10, 50, or 100 micrograms/m2 was followed 5 minutes later by an intramuscular injection of 10, 50, or 100 micrograms/m2 of tumor necrosis factor-alfa (TNF alpha) at another site every other day for 20 days (10 doses). The addition of TNF alpha to IFN gamma reduced both the magnitude and duration of IFN gamma-mediated effects on peripheral blood monocyte expression of Fc receptors (FcRs) and HLA-DR and production of hydrogen peroxide. This inhibition was related to the dose of TNF alpha. On the other hand, TNF alpha and IFN gamma appeared to have an additive stimulatory effect on the production of neopterin by monocytes. The highest serum levels of neopterin were detected in patients who received the highest doses of both IFN gamma and TNF alpha. Thus, conflicting conclusions regarding the effect of the combination on immune activation are possible. If the activation of peripheral blood monocytes is the appropriate surrogate measure of the immune enhancement of the combination, then the simultaneous administration of IFN gamma and TNF alpha is ineffective, and future attempts to exploit the potential additive or synergistic effects of this combination of cytokines in humans may need to explore sequential administration schemata. On the other hand, if serum neopterin levels are a more reliable index of immune activation, simultaneous administration of 100 micrograms/m2 IFN gamma and 50 micrograms/m2 TNF alpha every other day (the maximally tolerated dose [MTD]) should be used in phase II testing. This dilemma points out the limitations of currently available methods of human immune assessment and the inadequacies in our capacity to gauge what particular immune measure or set of measures predict for in vivo antitumor effects.     

A phase I study of cisplatinum plus 5-fluorouracil in modulation with citrovorum factor in metastatic colorectal carcinoma

A phase I study of 5-fluorouracil 600 mg/m2/week and folinic acid 500 mg/m2/week on day 1 and cisplatin administered weekly on day 2 was carried out on 30 patients with metastatic colorectal carcinoma of which 20 patients were pretreated with 5-fluorouracil. The first group of patients received cisplatin at the dose of 5 mg/m2/week. Cisplatin was then escalated to 10, 15, 20, 25, 30, and 35 mg/m2/week for subsequent groups of patients. Gastrointestinal side-effects were the dose-limiting toxicity. A therapy related death was seen at the dose of 35 mg/m2/week of cisplatin. The maximally tolerated dose of cisplatin in combination with 5-fluorouracil and citrovorum factor is 20 mg/m2/week. The optimally tolerated dose of 5-fluorouracil is 400 mg/m2/week in modulation with citrovorum factor 500 mg/m2/week. The recommended doses for a phase II study are cisplatin 20 mg/m2/week, 5-fluorouracil 400 mg/m2/week, and citrovorum factor 500 mg/m2/week.     

Preclinical and phase I study of oxaliplatin and topotecan in combination in human cancer.

BACKGROUND: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors. MATERIALS AND METHODS: We studied the effect of a sequential schedule of oxaliplatin on day I and topotecan on days 2-5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial. RESULTS: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro. We then demonstrated that the two agents in combination markedly inhibit tumor growth in nude mice. We translated these results into a clinical setting, conducting a phase I study in cancer patients with oxaliplatin 85 mg/m2 on day 1 and topotecan at doses escalating from 0.5 to 1.5 mg/m2 on days 2-5. Sixty cycles of treatment were administered to 18 patients affected prevalently by ovarian and colorectal cancer. Combination with topotecan 1.5 mg/m2 caused a dose-limiting toxicity. Therefore the maximum tolerated dose of topotecan was 1.25 mg/m2, at which six patients experienced a mild hematological and gastrointestinal toxicity. We also obtained evidence of clinical activity, particularly in ovarian cancer. CONCLUSIONS: Our results provide a solid biological and clinical rationale for a phase II trial at the recommended doses of oxaliplatin 85 mg/m2 and topotecan 1.25 mg/m2, possibly in ovarian cancer patients.     

A phase I study to determine the safety,pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor,brivanib, in patients with advanced or metastatic solid tumors

BackgroundThis study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.Patients and methodsNinety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD.ResultsAcross part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180–800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts.ConclusionIn patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.     

Pharmacokinetics and toxicity of continuous infusion (6S)-folinic acid and bolus 5-fluorouracil in patients with advanced cancer.

