A phase I and pharmacokinetic study of paclitaxel and epirubicin in advanced cancer

The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0–2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m² without G-CSF and 175/90 mg/m² with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m² paclitaxel and 90 mg/m² epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m² and epirubicin 75 mg/m² is recommended for phase II and III studies.     

A phase I pharmacokinetic study of the P-glycoprotein inhibitor,ONT-093, in combination with paclitaxel in patients with advanced cancer

Background: ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg. Methods: Phase I pharmacokinetic trial of ONT-093 in doses from 300 to 500 mg administered before and after intravenous paclitaxel doses of 150 to 175 mg/m² repeated every 21 days. All patients received paclitaxel alone on cycle 1. Results: 18 patients were enrolled onto 4 dose levels. Toxicity of the combination included neutropenia, arthralgia, myalgia, and peripheral neuropathy. Four of 6 patients receiving 500 mg doses of ONT-093 and paclitaxel at 175 mg/m² (dose level 4) had higher-grade neutropenia with cycle 2, with 1 patient experiencing febrile neutropenia. Plasma pharmacokinetic parameters of paclitaxel were unchanged between cycle 1 and 2 for dose levels 1 to 3, but at dose level 4, 45–65% increases in paclitaxel AUC were observed in 4 of the 6 patients. Mean C_max of ONT-093 was 9 μM (range 5–15 μM) which were 3- to 5-fold higher than in single agent studies of ONT-093. Conclusions: Doses of ONT-093 achieving serum concentrations associated with biological activity were well tolerated in combination with standard doses of paclitaxel. Toxicities of the combination in this schedule were mainly attributable to paclitaxel and dose-limiting toxicity was limited to febrile neutropenia. There was an apparent pharmacokinetic interaction between paclitaxel and ONT-093, possibly related in part to the excipient, Cremophor, present in the paclitaxel formulation.     

A Phase I Clinical and Pharmacokinetic Study of Fenretinide Combined with Paclitaxel and Cisplatin for Refractory Solid Tumors

Summary Background: Fenretinide is a semi-synthetic retinoid that has pro-apoptotic effects as a single agent and synergistically with chemotherapy in vitro. We performed this study to determine the toxicity of cisplatin, paclitaxel and fenretinide in patients with advanced cancer, the recommended phase II dose of these agents together, and the pharmacokinetics (PK) of fenretinide when administered with chemotherapy. Patients and methods: Fourteen patients (mean age 57.3) were assessable for pharmacokinetics, toxicity and response. Fenretinide was given orally in 2 divided daily doses for 7 days, starting 24 hours prior to cisplatin and paclitaxel. Cisplatin and paclitaxel were given in standard fashion. Cycles were repeated every 3 weeks. Cycle one fenretinide PK was obtained on days 2 and 8. Results: Dose limiting toxicity (Gr 3 diarrhea and Gr 4 neutropenia) was encountered in two patients during cycle one at 80/175/1800 mg/m² of cisplatin/paclitaxel/fenretinide (dose level 2), respectively. Seven patients received 2–8 cycles at the recommended level of 60/135/1800 (dose level 1). Severe cumulative toxicities included fatigue, nausea/vomiting, neuropathy, and dehydration. Two patients had a partial response and 4 patients had stable disease for up to 8 cycles. PK analysis demonstrated a reduction in fenretinide Cmax on day 8 compared to day 2, accompanying a decrease in AUC. Conclusions: Cisplatin/paclitaxel/fenretinide can be administered safely at 60/135/1800 mg/m² respectively on an every three-week schedule. This combination may have activity in a variety of tumors, however, the number of pills required complicates oral dosing of fenretinide, and limits the applicability of this regimen.     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m² followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m², which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m² as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.     

