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.     

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.     

Preliminary Phase II Study of Aclacinomycin A in Patients With Adult Acute Leukemia

Seventeen patients with adult acute leukemia in relapse weretreated with aclacinomycin A in 5-day courses given at a doseof 90 to 210 mg/m²/5 days as a daily bolus injection. Completeremission was achieved in patients treated with 130 or moremg/m²/5 days. Three out of seven patients with acute nonlymphocyticleukemia achieved complete remission lasting 15 mo, 14+ mo,and 2 mo. Of seven patients with acute lymphocytic leukemia,one achieved complete remission which lasted more than 11 mo.One patient with refractory anemia with an excess of blast cellsalso achieved complete remission. Neutropenia and thrombocytopeniaoccurred in all patients. The dose-limiting factors were gastrointestinalsymptoms and stomatitis, the latter occurring in three of theseven patients who received 200–210 mg/m²/5 days. Hyperbilirubinemiaassociated with antibiotic therapy was seen in four patients.Since aclacinomycin A has significant activity in acute nonlymphocyticleukemia, consideration should be given to exploring its usein combination with other active drugs.     

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     

A phase II study of weekly Edatrexate (10-EDAM) in metastatic melanoma: A National Cancer Institute of Canada Clinical Trials Group Study

BACKGROUND: Phase I and II clinical trials have demonstrated acceptabletoxicity and promising activity of Edatrexate (10-EDAM). Theobjective of this multicentre phase II study was to determinethe efficacy and toxicity of this agent in patients with metastaticmelanoma. PATIENTS AND METHODS: Sixteen previously untreated patients with metastatic melanomareceived 10-EDAM, 80 mg/m²/week intravenously. Patients wereevaluated for response and toxicity. RESULTS: There were no objective responses. The median dose intensityof 10-EDAM actually delivered was 56.25 mg/m²/week (70% of projected).Mucositis of any degree was encountered in 93.8% of patients.Grade 3 or 4 mucositis, skin rash, nausea, abdominal pain, neutropenia,thrombocytopenia, anemia and hyperbilirubinemia each were encounteredin 1–2 patients. There was 1 toxic death due to 10-EDAM. CONCLUSION: 10-EDAM is an inactive agent in metastatic melanoma.     

Treatment of Acute Nonlymphocytic Leukemia by Concurrent Administration of N4-Behenoyl-1-{beta}-D-Arabinofuranosylcytosine, Aclacinomycin A, 6-Mercaptopurine and Prednisolone: A Pilot Study

N⁴-behenoyl-1-ß-d-arabinofuranosylcytosine (BH-AC),a newly synthesized derivative of cytosine arabinoside witha longer plasma half life and marked dose independency in itsanti-L1210 leukemia effect, and aclacinomycin A, a new anthracyclineantibiotic which is as effective as daunorubicin against L1210leukemia and reportedly induces no alopecia and is much lesscardiotoxic, were combined with 6-mercaptopurine and prednisolonein a pilot study of the effect on acute nonlymphocytic leukemiaof adults. The treatment schedule consisted of daily administrationof BH-AC, 116 to 234 mg/m² as a 2-hr intravenous infusion; aclacinomycinA, 12 to 16 mg/m² as a 30-min intravenous infusion; 6-mercaptopurine,100 mg/m² orally; and prednisolone, 40 mg/m² orally. A course of treatment was continued until the bone marrow becameseverely hypoplastic, not extending over 14 days. Eight patientswere entered in the study, one of whom was nonevaluable becauseof early death from renal failure. Six out of the seven evaluablepatients attained complete remission and the other good partialremission. Only one course of treatment was administered tofive of the patients who attained complete remission. It shouldbe noted that complete remission was obtained in two of threepatients not responding to treatment with daunorubicin, cytosinearabinoside, 6-mercaptopurine riboside and prednisolone in combination.The median duration of complete remission and survival were5 + (range: 4 + to 6 +) mo and 9 + (range: 6 + to 27+) mo, respectively. The most frequent side effects were malaise and gastrointestinalsymptoms, which were well tolerated. Flat T waves were notedin the electrocardiogram of one elderly patient; the changewas not clearly attributable to the drugs employed. Mild alopeciawas seen in two patients. This regimen was quite effective asa remission inducer in acute nonlymphocytic leukemia of adults,and deserves further study.     