Twenty-seven patients with advanced cancer were entered in a phase I study of bolus i.v. 5-fluorouracil at a dose of 370 mg/m2/day for 5 days combined with a continuous i.v. infusion of (6S)-folinic acid for 5.5 days, starting 24 h in advance of the first 5-fluorouracil dose. The dose of (6S)-folinic acid was escalated in cohorts of patients from 250 mg/m2/day to a maximum of 1000 mg/m2/day. The pharmacokinetics of (6S)-folinic acid were studied in the 3 patients given 250 mg/m2/day and in 6 patients given 1000 mg/m2/day. The mean steady-state plasma concentrations of (6S)-folinic acid and its principal metabolite (6S)-5-methyltetrahydrofolate at the 250 mg/m2/day dose were 2.7 and 5.1 microM, respectively. Both concentrations were comparable to the concentrations produced when (6S)-folinic acid was administered as half of a (6R,S)-folinic acid mixture (E. M. Newman et al., Cancer Res., 49:5755-5760, 1989). At the 1000 mg/m2/day dose of (6S)-folinic acid, the concentration of (6S)-folinic acid was 15.3 microM, more than the 4-fold increase predicted by linear pharmacokinetics, while the concentration of (6S)-5-methyltetrahydrofolate was only 16.5 microM. The change in the ratio of the parent compound to its metabolite was accounted for by a decrease in the nonrenal clearance of (6S)-folinic acid, probably indicating saturation of its metabolism. The toxicities observed in this phase I trial, including stomatitis, diarrhea, neutropenia, and anemia, did not differ in nature or severity from those produced by 5-fluorouracil and (6R,S)-folinic acid when administered on the same schedule. Finally, the degree of toxicity did not appear to depend on the dose of (6S)-folinic acid over the range of doses tested.     

Biological and clinical effects of the combination of beta- and gamma-interferons administered as a 5-day continuous infusion

A phase I trial involving continuous infusion of both beta- and gamma-interferon (IFN-beta and IFN-gamma) was conducted in 20 patients in order to determine whether combinations of high doses of IFN-beta and IFN-gamma were tolerable when administered under conditions which mimic conditions of in vitro antiproliferative studies. Patients received a 5-day continuous infusion of IFN-beta/IFN-gamma, followed by a 9-day rest period. Two cycles were administered. Doses of IFN-beta/IFN-gamma were escalated between 4 dose levels, with 5 patients per dose level. Dose-dependent side effects, consisting primarily of constitutional symptoms typical of those experienced with IFN, were observed. The maximally tolerated dose of continuous IFN-beta/IFN-gamma infusion was 3 x 10(6) units of IFN-beta and 200 micrograms of IFN-gamma. Dose-limiting side effects consisted of severe headache, fatigue, fever, and hepatic toxicity. No clinical responses were observed. Serum IFN was measurable only at the highest 3 dose levels. Only 5 patients (4 at the highest dose level) had total serum levels which exceeded 50 laboratory units/ml (55, 63, 800, 800, and 550 laboratory units/ml, respectively). In order to confirm the biological effectiveness of this schedule, we measured IFN-inducible proteins prior to therapy, 24 h after the initiation of the infusion, and at the completion of the 5-day infusion. 2'-5'-Oligoadenylate synthetase, serum beta 2-microglobulin, neopterin, and p78 levels all increased significantly, and serum tryptophan decreased significantly within 24 h after the initiation of treatment (P less than 0.0001). A dose-response effect was observed for serum beta 2-microglobulin, neopterin, and p78 (P less than 0.02). We retrospectively compared the results of this trial with those of another IFN-beta/IFN-gamma trial in which IFN-beta and IFN-gamma were administered by i.v. bolus. Within the limitations of a retrospective comparison, continuous infusion was less well tolerated than our previous schedule of bolus administration 3 times/week. However, the continuous infusion schedule appeared to be more effective in enhancing 2'-5'-oligoadenylate synthetase levels in mononuclear cells. We conclude that tolerable doses of IFN-beta and IFN-gamma do not result in serum IFN levels which produce significant synergistic antiproliferative responses in vitro. This study and other findings suggest that, unless higher doses can be achieved, combinations of IFN-beta and IFN-gamma are unlikely to have significant therapeutic activity.     