Phase I Study of N1-N11-Diethylnorspermine (DENSPM) Administered TID for 6 Days in Patients with Advanced Malignancies

This was a dose escalation Phase 1 trial designed todetermine the maximum tolerated dose (MTD) and dose-limitingtoxicities (DLT) of DENSPM. Methods: Adult patientswith refractory solid tumors were treated with DENSPMadministered by intravenous infusion in 100 ml of normalsaline over 30 minutes. The daily dose of DENSPM was dividedinto three equal doses administered approximately every eighthours for six days. Courses were repeated every 28 days.Results: Twenty-eight patients were enrolled in thestudy. Dose levels of DENSPM explored were 25mg/m²/day (3 patients), 50 mg/m²/day (9patients), 60 mg/m²/day (5 patients), 75mg/m²/day (6 patients), 94 mg/m²/day (3patients) and 118 mg/m²/day (2 patients). The DLTfor DENSPM was central nervous system toxicity characterizedby aphasia, ataxia, dizziness, vertigo and slurred speechoccurring at dose levels 94 mg/m²/day, whichwas also the MTD. Safety: The most frequent drug-relatedadverse events were asthenia (9 patients), injection sitereaction (6 patients) and anemia (6 patients). One patient wasremoved from the study due to CNS toxicity. There were notreatment-related deaths. No trends were observed regardinghematologic toxicities, biochemical changes or changes invital signs. Efficacy: Nineteen of the 28 patients enrolled inthe study were assessed for response. No objective responseswere observed. Five patients had stable disease as the bestresponse to therapy. Conclusions: Because the DLT wasCNS and because of the relatively low doses that could besafely administered on this schedule as compared with aonce-a-day schedule, this regimen was not recommended forPhase 2.     

Phase I study of high dose etoposide phosphatase with filgrastim (G-CSF) in the treatment of advanced refractory malignancies

Purpose: To define the maximum tolerated dose of etoposide phosphate when used with G-CSF in the treatment of patients with refractory malignancies.Patients and methods: Eleven patients with advanced cancer refractory to standard therapy were treated with etoposide phosphate given over 1–2 hours on three consecutive days. The first cohort of patients received a total dose of 1596 mg/m² (equivalent to etoposide 1400 mg/m²); doses were escalated in subsequent patient cohorts. G-CSF 5 µg/kg was administered subcutaneously from day 4 until the total leukocyte count rose to > 10,000/µL. Two courses were given at 28 day intervals.Results: Toxicity produced by high dose etoposide phosphate included myelosuppression and mucositis. Three of five patients treated at the 2280 mg/m² dose level (equivalent to etoposide 2000 mg/m²) had dose limiting toxicities (grade 4 leukopenia for 7 days, 2 patients; grade 4 mucositis + leukopenia, 1 patient). In addition, median days with severe thrombocytopenia (< 50,000/µL) rose to six days at this dose. Other toxicity was uncommon.Conclusions: In pretreated patients, the maximum tolerated dose of etoposide phosphate with G-CSF is 1938 mg/m² (equivalent to etoposide 1700 mg/m²). Dose-limiting toxicities were myelosuppression and mucositis, as with high dose etoposide. Etoposide phosphate can be substituted for etoposide in high dose regimens; due to its greater solubility, administration can be more rapid, requires less fluid volume, and is not associated with acidosis.     

Feasibility of adding everolimus to carboplatin and paclitaxel,with or without bevacizumab,for treatment-naive,advanced non–small cell lung cancer

Introduction One standard of care for advanced non–small cell lung cancer (NSCLC) is paclitaxel plus carboplatin?±?bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin?±?bevacizumab for advanced NSCLC. Methods Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m² q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m² q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n?=?13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n?=?13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n?=?13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n?=?13). End-of-cycle 1 DLT rate was 16.7 % (step 1 daily), 30.8 % (step 1 weekly), 30.0 % (step 2 daily), and 16.7 % (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions The feasible everolimus doses given with carboplatin and paclitaxel?±?bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.     

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest

JM216 is an orally administered platinumanalogue. We undertook this study todetermine the maximally tolerated dose(MTD) of JM216 when administered withconcomitant radiotherapy to the chest(200 cGy daily, 5×/week) in patients withlocoregionally advanced non-small cell lung(NSCLC) or esophageal cancer. Patientswere excluded for inadequate bone marrowreserve, prior radiotherapy to the primarytumor or previous treatment with platinumdrugs. A dose-limiting toxicity (DLT) wasdefined using the National Cancer Institute(NCI) Common Toxicity Criteria (CTC) andconsisted of grade 2 renal, hepatic,cardiac, or pulmonary toxicity or grade 3hematologic, neurological, orgastrointestinal toxicity. A total of 23patients were registered; two neverreceived treatment and are excluded fromanalyses. Six patients were treated at adose of 30 mg/m²/day for 5 days withtwo grade 2 DLT's: cough (1 pt) andelevated trans-aminases (1 pt). Sevenevaluable patients were treated at60 mg/m²/day and seven experiencedgrade 3 or 4 toxicity, five related tomyelosuppression. The dose was thenreduced to 45 mg/m²/d. Eight patientswere evaluable for toxicity, of which 5experienced DLT: myelosuppression (3 pts),esophagitis (2 pts), dyspnea (1 pt), andelevated creatinine (1 pt). Fourteenpatients were evaluable for efficacy, ofwhich 6 had an objective response,including one complete response. Therecommended phase II dose of JM216 withconcurrent radiation therapy is30 mg/m²/d for 5 days. The major DLTis myelosuppression with only limitedincreased toxicity within the field ofradiation. This conceivably may limit theuse of JM216 as a radiation sensitizer.     

