Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: A phase I study

BACKGROUND:: ifosfamide and paclitaxel are active drugs in the managementof non-small-cell lung cancer. We have performed a phase I studyusing a fixed dose of ifosfamide with escalating doses of paclitaxel,with G-CSF support, in an effort to determine the maximum tolerateddose (MTD) of paclitaxel in this combination, and to describethe dose-limiting toxicities of the combination at the recommendedphase II dose of paclitaxel. We also studied the feasibilityof delivering the paclitaxel as a one-hour infusion at the recommended phase II dose. PATIENTS AND METHODS:: Thirty-one patients were treated, 25 with stage IV disease,and 6 with stage IIIB disease. Ifosfamide was administered ata dose of 1.6 g/m² i.v. bolus daily x 3 days, with mesna uroprotection.Paclitaxel was administered as a 24-hour infusion at dose levelsof 135, 170, 200, 250, and 300 mg/m² six patients were treatedwith a one-hour infusion, at a dose of 250 mg/m² G-CSF, 5 µ/kg,was administered subcutaneously on days 4 through 10, or untilthe absolute neutrophil count exceeded 4000/µl. Cycleswere repeated every 21 days. RESULTS:: The dose-limiting toxicity was granulocytopenia, which increasedwith increasing dose levels of paclitaxel. The MTD was 300 mg/m²of paclitaxel, and the recommended phase II dose 250 mg/m² administeredas a 24-hour infusion. Other toxicities were generally mild,with only 5 patients demonstrating grade 3 neurotoxicity and5 with grade 3 thrombocytopenia. Partial responses were seenin seven patients (23%), all in the 18 patients who receiveddose levels of 250 mg/m² or higher. CONCLUSIONS:: Ifosfamide plus paclitaxel is an active treatment regimen inadvanced non-small-cell lung cancer, and compares favorablywith the results of cisplatin-based chemotherapy. A phase IIstudy is in progress by the Cancer and Leukemia Group B, inan effort to better characterize the tolerance of the regimen,as well as its effect on tumor response and survival. non-small-cell lung cancer, chemotherapy, ifosfamide/paclitaxel     

A phase I study of bi-weekly paclitaxel/cisplatin as initial therapy for advanced ovarian cancer: A study of the National Cancer Institute of Canada Clinical Trials Group

PURPOSE:: Given the potential for improved outcomes, a phase I trial wasinitiated to develop a paclitaxel/cisplatin regimen that couldbe delivered every two weeks to women with newly diagnosed advancedovarian cancer. PATIENTS AND METHODS:: From 1992 to 1994, 29 (28 eligible) patients were enrolled ina dose-seeking trial. All received 60 mg/m² of cisplatin precededby paclitaxel infused over three hours. The paclitaxel dosewas excalated from an initial level of 90 mg/m² by 10 mg/m²increments in successive cohorts of patients. RESULTS:: At 1^{20 mg/m}2 of paclitaxel, the dose-limiting toxicity was granulocytopeniawhich prevented retreatment on time. The recommended dose levelwas therefore paclitaxel 110 mg/m² infused over three hourswith cisplatin 60 mg/m², repeated bi-weekly for eight cycles. CONCLUSION:: This bi-weekly schedule of paclitaxel/cisplatin provides noadvantage in terms of dose-intensity nor total dose of paclitaxelin comparison to more common regimens given tri-weekly. cisplatin, ovarian cancer, paclitaxel, phase I study     

Weekly high-dose cisplatin in malignant pleural mesothelioma

BACKGROUND:: Cisplatin at conventional doses has marginal activity in mesothelioma.A dose-response relation for cisplatin has been suggested inother tumor types. In a phase I study on weekly cisplatin administration,3 of 5 patients with mesothelioma responded. Therefore, a phaseII study with weekly cisplatin was started with the recommendeddose of 80 mg/m²/week for six weeks. PATIENTS AND METHODS:: Fourteen patients with mesothelioma stage II, with measurablelesions, were treated with cisplatin at a dose of 80 mg/m² weeklyfor six weeks. Cisplatin was administered in 3% NaCl and combinedwith ondansetron as antiemetic. RESULTS:: Five patients had partial responses (response rate 36%; 95%confidence interval 12%–65%) lasting 2–8 months.Seven patients had stable disease. Ototoxicity, grade 2 in 3patients and grade 3 in 2, was the most troublesome side effect. CONCLUSIONS:: Cisplatin given at a higher dose intensity than in conventionalschedules is active in mesothelioma. The response duration isshort, however, possibly due to lack of effective maintenancetherapy. cisplatin, phase II study, mesothelioma     