A phase I clinical trial of recombinant DNA gamma interferon

Recombinant gamma interferon (r-GIFN) demonstrates in vitro and in vivo characteristics that contrast with those of alpha and beta interferons. It has relatively weak antiviral properties, yet relatively potent immunomodulatory effects. A phase I trial was performed with r-GIFN (specific activity 2.6 X 10(6) IU/mg protein), administered as a continuous intravenous (IV) infusion over 24 hours for five days (Cl X 5) and repeated every 28 days. This schedule was chosen based on the short half-life of r-GIFN in animal systems and the in vitro augmentation of biologic effects with continuous exposure to interferons. Twenty-one patients with refractory solid tumors received 46 evaluable courses of therapy. The dose-limiting toxicities included fever, flu-like symptoms, cardiovascular toxicity, and neurotoxicity. The cardiovascular toxicity included hypotension and one episode of cardiac ischemia with chest pain. Neurotoxicity consisted of lethargy and confusion. These toxicities were reversible, and although dose-limiting, occurred sporadically throughout all dosage levels. Mild to moderately severe non-dose-limiting toxicities included nausea and vomiting, leukopenia, and liver function abnormalities. Other infrequent toxicities included hypocalcemia, diarrhea, constipation, and alopecia. The maximally tolerated dose of r-GIFN on this schedule is 0.5 X 10(6) IU/m2/d. Partial responses were seen in one patient with metastatic melanoma and in one patient with renal cell carcinoma. Toxicity and antitumor activity were seen at doses where interferon serum levels could not be detected by radioimmunoassay. In addition, the toxicity and antitumor activity seen were at much lower doses than previously described for shorter infusion schedules of other recombinant gamma interferon preparations. Differences in biologic activity of interferon preparations and/or differences in scheduling may account for this variability. Although this study defines a recommended phase II dose of r-GIFN based on the maximally tolerated dose, the optimal therapeutic index may exist at a lower dosage level.     

A phase I clinical trial of low-dose interferon-α-2A, thalidomide plus gemcitabine and capecitabine for patients with progressive metastatic renal cell carcinoma

Background We have conducted a phase I trial to determine the maximum tolerated dose of gemcitabine in combination with interferon, thalidomide and capecitabine. Methods Patients received oral capecitabine 1,000 mg/m² per day, divided in 2 daily doses, 2 weeks on, 1 week off; subcutaneous interferon-α 1 mIU twice a day without an interruption; daily oral thalidomide 200 mg/day for the first 7 days, then escalated to 400 mg/day without an interruption. Gemcitabine was given by intravenous administration over 30 min on day 1, week 1 and day 8, week 2. Initial dose level of gemcitabine was 400 mg/m². The dose of gemcitabine was the phase I variable. One cycle was 3 weeks. Results and discussion We treated 12 patients, 6 patients were entered at a dose level of 0 (gemcitabine 400 mg/m²) and 6 patients entered at a dose level-1 (gemcitabine 200 mg/m²). Eight of 12 patients completed at least 12 weeks of therapy. Three partial responses and two stable disease were observed. The remaining patients had progressive disease. Non-hematologic toxicity was either grade 1 or 2. Hematologic toxicity at dose level 0 consisted of 3 patients with grade 3/4 neutropenia, and 1 patient with grade 3 thrombocytopenia. At dose level-1 grade 1/2 neutropenia was observed. Conclusions The completion of our phase I experience determined our maximum tolerated dose to be dose level-1. The phase II trial is currently being proposed for patients with rapidly growing clear cell, other histologies that may contain sarcomatoid elements or collecting duct tumor.     

Phase II clinical trial of cisplatin, 5-fluorouracil, and ifosfamide as treatment for advanced locoregional head and neck carcinoma

The association of ifosfamide with cisplatin and 5-fluorouracil for the management of advanced squamous cell carcinoma of the head and neck was assessed in this trial. Ifosfamide was given initially to 12 patients in combination with standard fixed doses of cisplatin and 5-fluorouracil, at 1,000 mg/m2 daily on days 2, 3, and 4. Two patients died of neutropenia and severe infection, and the authors recruited seven more patients who were treated with a lower dose of ifosfamide, 800 mg/m2 daily on days 2, 3, and 4. One of the seven patients died of neutropenia and severe infection. Three complete remission were observed in 18 patients evaluable for efficacy. The study was closed early because of the severe toxicity profile demonstrated by this scheme and because of no clear advantage in efficacy versus cisplatin plus 5-fluorouracil combinations.     

Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial

Background. Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. Methods. Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m², respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m², respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III–IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III–IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. Results. Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m² for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III–IV hematological or nonhematological toxicity. Conclusion. The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m² on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials. Received: January 29, 2001 / Accepted: September 13, 2001     

Phase I and pharmacokinetic study of 5-fluorouracil administered by 5-day continuous infusion in patients with hepatocellular carcinoma

PURPOSE: In this study the maximum tolerated dose of 5-fluorouracil administered by 5-day (120-h) continuous infusion every 4 weeks was investigated and the pharmacokinetics in patients with hepatocellular carcinoma were evaluated. METHODS: Patients with hepatocellular carcinoma no longer amenable to established forms of treatment were eligible for the study. The starting dose of 5-fluorouracil was 300 mg/m(2) per day and doses were escalated in 50 mg/m(2) per day increments in successive cohorts of three new patients if tolerated. Pharmacokinetic studies were performed at the time of the first course of therapy. RESULTS: Enrolled in the study were 20 patients. The maximum tolerated dose was 500 mg/m(2) per day and the dose-limiting toxicity was stomatitis. Other toxicities were mild and well tolerated. Age, gender and associated liver cirrhosis were significant factors influencing 5-fluorouracil clearance. With regard to biochemical parameters, serum alanine aminotransferase and cholesterol levels were correlated with 5-fluorouracil clearance. CONCLUSIONS: The maximum tolerated dose for 5-day continuous infusion of 5-fluorouracil in hepatocellular carcinoma patients was 500 mg/m(2) per day. The recommended dose for phase II studies using this schedule is 450 mg/m(2) per day. Furthermore, the pharmacokinetic data obtained in this study may be useful in determining chemotherapy dosage adjustments for reduction of toxicity.     

Phase I/II study of daily carboplatin, 5-fluorouracil and concurrent radiation therapy for locally advanced non-small-cell lung cancer

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities and the response rate of carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, unresectable stage IIIA or IIIB non-small-cell lung cancer (NSCLC) were enrolled. Carboplatin (20-40 mg m(-2) 2-h infusion, daily) and 5-fluorouracil (200 mg m(-2) 24-h continuous infusion, daily) were administered concurrently with radiotherapy on days 1-33. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions on days 1-40. In the phase I portion, the daily dose of carboplatin was escalated from 20 to 40 mg m(-2). Once the maximum tolerated dose (MTD) and recommended dose (RD) of carboplatin was determined, the study entered the phase II portion. In the phase I portion, the daily MTD and RD of carboplatin were 40 and 35 mg m(-2), respectively. The dose-limiting toxicity was neutropenia. In the following phase II study, 30 patients were entered and the objective response rate was 76.7% (95% CI, 62-92%) and the local control rate was 85.7%. The median survival time was 19.8 months, with a survival rate of 70% at 1 year, 36.7% at 2 years. The major toxicities of treatment were neutropenia (>or=grade 3, 87.9%) and thrombocytopenia (>or=grade 3, 23.3%). This combined therapy for locally advanced non-small-cell lung cancer is promising and shows acceptable toxicity.     

Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.     

A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily.

Imiquimod is an orally active interferon inducer with anti-tumour activity in experimental animals. In this study the tolerability, toxicity and biological effects of daily oral imiquimod administration were investigated in 21 patients with refractory cancer. Patients were treated with doses of 25 mg, 50 mg, 100 mg or 200 mg on a projected 112 day course. Only three patients completed the course, all at the 50 mg dose. Treatment toxicities were dose related and mainly comprised flu-like symptoms, nausea and lymphopenia. Of the 21 patients, five received dose reductions and in five treatment was discontinued because of treatment-related toxicity. The biological activity of imiquimod was confirmed by significant and sustained rises in peripheral blood mononuclear cell (PBMC) 2-5A synthetase (2-5AS) levels at all doses. At 100 mg and 200 mg these occurred within the first 24 h of administration. Levels of neopterin and beta 2-microglobulin (beta 2M) were also significantly elevated when assessed after three weeks'' treatment. Interferon production was not demonstrated within the first 24 h of the initial dose but, following repeated doses, ten of the patients developed detectable serum interferon concentrations with a maximum value of 5600 IU ml-1 recorded. Administration of imiquimod did not have any significant effect on serum levels of tumour necrosis factor (TNF) or interleukin 1 (IL-1), nor did it lead to development of detectable levels of antibodies to interferon. One mixed clinical response was observed after 4 weeks'' treatment at 100 mg in a patient with renal cell cancer. Daily administration of imiquimod causes activation of the interferon production system but at higher doses results in unacceptable toxicity. Further investigation of imiquimod as an interferon-inducing agent in cancer patients is suggested at either the lower dose levels or employing alternative dosing schedules.     