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Summary Purpose: This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine. Experimental design: Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m²/day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h. Results: In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m²). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/ m² dose level. Objective evidence of clinical activity was observed in four patients. Conclusions: The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m²/day of 3-AP on days 2–5 given prior to cytarabine administered at a dose of 1,000 mg/m²/day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.     

Gemcitabine and paclitaxel in metastatic or recurrent squamous cell carcinoma of the head and neck: a phase I-II study

The purpose of this study was to determine the maximum tolerated dose, toxicity profile and anti-tumor activity of paclitaxel in combination with gemcitabine when administered to patients with unresectable locally recurrent or metastatic squamous cell carcinoma of the head and the neck (SCCHN). Twenty-seven patients were treated in a phase I-II study with gemcitabine at a dose of 800 mg/m on days 1 and 8, escalating to a dose of 1,000 mg/m, plus escalating doses of paclitaxel (100, 135 and 175 mg/m) on day 2. Treatment consisted of 6 cycles repeated every 3 weeks. The main toxicity was myelosuppression. Other toxicities were mild and manageable. Due to grade 4 neutropenia at higher doses the recommended dose level of the gemcitabine/paclitaxel combination was 1,000/135 mg/m. Four patients achieved a partial response and no patient had a complete remission, giving an overall response rate of 14.8%. The median time of survival was 24 weeks. We conclude that the combination of paclitaxel and gemcitabine is tolerated, but shows insufficient clinical activity in patients with recurrent and/or metastatic SCCHN to warrant further testing.     

A Phase I trial of spirogermanium administered on a continuous infusion schedule

We have evaluated the toxicity of the antitumor agent spirogermanium on a schedule of continuous intravenous administration for periods up to five days. The doses tested were between 100 mg/m²/day and 500 mg/m²/day. Peripheral vein phlebitis occurred at all dose levels and was not relieved by addition of hydrocortisone or heparin to the infusion. No phlebitis occurred when the drug was administered through a central vein. The dose limiting toxicity of spirogermanium was neurologic, notably tremors and mental confusion. These problems became progressively more severe at doses above 250 mg/m²/day. There was no discernible bone marrow, renal or hepatic toxicity. One patient developed reversible interstitial pneumonitis. The recommended Phase II dose of spirogermanium is 200 mg/m²/day for five days, with the possibility of escalation in selected patients. Because spirogermanium is more toxic to tumor cells with prolonged exposure than with intermittent exposure, this schedule could be considered for Phase II trials, particularly in diseases thought to be especially sensitive such as ovarian and prostatic carcinoma or lymphomas.     

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia

Summary Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m²/day to 130 mg/m²/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2 + months. Both patients were treated at a dose of 100 mg/m²/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.     

A phase I trial of ametantrone acetate (NSC-287513)

Ametantrone acetate is an intensely blue anthracenedione undergoing clinical trials in man. In this Phase I study, 20 patients received 39 courses of drug as a single IV dose given daily for five days and repeated every three weeks (21 days). Dosage escalations proceeded from 15 mg/m² to 35 mg/m². Predictable and reversible leukopenia was the dose limiting toxicity. One previously untreated patient with renal cell carcinoma metastatic to the lungs and right arm experienced a partial response of 51 days duration. Nine patients had pharmacokinetic studies performed during the study. Ametantrone was extensively distributed (apparent volume of distribution, 26.3 1/m²) and demonstrated a short half-life (harmonic mean half-life, 0.38 hour). The maximum tolerated dose in this study was 35 mg/m². Recommended doses for Phase II trials are 30 mg/m² in good risk patients and 25 mg/m² in poor risk patients. Because of the partial response seen in one patient with renal cell carcinoma, Phase II trials should include this tumor category in order to better define the activity of ametantrone in this disease. In addition, since the total amount of drug that could be given to patients receiving the five day schedule (125–150 mg/m²) was approximately the same amount that could be administered as a single dose (140 mg/m²), it would appear that the only advantage of the daily times five day dosage schedule would be in the lower incidence of bluish skin discoloration.     