A phase I study of combination therapy of the oral fluorinated pyrimidine compound S-1 with low-dose cisplatin twice-a-week administration (JFMC27-9902 Step2) in patients with advanced gastric cancer using a continual reassessment method

Objective: We conducted a Phase I study to evaluate the safety and efficacyof a combination of S-1 with semi-weekly low-dose cisplatinin patients with unresectable/recurrent gastric cancer to determinethe recommended dose (RD) for a subsequent Phase II study. Methods: S-1 was administered orally at 80–120 mg/body/day basedon body surface area. One cycle consisted of the consecutiveadministration of S-1 for 28 days followed by 14 days rest.Three dose levels, 7.5, 10, and 15 mg/m²/day, were set for cisplatin,which was administered twice-a-week for 4 weeks followed by2 weeks of rest in each cycle. Dose-limiting toxicity (DLT)data were continually monitored to enable decisions regardingcisplatin dose escalation and deescalation based on a new dose-findingalgorithm using a continual reassessment method (CRM). The CRMtarget toxicity level to estimate the RD was set at 20%. Results: Eight and five patients were treated at cisplatin dose levelsof 10 and 15 mg/m²/day, respectively. Two DLTs occurred at bothdose levels. On the basis of this data, the CRM estimated theRD to be 10 mg/m²/day of cisplatin. Three patients of eightpatients treated with 10 mg/m²/day of cisplatin exhibited aconfirmed partial response during the treatment period. Conclusion: For future trials examining the safety and efficacy of dailyS-1 with semi-weekly cisplatin in patients with unresectable/recurrentgastric cancer, we found a cisplatin RD of 10 mg/m²/day.     

Dose-escalation Study of Oral Etoposide and Carboplatin in Patients with Advanced Lung Cancer

A dose-escalation study of daily etoposide and carboplatin wascarried out on 23 patients with advanced lung cancer using astarting dose of 40 mg/m²/day etoposide given orally for 21days and 250 mg/m² carboplatin given intravenously (IV) on day1. A total of 41 courses were given. Myelosuppression was themajor dose-limiting toxicity. The maximum tolerated dose wasreached at the fourth level with 40 mg/m²/day etoposide for21 days and 400 mg/m² carboplatin on day 1, once every 4 weeks.Non-hematological toxicities were generally mild or reversible.The recommended doses of this combination chemotherapy are 40mg/m²/day etoposide for 21 days and 350 mg/m² carboplatin onday 1. The response rate for non-small cell lung cancer andsmall cell lung cancer was 16.7% and 60% (95% confidence intervalsof 3.6% to 41.4%, and 14.7% to 94.7%), respectively. A phaseII study is necessary to define the efficacy and safety of thiscombination chemotherapy.     

Pharmacokinetic Re-evaluation and Phase I Study of High Dose Epirubicin in Advanced Non-small Cell Lung Cancer

We performed a phase I trial to evaluate the toxicity and themaximum tolerated dose of high dose epirubicin on a three-consecutive-dayschedule on Japanese patients with advanced non-small cell lungcancer. Fourteen patients were entered in the study. At leastthree patients were assigned to each different dose level. Epirubicinwas given intravenously daily for three day by bolus injection.The dose was started at 60 mg/m²/course and escalated by 30mg/m²/course. Granulocytopenia was found to be the dose limitingtoxicity with a maximum tolerated dose of 150 mg/m²/course.Thrombocytopenia and non-hematological toxicities were mildand well tolerated. The maximum tolerated dose was lower thanthat in Europe and Canada. Partial responses were observed intwo out of five patients on 150 mg/m²/course. The recommendedphase II dose for high dose epirubicin was demonstrated to be120 mg/m²/course. A further dose-escalating study of epirubicinin conjunction with the administration of granulocyte colonystimulating factor is scheduled for the determination of itsantitumor activity in non-small cell lung cancer.     