Phase I evaluation of continuous 5-fluorouracil infusion followed by weekly paclitaxel in patients with advanced or recurrent gastric cancer

OBJECTIVE: We conducted a phase I trial of escalating doses of weekly paclitaxel (Taxol) in combination with a fixed systemic administration of 5-fluorouracil (5-FU) in patients with advanced or metastatic gastric cancer. METHODS: Patients with advanced or recurrent gastric cancer were treated with escalating doses of weekly paclitaxel as a 60 min intravenous (i.v.) infusion, along with a fixed dose of continuous 5-FU infused over 5 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel. RESULTS: Eighteen patients received combination therapy at four dose levels of weekly Taxol, ranging from 60 to 90 mg/m2/week. Dose-limiting toxicities > grade 3 were observed at the 90 mg/m2/week dose level. Toxicities included anemia, neutropenia, thrombocytopenia, nausea and alopecia. Two episodes of grade 4 neutropenia occurred in two of the three patients receiving this dose. At each dose level, pharmacological studies documented the persistence of significant serum paclitaxel levels over 24 h after drug administration. The maximum tolerated dose (MTD) for this regimen was 90 mg/m2/week of paclitaxel for 3 weeks plus 600 mg/m2/day of continuous 5-FU for 5 days. CONCLUSIONS: The combination of weekly paclitaxel and 5-FU demonstrated an acceptable toxicity profile and feasible pharmacokinetic results suggesting its practical applicability. Based on these findings, the recommended dose and schedule for phase II study of combination chemotherapy is paclitaxel 80 mg/m2/week x 3 over 4 weeks, and continuous 5-FU 600 mg/m2/day x 5 days every 4 weeks.     

A phase II trial of continuous infusion cisplatin and 5-fluorouracil with oral calcium leucovorin in colorectal carcinoma.

Twenty previously untreated patients with advanced colorectal adenocarcinoma were entered on a Phase II trial of 3-day continuous infusion cisplatin (25 mg/m2/day) and 5-fluorouracil (800 mg/M2/day) with oral calcium leucovorin (30 mg/dose) every 6 hours. There were four partial responses (20%) and two complete responses (10%) for a total response rate of 30% (95% confidence limits +/- 20%). Patients received a median of 4.5 cycles of therapy (range 2-9 cycles). Three patients experienced neutropenia; one had a life-threatening infection. One developed neuropathy at 375 mg/M2 cumulative dose. Four patients developed mucositis. Treatment was stopped for one patient with stable disease after 5 cycles because of anorexia and nausea and vomiting; treatment was stopped for four patients because of excessive fatigue. The median duration of responses was 4 months (range 3-6 months). Although this regimen is active, the response rate, cumulative nature of the toxicity, and the requirement for hospitalization led us to conclude that this regimen does not warrant Phase III testing but might be a basis for further Phase II therapeutic trials.     

A phase I trial of cisplatin in hypertonic saline and escalating doses of 5-fluorouracil by continuous intravenous infusion in patients with advanced malignancies

Thirty-four patients with incurable solid tumors were treated in a Phase I trial with a fixed dose of high-dose cisplatin (CDDP) administered in hypertonic saline and escalating doses of infusional 5-fluorouracil (5-FU). Five treatment levels of 5-FU, ranging from 500 to 900 mg/m2/day for 5 days, were studied. Leukopenia, thrombocytopenia, and oral mucositis were the dose-limiting toxicities encountered. Nephrotoxicity was minimal. Ototoxicity and peripheral neuropathies were rare and mild in this patient group, but most patients received only a small number of treatment cycles. Diarrhea was not dose-limiting. Two complete responses (one non-small cell lung cancer and one sweat gland carcinoma) were observed. No other major responses were noted. With the dose of CDDP set at 35 mg/m2/day for 5 consecutive days, the maximum tolerated dose (MTD) of a concurrent 5-day 5-FU infusion was found to be 900 mg/m2/day. The recommended dosages for Phase II trials are 35 mg/m2/day CDDP and 800 mg/m2/day 5-FU for 5 consecutive days. Cancers of the lung, breast, gastrointestinal tract, and genitourinary tract would be reasonable targets for Phase II studies.     

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.     

Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors.

PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol. PATIENTS AND METHODS: Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients. RESULTS: Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m(2) and flavopiridol doses of 10 and 20 mg/m(2), respectively. With 3-hour paclitaxel at 100 mg/m(2), flavopiridol could be escalated to 70 mg/m(2) without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m(2), dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m(2). This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m(2), dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m(2). Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. CONCLUSION: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m(2) on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m(2) on day 2. Flavopiridol dose escalations to 80 mg/m(2) are possible. At these doses, toxicities are manageable and clinical activity is promising.