Multiple resistance modulators combined with carboplatin for resistant malignancies: A pilot study

Background: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent resistance modulators in 53 patients with resistant cancers.Methods: Pentoxifylline and dipyridamole were added to carboplatin 400 mg/m² in cohort 1, and metronidazole was also given in cohort 2. Mannitol and saline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3 received the same modulators as in cohort 2 but with a reduced dose of carboplatin (200 mg/m²). Subsequent patients had the following drugs added to those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators along with carboplatin 300 mg/m².Results: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m², but was minimal at lower doses. Other toxicity was generally tolerable and reversible, particularly at carboplatin doses 300 mg/m², although gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor responses) were seen in this patient population with heavily pretreated or primarily resistant cancers.Conclusions: Acceptable doses for phase II studies are carboplatin 300 mg/m², 20% mannitol 250 ml plus normal saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m²/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m² p.o. q6h × 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m² p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m² suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin; and 500 mg/m² i.v. right after carboplatin), novobiocin 600 mg/m² p.o. q12h × 6 days starting 24 hr before carboplatin, and tamoxifen 100 mg/m²/day plus ketoconazole 700 mg/m²/day × 3 days starting the day before carboplatin, with oral dexamethasone and ondansetron as antimetics.     

Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer

Summary Purpose: We studied the toxicities, potential pharmacokinetic interactions, and preliminary antitumor activity of the combination of docetaxel and irinotecan with celecoxib, a selective cyclooxygenase-2 inhibitor. Patients and methods: Eligible patients had advanced non-small lung cancer (NSCLC) with measurable disease, good performance status, and adequate end organ function. Docetaxel and irinotecan were administered intravenously on days 1 and 8, every 21 days, and their doses were escalated on successive patient cohorts at three dose levels: 30/50, 30/60, and 35/60 (doses in mg/m²). Celecoxib was administered at a starting dose of 400 mg orally twice daily without interruption, beginning on day 2 of cycle 1. Pharmacokinetic studies were performed on day 1 of cycle 1 and day 1 of cycle 2. Results: Seventeen patients with advanced NSCLC were enrolled and collectively received 78 cycles of therapy. Diarrhea was the most common toxicity; it was noted in 13 patients (76%). Dose-limiting toxicities occurred at dose level 1 (myocardial infarction in a patient with multiple coronary artery disease risk factors) and dose level 3 (grade 4 neutropenia with fatal urosepsis). Other major toxicities were: grade 3 neutropenia (2 patients); grade 3/4 diarrhea (3/1); grade 3 nausea (2); grade 2 rash (1); and grade 3 pneumonitis (1). The maximum tolerated dose was at dose level 3, i.e., docetaxel 35 mg/m² and irinotecan 60 mg/m² on days 1 and 8, plus celecoxib 400 mg twice daily, repeated every 21 days. Five of 15 evaluable patients achieved an objective response. The pharmacokinetics of docetaxel were not altered by celecoxib. However, we observed an 18% increase in the average elimination clearance of irinotecan coincident with the addition of celecoxib. Conclusions: The addition of celecoxib to docetaxel and irinotecan was generally well tolerated but unpredictable fatal toxicity occurred. Diarrhea was the most common toxicity. Antitumor activity was promising. The alteration of irinotecan pharmacokinetic parameters observed may not be clinically relevant. Supported in part by grant M01 RR-00048 from the National Center for Research Resources, National Institutes of Health, and by Pfizer Global Pharmaceuticals, New York, NY, and by Aventic Pharmaceuticals, a member of the Sanofi-Aventis Group.     

Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N¹N¹¹diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase.These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m²/day (12.5 mg/m²/dose) with escalation by a modified Fibonacci search.Doses of 25 and 50 mg/m²/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m²/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m²/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t² of 0.12h.We conclude that great caution is warranted in administering DENSPM on this schedule at doses of 83 mg/m²/day.     

Phase II study of AMSA alone and in combination with DTIC in patients with metastatic melanoma

Summary A randomized phase II study of AMSA (amsacrine) alone and AMSA combined with DTIC (dacarbazine) was carried out in 31 and 39 patients with metastatic melanoma respectively. AMSA was used at a starting dose of 40 mg/m²/day × 3 days with escalation to 50–60 mg/m²/day × 3 days in 8 pts. For AMSA + DTIC the starting dose was: AMSA 30 mg/m²/day × 3 days; DTIC, 800 mg/m² × 1 day. Additionally, seven pts received AMSA in a similar dose schedule but DTIC was used in a 5-day schedule of 250 mg/m²/day. Twentyfive patients were evaluable for response in the AMSA group and 36 in the AMSA + DTIC group. The objective response to AMSA included 1(4%) partial response compared with 11 complete or partial responses (30%) with AMSA + DTIC therapy. The median lowest absolute granulocyte count was 1100/l in AMSA group compared with 1000/l in the AMSA + DTIC group. Severe neutropenia of < 500 granulocytes/l was observed in 5 pts in the AMSA group compared with 13 pts in the AMSA + DTIC group. We concluded that AMSA has no significant activity against melanoma, although the combination of AMSA + DTIC seemed to be more active than DTIC alone.     

Pemetrexed combined with paclitaxel: a dose-finding study evaluating three schedules in solid tumors

Summary  The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed–paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m² on d1; (S2) 400 mg/m² d1 and 40 mg/m² d1 and d8; S3) 400 mg/m² d8 and 30 mg/m² d1 and d8. MTD was 500/135 mg/m² (S1), 400/40 mg/m² (S2), and 500/120 mg/m² (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m² (d8) and paclitaxel 90 mg/m² (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.     

CT-2103: emerging utility and therapy for solid tumours

CT-2103 (XYOTAX?, Cell Therapeutics, Inc.) is a conjugate of paclitaxel to a polyglutamate polymer. Its macromolecular nature exploits enhanced permeability and retention in tumour tissues. This compound is stable and inactive in aqueous solution and undergoes predominantly intracellular metabolism at the site where active paclitaxel is released. Because it does not require a Cremophor^® EL vehicle, it can be administered by short infusion into peripheral veins. In preclinical models, compared with the same dose of unconjugated paclitaxel in Cremophor EL-ethanol, CT-2103 yields ≥ 12-fold increase in area under the curve in both plasma and tumour tissue. This alteration in drug pharmacokinetics and biodistribution is attributable to the ability of macromolecules to concentrate in areas of vascular leakiness, such as tumour tissue. CT-2103 is taken up by both tumour cells and normal phagocytic cells and is transported to lysosomes, where it is released by specific proteases through enzymatic action. In syngeneic and xenogeneic tumour models, at the maximally tolerated dose, CT-2103 appears to be more active than the standard doses of paclitaxel. It has also demonstrated activity in paclitaxel-resistant tumour models. Its potential enhancement of efficacy and decrease in drug-related toxicities make this agent an attractive option for therapeutic investigation. In Phase I trials it has been relatively well-tolerated, with acceptable toxicity at doses ≤ 225 mg/m² every 3 weeks. In combination with carboplatin the maximum tolerated dose is 235 mg/m² and the recommended Phase II dose 210 mg/m². Activity has been demonstrated in both non-small cell lung carcinoma (NSCLC) and in ovarian cancer, Phase III studies are currently testing this agent versus standard paclitaxel as maintenance therapy for first-line treatment-naive ovarian cancer. In addition, CT-2103 at a dose of 210 mg/m² (performance status [PS] 0 – 1) or 175 mg/m² (PS 2) is being compared with docetaxel (75 mg/m²) for the second-line treatment of NSCLC. In front-line PS 2 NSCLC patients, this agent in combination with carboplatin is undergoing comparison with paclitaxel/carboplatin; in a separate effort, single-agent CT-2103 is being compared with either gemcitabine or vinorelbine. These studies will determine whether the preclinical and early clinical promise of this agent can be realised in the clinical treatment of solid tumours.