Weekly administration of topotecan and paclitaxel in pretreated advanced cancer patients: a phase I/II study

Purpose This study was a phase I/II, cohort, dose-escalation trial of topotecan and paclitaxel. Its aim was to determine the dose-limiting toxicity (DLT) of the combination and to define the maximum tolerated dose (MTD), as a recommended dose for phase II, as well as to get preliminary data on the efficacy (activity) of the drug in pretreated patients with ovarian cancer, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC).Methods Included in the study were 52 pretreated patients, 19 with ovarian cancer, 20 with SCLC and 13 with NSCLC. The doses of topotecan were escalated from 1.25 to 2 mg/m² and of paclitaxel from 60 to 80 mg/m². A minimum of four patients were included at each of the six levels of dose escalation.Results We found that DLT due to grade 3 and 4 myelotoxicity was at levels 5 and 6 at doses of 1.75 and 80 mg/m² (level 5) and 2 and 80 mg/m² (level 6) for topotecan and paclitaxel, respectively. The MTD and recommended accepted doses are 1.75 mg/m² for topotecan and 70 mg/m² for paclitaxel. Of the 52 patients, 17 (33%) showed a response: 1 complete response (1.92%) and 16 partial responses (30.77%).Conclusions Topotecan combined with paclitaxel administered once weekly for three consecutive weeks repeated for every 28 days resulted in well-tolerated toxicity at doses of 1.75 and 70 mg/m², respectively, and a response rate of 33% in pretreated cancer patients.     

Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies

BACKGROUND:: CPT-11 (irinotecan), a camptothecin-derived anticancer agentwith DNA topoisomerase 1 inhibitory activity, has demonstrateda broad spectrum of in vitro and in vivo activity in solid tumourmodels including multidrug-resistant tumours. This review detailsthe rationale for the dosage schedule of CPT-11 selected forphase II studies, based on the results of 3 European phase Idose-escalating trials in patients with solid tumours. PATIENTS AND METHODS:: CPT-11 was administered as a 30-minute intravenous infusiononce every 3 weeks (schedule 1), once daily for 3 consecutivedays every 3 weeks (schedule 2) or once weekly every 3 out of4 weeks (schedule 3). RESULTS:: Neutropenia and diarrhoea were the major doselimiting toxicitiesin all of the studies. The maximum tolerated dose of CPT-11was 115 and 145 mg/m²/day for schedules 2 and 3, respectively.With schedule 1, diarrhoea became dose-limiting at 350 mg/m²but was manageable with highdose loperamide therapy. CONCLUSIONS:: CPT-11 350 mg/m² administered as an intravenous infusion onceevery 3 weeks was chosen for further evaluation in early phaseII studies, since this dosage regimen allowed the highest doseintensity with the least toxicity and was convenient for outpatientuse. The place of higher doses (with intensive antidiarrhoealsupport) and other administration schedules (e.g., protractedinfusion) warrant further investigation. chemotherapy, CPT-11, dosage schedules, irinotecan, DNA topoisomerase I inhibitor, solid tumours     

A randomised dose intensity study in ovarian carcinoma comparing chemotherapy given at four week intervals for six cycles with half dose chemotherapy given for twelve cycles

BACKGROUND:: The importance of dose intensity has not been clearly definedin ovarian cancer and we present a prospectively randomisedtrial of dose intensity in patients with ovarian cancer. PATIENTS AND METHODS:: Ninety-nine patients with FIGO stage Ic, II, III and IV epithelialovarian cancer were randomised to receive cycles of standarddose cyclophosphamide (600 mg/m²) and carboplatin (300 mg/m²)alternating with adriamycin (50 mg/m²) and ifosfamide (5 G/m²)for 6 cycles at monthly intervals (49 patients) or cycles ofhalf dose cyclophosphamide (300 mg/m²) and carboplatin (150mg/m²) alternating with adriamycin (25 mg/m²) and ifosfamide(2.5 G/m²) for 12 cycles at monthly intervals (50 patients).Patients in each arm were well balanced for major prognosticfactors. RESULTS:: The combined clinical response rate (complete response and partialresponse) on the 6 month arm was 76% compared with 48% on thelow dose intensity arm (p = 0.009). With a median follow upof 25.7 months the median survival on the low dose intensityarm is 20.9 months. The median survival point on the 6 montharm has not yet been reached. The median progression free intervalon the 12 month arm was 19.8 months, the median value has notyet been reached on the standard arm. The amount of residualtumour following initial laparotomy was the only significantindependent variable affecting survival (p = 0.0001). The meanreceived dose intensity of each drug was greater than 80% ofthe planned dose intensity. More patients had clinical diseaseprogression during treatment on the low dose intensity arm (42%)when compared to the standard dose intensity arm (8%) (p = 0.0003).Fifteen patients on the standard dose arm experienced a totalof 18 delays and 5 patients on the low dose arm experienced17 delays. Nausea, vomiting and diarrhoea were similar for bothstandard and low dose cycles of chemotherapy with a consequentbenefit for patients receiving fewer cycles even though thesewere of higher dose. CONCLUSIONS:: The combination studied was more effective when given at thehigher dose intensity and the improved response and survivalwas not accompanied by a significant increase in toxicity. dose intensity, combination chemotherapy, ovarian carcinoma, toxicity     

Paclitaxel and vinorelbine in anthracycline-pretreated breast cancer: A phase II study

BACKGROUND:: Paclitaxel and vinorelbine are active in advanced breast cancerpretreated with anthracyclines We therefore conducted a phaseII study to define the toxicity and activity of paclitaxel andvinorelbine administered in combination. PATIENTS AND METHODS:: Our patient population consisted of 37 patients with metastaticbreast cancer, 35 of whom had received prior chemotherapy includinganthracyclines. The treatment regimen included vinorelbine (25mg/m² i.v.) followed by paclitaxel (135 mg/m² i.v. as a 3-hourinfusion) on day 1; vinorelbine was repeated on day 8 in thefirst 14 patients and on day 3 in the remaining 23 patients. RESULTS:: Because of grade 4 neutropenia, the second dose of vinorelbinewas reduced or omitted in 88% of the courses on the days 1 and8 schedule and in 48% of the courses on the days 1 and 3 schedule.As a consequence the administered dose intensity of vinorelbinewas significantly higher on the days 1 and 3 schedule (13 mg/m²/wkversus 8.3 mg/m²/wk, P = 0.005). The overall response rate was38% (95% CI: 22–55); four responses have been observedin the ten patients with absolute anthracycline resistance.The median duration of response was 6.5 months. CONCLUSIONS:: The combination of paclitaxel and vinorelbine is a feasibleand active salvage regimen in advanced breast cancer patientspretreated with anthracyclines. breast cancer, paclitaxel, vinorelbine     

Combination Phase I/II Study of Irinotecan Hydrochloride (CPT-11) and Carboplatin in Relapsed or Refractory Non-Hodgkin's Lymphoma

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecinwhich inhibits topoisomerase I. Phase II studies have demonstratedthat CPT-11 is active against a broad spectrum of neoplasmsincluding intractable non-Hodgkin's lymphoma. An early phaseII study in lymphoma suggested that a schedule of daily infusionsof 40 mg/m²/day for three or five consecutive days is more effectivethan a single infusion of 200 mg/m² every three to four weeks.Carboplatin is also an active agent against lymphoma, and preclinicalstudies have shown that CPT-11 and its active metabolite havea synergistic effect with platinum compounds. To evaluate themaximal tolerated dose (MTD) and the therapeutic efficacy ofCPT-11 in combination with carboplatin in relapsed or refractorynon-Hodgkin's lymphoma, we conducted a combination phase I/IIstudy. The starting dose of CPT-11 was 20 mg/m²/day (days 1through 3 and 8 through 10), and dose escalations of 5 mg/m²/dayincrements were planned, with a fixed dose of carboplatin (300mg/m², day 1). Six of the eight patients receiving both agentsat the starting dose level developed critical toxicities suchas grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8)and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminaseelevation 1/8). Further dose escalation of CPT-11 was halted,and the starting doses were judged to be the MTDs. The responserate (25%, 2/8) to the combination of the MTDs was not superiorto that of CPT-11 alone in a previous phase II study (38%, 26/69),and the MTD of CPT-11 in combination with carboplatin was lessthan half the single-agent dose. We conclude that carboplatinis not recommendable for combination with CPT-11 in lymphomapatients. Other suitable agents for such a combination shouldbe sought.     

Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors

BACKGROUND: We conducted a phase I and pharmacokinetic study to determinethe maximum tolerable dose (MTD), toxicities, pharmacokineticprofile, and antitumor activity of Irinotecan (CPT-11) in patientswith refractory solid malignancies. PATIENTS AND METHODS: Forty-six patients were entered in this phase I study. CPT-11was administered intravenously over 30 minutes for 3 consecutivedays every 3 weeks. Dose levels ranged from 33 mg/m²/day to115 mg/m²/day on days 1 through 3. The pharmacokinetics of totalCPT-11 and its active metabolite SN-38 were assayed by HPLC. RESULTS: The combination of leukopenia and diarrhea was dose-limitingtoxicity at 115 mg/m²/day dose level, since 50% of the patients(5/10) experienced either grade 3–4 leukopenia, or diarrhea,or both. Leukopenia appeared to be a cumulative toxicity, witha global increase in its incidence and severity upon repeatedadministration of CPT-11. Other toxicities included nausea,vomiting, fatigue and alopecia. CPT-11 and active metaboliteSN-38 inetics were determined in 21 patients (29 courses). BothCPT-11 and SN-38 pharmacokinetics presented a high interpatientvariability. CPT-11 mean maximum plasma concentrations reached2034 ng/ml at the MTD (115 mg/m²). The terminal-phase half-lifewas 8.3 h and the mean residence time 10.2 h. The mean volumeof distribution at steady state was 141 l/m²/h. CPT-11 reboundconcentrations were observed in many courses at about 0.5 to1 hour following the end of the i.v. infusion, which is suggestiveof enterohepatic recycling. Total body clearance did not varywith increased dosage (mean=14.3 l/h/m²), indicating linearpharmacokinetics within the dose range administered in thistrial. The total area under the plasma concentration versustime curve (AUC) increased proportionally to the CPT-11 dose.Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD.A significant correlation was observed between CPT-11 area underthe curve (AUC) and its corresponding metabolite SN-38 AUC (r=0.52,p < 0.05). S-38 rebound concentrations were observed in manycourses at about 0.5 to 1 hour following the end of the i.v.infusion, which is suggestive of enterohepatic recycling. Mean24-h urinary excretion of CPT-11 accounted for 10% of the administereddose by the third day, whereas SN-38 urinary excretion accountedfor 0.18% of the CPT-11 dose. In this phase I trial, the hemato-logicaltoxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrheagrade correlated significantly with CPT-11 AUC. Two partial(breast adenocarcinoma and carcinoma of unknown primary) and2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responseswere observed. CONCLUSION: The MTD for CPT-11 administered in a 3 consecutive-days-every-3weeks schedule in this patient population is 115 mg/m²/day.The recommended dose for phase II studies is 100 mg/m²/day. CPT-11, camptothecin analogue, topoisomerase I inhibitor, phase I, pharmacokinetics     

Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors

BACKGROUND: In a previous phase I study we showed that single-agent cisplatincan be given weekly for six weeks at a dose of 80 mg/m²/wk.It has been suggested that etoposide has synergistic activitywith cisplatin and the drug can be given orally continuously.We therefore performed a phase I study with weekly cisplatincombined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were enteredin the study. Cisplatin was administered in hypertonic saline(NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m²for six weeks combined with daily oral etoposide at a dose of50 mg. At the maximum tolerable dose of cisplatin 75 mg/m²/wkand etoposide 50 mg/m² daily, leukocytopenia and thrombocytopeniawere dose-limiting toxic effects which resulted in frequenttreatment delays. Other toxicities were mild. Finally, a doseof cisplatin 70 mg/m²/wk weeks 1–2–3 and weeks 5–6–7in combination with etoposide 50 mg orally days 1–15 anddays 29–43 combined a high median cisplatin dose intensityof 52.5 mg/m²/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combinationwith oral etoposide. Leuko-cytopenia and thrombocytopenia aredose-limiting toxicities. The schedule will be explored furtherin phase n studies. phase I, cisplatin, etoposide, dose intensity     

Phase II trial of intraperitoneal carboplatin in ovarian carcinoma patients with macroscopic residual disease at second-look laparotomy: A multicentre study of the French Federation Nationale des Centres de Lutte Contre le Cancer

BACKGROUND: Because of its antitumour activity and its pharmacological advantagewhen administered by the intraperitoneal route, carboplatinwas studied in a phase II multicen-tric trial. The aim of thestudy was to determine the response rate and the toxicity ofcarboplatin administered intraperito-neally and to determineif pathological complete response could be attained in womenwith macroscopic residual ovarian cancer at second-look laparotomyafter intravenous cis-platin chemotherapy. PATIENTS AND METHODS: Twenty-nine patients with macroscopical residual disease afterintravenous cisplatin-based chemotherapy at second-look laparotomy,were treated at that time with 300 mg/m² of carboplatin administeredin the abdominal cavity every four weeks for six cycles. Ininstances of negative findings at physical and CT scan examination,laparotomy evaluation was performed and the catheter was removed.The dose of carboplatin was increased or decreased accordingto hematological toxicity. RESULTS: Efficacy is evaluable in 25 pts: 2 pts had pathological completeresponses and 1 pt had microscopic disease (12% response rateof evaluable patients). Toxicity is evaluable for 135 cyclesin 29 patients. No grade 4 hematological toxicity was observed,2 pts had grade 3 leukopenia and 3 pts had grade 3 thrombocytopenia;grade 3 vomiting was observed in 11% of cycles. No peritonealcomplication was observed; catheter dysfunction occurred afterthe first cycle in one patient who refused a surgical procedureto remove the catheter and to pursue treatment. CONCLUSION: Intraperitoneal carboplatin demonstrates efficacy in patientswith macroscopical residual disease at second-look laparotomyafter first-line cisplatin chemotherapy. The recommended dosefor further studies is 300 mg/m² administered every 4 weeks.A low response rate does not favour a randomised study. ovarian cancer, intraperitoneal chemotherapy, carboplatin, second look     

Phase I clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neo-adjuvant treatment in stages II and IIIA, HER2-overexpressing breast cancer patients. GEICAM 2003-03 study

Background: We carried out a phase I clinical trial to establishthe dose-limiting toxicity (DLT) and the maximum tolerated dose(MTD) of the combination of liposome-encapsulated doxorubicincitrate (LD) and docetaxel in breast cancer patients. Patients and methods: Patients with HER-2-overexpressing stagesII and IIIA breast cancers were treated in different dose cohortsof three patients. The MTD cohort was expanded up to six patients.The patients received LD and docetaxel every 21 days, plus weeklytrastuzumab, with pegfilgrastim support. Results: A total of 20 patients were enrolled, 18 of them beingassessable for toxicity and response. DLTs observed for thiscombination were diarrhea, fatigue, febrile neutropenia, stomatitis,myalgia, and nonneutropenic infection (pneumonia). LD 50 mg/m²and docetaxel 60 mg/m² every 21 days have been the MTD, withno episode of DLT observed. Seven patients developed left ventricularejection fraction decline (six grade 1 and one grade 2). Nointerruptions of the treatment were needed as a consequenceof cardiac toxicity. Pathologic complete response was achievedin eight patients (44%). Conclusions: The MTD and recommended dose for phase II trialsof LD and docetaxel are 50 and 60 mg/m², respectively. The achievedresults on cardiotoxicity are promising. Key words: Her2 positive, breast cancer, neoadjuvant chemotherapy, liposomal doxorubicine, docetaxel, trastuzumab, cardiotoxicity Received for publication August 26, 2008. Accepted for publication September 5, 2008.     

Phase I/II study of the combination of carboplatin and paclitaxel as first-line chemotherapy in patients with advanced epithelial ovarian cancer

Purpose: We performed a phase I/II study evaluating the combination ofpaclitaxel and carboplatin as first-line chemotherapy in patients withadvanced ovarian cancer. The aim of this study was to define a feasible andsafe combination regimen that could be recommended for future phase IIIstudies.Design: This study was a parallel two-arm, non-randomized, open trial. Ina first step, carboplatin was administered at a fixed dose of AUC 5 andpaclitaxel was escalated in 25 mg/m² steps starting at 135mg/m². Paclitaxel was given as a three-hour infusion.Carboplatin was administered on day 1 following paclitaxel in one study armand 24 hours after paclitaxel infusion on day 2 in the other study arm.Carboplatin was escalated to AUC 6 and AUC 7.5 after the MTD for paclitaxelhad been defined. Treatment was repeated every three weeks.Patients: Sixty-one patients with untreated histologically confirmedepithelial ovarian cancer were recruited of whom 59 were found eligible andevaluable for toxicity. Thirty-three patients with bidimensionally measurabledisease were evaluable for tumor response.Results: We could not detect any advantage of the two-day schedule comparedwith the more convenient one-day schedule. Dose limiting toxicities wereneutropenia, thrombocytopenia, and neurotoxicity. Except for two patients,toxicity was acceptable and clinically managable. One patient died ofneutropenic sepsis and one further patient developed grade III peripheralneurotoxicity that did not resolve within two months after chemotherapy hadbeen terminated. Overall objective response rate was 70%. The MTD forpaclitaxel was 185 mg/m² and AUC 6 for carboplatin,respectively. Secondary prophylaxis with G-CSF did not allow further doseescalation and therefore is not generally recommended.Conclusions: Paclitaxel 185 mg/m² given as three-hourinfusion followed by carboplatin AUC 6 is a feasible and safe regimen and canbe recommended for phase III trials. Observed response rates justify furtherevaluation of this combination. A randomized phase III trial comparing athree-hour infusion of paclitaxel 185 mg/m² combined witheither carboplatin AUC 6 or cisplatin 75 mg/m² as first-linechemotherapy of advanced ovarian cancer has recently been initiated by ourgroup.     

Combination chemotherapy with tauromustine (TCNU), 5-fluorouracil and leucovorin in advanced colorectal carcinoma: A dose-finding study

Background: In preparation for a phase II trial we performeda dose-finding study involving tauromustine (TCNU), fluorouracil(5-FU) and leucovorin (LV), applied in patients with colon cancer.To prevent TCNU/5-FU antagonism, a phenomenon recently demonstratedin vitro, special attention was paid to the sequencing of theseagents. Patients and methods: In 25 patients with advanced colorectalcarcinoma (13 M, 12 F, median age 51 yrs), four dose levelsof TCNU (25, 30, 35 or 40 mg/m²) were investigated. The agentwas administered orally once per week in weeks 1 through 4,in combination with fixed i.v. doses of 400 mg/m² 5-FU and 80mg/m² LV, once a week, weeks 1 through 8. Unless progressionoccurred, two 8-week cycles were applied. TCNU was administeredat least 24 hours prior to 5-FU, because recent in vitro studiessuggested that such an interval is required to obtain additivecytotoxicity. Results: All 25 patients were evaluable for toxicity; 23 patientsreceived at least one full 8-week course, and 13 were eligiblefor second cycles. Significant haematologic toxicity, predominantlythrombocytopenia WHO grade 3 or 4, was mainly encountered atthe 35 and 40 mg/m² dose levels. Although occasionally severe,myelosuppression did not result in toxic deaths; spontaneoushaemorrhage was never observed, and platelet transfusions werenot required. Additional toxicity, also related to the two higherdose levels, consisted of diarrhea (WHO grade 3) and the ‘handand foot syndrome’, both occurring in a single patient;two patients developed fever of undetermined origin, but onlyone of them required hospitalization and antibiotic treatment.The overall response rate was 20% (7 partial responses in 25evaluable patients). Conclusions: For phase IL studies, we recommend a weekly oraldose of 40 mg/m² TCNU, weeks 1 through 4, in combination with400 mg/m² 5-FU and 80 mg/m² LV (IV), once a week, weeks 1 through8. chemotherapy, colorectal carcinoma, TCNU     

High Efficacy of Paclitaxel and Doxorubicin as First-Line Therapy in Advanced Breast Cancer: A Phase I-II Study

Abstract

The aim of this study was to define the maximum tolerated dose (MTD) of paclitaxel (TAX) in combination with doxorubicin (ADM). To evaluate the efficacy and tolerability of this combination, TAX was administered in escalating doses of 30 mg/m², starting from 120 mg/m², by 1 hour continuous infusion, per group of three patients; ADM was administered at a fixed dose of 50 mg/m², 24 hours before administering TAX (phase I). The combination was recycled every 3 weeks. In phase II, TAX was administered at the MTD defined in phase I.

Thirty-six women were enrolled. The MTD of TAX was 220 mg/m². Objective responses were observed in 28/34 (82%) assessable patients. The median progression-free survival was 11.8 months and overall survival 27.8 months. The main clinical toxicity was neutropenia (grade III-IV) of short duration (94%). Two patients developed cardiac toxicity.

The combination TAX+ADM is very effective in advanced breast cancer.     

Phase II study of a closely spaced ifosfamide--cisplatin schedule with the addition of G-CSF in advanced non-small-cell lung cancer and malignant melanoma

BACKGROUND:: Ifosfamide and cisplatin are frequently combined cytotoxic agents.Both have a dose-response relationship. In view of this it appearsattractive to study regimens with a higher dose intensity thanusual. One way to increase the dose intensity is to shortenintervals between chemotherapy cycles. As bone marrow toxicityis dose limiting in ifosfamide-cisplatin combinations we starteda phase II study with both drugs administered every 2 weeksin combination with G-CSF. PATIENTS AND METHODS:: Patients with advanced non-small-cell lung cancer or malignantmelanoma were eligible for the study. The treatment consistedof ifosfamide 2 gram/m²/day days 1–3 combined with mesna,and cisplatin 33 mg/m²/day days 1–3, administered in hypertonicsaline (3% NaCl). G-CSF was started on day 4 at a dose of 5µg/kg/day and was continued until day 12. The cycles wereto be repeated every 2 weeks for a maximum of 6 cycles. RESULTS:: Thirty-two patients were entered in the study; 30 patients wereevaluable for response and toxicity. Neutropenia (grade 4 in16 patients) and thrombocytopenia (grade 4 in 15 patients) werethe most common toxicities. Thrombocytopenia incidence and -durationincreased per cycle and was the main cause of treatment delaysespecially after the third cycle. Only 4 patients were ableto complete the planned treatment without any delay or dosereduction and reached the intended dose intensity of 3 gram/m²/weekof ifosfamide and 50 mg/m²/week of cisplatin. Non haematologictoxicities were generally mild. Out of 22 evaluable patientswith non-small cell lung cancer 6 responded (27%; 95% CI: 10%–48%)while only one out of 8 patients with melanoma responded. Themedian response duration was 26 weeks (range 16–36 weeks). CONCLUSION:: The planned high-dose intensity of ifosfamide and cisplatincould be reached only for the first 2–3 cycles. Haematologictoxicity, especially cumulative thrombocytopenia, necessitatedtreatment delays jeopardizing the dose intensity. The responserate in non-small-cell lung cancer and melanoma was not superiorto what can be expected from more conventional regimens. cisplatin, G-CSF, ifosfamide, phase II study     

Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I-II clinical trial

Background: Vinorelbine (VNR) is highly active in metastatic breast cancer (MBC) and has shown an overall response rate of 40%-50% as first-line treatment. In vitro, a synergy has been observed between this drug and ifosfamide (IFX). In addition, the pharmacokinetics of IFX suggest that it may have greater activity when given by continuous-intravenous infusion (C.I.V.I.). The aim of this study was therefore to assess the antitumor efficacy and toxicity of the combination of bolus VNR and C.I.V.I. IFX as second-line therapy in anthracycline-resistant breast cancer patients. Patients and methods: Forty-two patients with MBC who had already received anthracycline-based chemotherapy were treated with a regimen consisting of IFX, by C.I.V.I. for 72 hours and bolus VNR. The courses were repeated every three weeks for a maximum of eight cycles. Four dose intensification steps were planned. IFX, 1.5 g/m² on days 1-3 + VNR, 30 mg/m² on day 1 (six patients); IFX, 2 g/m² on days 1-3 + VNR, 25 mg/m² on day 1 (six patients); IFX, 1.8 g/m² on days 1-3 + VNR, 25 mg/m² on days 1 and 8 (six patients); IFX, 2 g/m² on days 1-3 + VNR, 25 mg/m² on days 1 and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) was associated with IFX at an infusion ratio of 1:1 and, once the infusion was completed, per os every four hours for three times. Results: All of the 42 patients entered were assessable for toxicity, and 41 of them for response. Neutropenia was the most frequently-occurring toxicity, but only five patients at the highest dose level (11.9%) presented grade 4, and none of those at the first three steps. Other significant toxic effects were mild (only grade I-II). The median relative dose intensity was 95% at the highest dose level and all the treatments were administered on an out-patient basis. The overall response rate was 36.5% with a CR rate of 4.8% (two of 41 patients, all at the highest dose level) and a PR rate of 31.7% (13 of 41 patients). The median response duration was 7.0 months (range 2-13 months). Conclusions: The present phase I-II study shows that the IFX and VNR combination is an active and well-tolerated treatment in MBC and provides an alternative to taxanes for patients previously treated with anthracyclines.