Phase II Study of 7-N-(p-Hydroxyphenyl)-Mitomycin C (KW2083) in Patients with Advanced Non-Small Cell Carcinoma of the Lung and Metastatic Pulmonary Tumors

Twenty-six patients with non-small cell carcinoma of the lungand 25 with metastatic pulmonary tumors were treated by intravenousinjection of 7-N-(p-hydroxyphenyl)-mitomycin C (KW2083), a derivativeof mitomycin C, either at a single 70-mg/m² dose or at a doseof 20–30 mg/m² once a week for 3 weeks. Two patients withadenocarcinoma among 21 evaluable patients with non-small cellcarcinoma of the lung, and one with embryonal cell carcinomaamong 21 patients with metastatic pulmonary tumors achievedpartial response lasting 5 to 7 weeks. In these three patients,KW2083 was administered by a single 70-mg/m² dose, and no patientswho received a dose of 20–30 mg/m² weekly achieved objectiveresponse. Myelosuppression, primarily thrombocytopenia, waspronounced with either treatment regimen and it was the majordose-limiting toxicity.     

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     

Oral fluoropyrimidines (capecitabine or S-1) and cisplatin as first line treatment in elderly patients with advanced gastric cancer: a retrospective study

Background: This study aimed to evaluate the safety and efficacy of oralfluoropyrimidines and cisplatin therapy in elderly patientswith untreated advanced gastric cancer (AGC) retrospectively.In addition, we evaluated the relative activity and toxicityof these agents in this patient population. Methods: Clinical data from 72 patients with previously untreated AGC,who were treated with capecitabine/cisplatin and S-1/cisplatin,were reviewed. Oral fluoropyrimidines were administered orallytwice a day on Days 1–14. The dose of capecitabine was1250 mg/m² and that of S-1 was 50 mg [body surface area (BSA)< 1.5 m³] or 60 mg (BSA > 1.5 m³) twice a day. Cisplatinwas administered intravenously on Day 1 (before the first doseof capecitabine or S-1) at a dose of 70 mg/m² over a 2 h period.The chemotherapy cycle was of 3 weeks (with oral capecitabineor S-1). Results: Thirty-two and 40 patients received the S-1 and capecitabineregimens, respectively, and were included in the analysis. TheS-1 protocol had a response rate of 40.6%, a median time-to-progression(TTP) of 5.4 months and a median survival of 9.6 months. Thecapecitabine had a response rate of 55%, a median TTP of 5.9months and a median survival of 10.2 months. Each protocol hada similar incidence of Grade 3 or 4 adverse events. However,there was a higher rate of the hand–foot syndrome (6 versus37%) and diarrhea (25 versus 32%) in the capecitabine group. Conclusion: Oral fluoropyrimidines and cisplatin in elderly patients withuntreated AGC showed encouraging results. The treatment waswell tolerated with a manageable toxicity profile. The comparisonof S-1 with capecitabine showed that capecitabine had a slightlyhigher response rate (statistically not significant) in additionto a higher rate of adverse events such as the hand–footsyndrome and diarrhea. These data should be warranted with furtherprospective studies.     

Phase I/II study of intraperitoneal mitoxantrone in refractory ovarian cancer

BACKGROUND:: Mitoxantrone has demonstrable clinical activity when administeredintravenously in a wide range of malignancies. The feasibilityand toxicity of intra-peritoneal administration was establishedin a phase I study. The optimal dose from the phase I was subsequentlyevaluated in a phase II study. PATIENTS AND METHODS:: 19 patients with refractory malignancies and extensive abdominaldisease (13 ovarian cancer, 4 breast cancer, 2 mesothelioma)were entered in a phase I study. The dose of intraperitonealmitoxantrone was escalated from 10 mg/m², administered in 21of fluid via a Tenkhoff catheter, to 55 mg/m², in incrementsof 5 mg/m². Cycles were repeated every three weeks. Sixty-sevencycles of mitoxantrone were administered, the maximum tolerabledose being 25 mg/m². A phase II study at this dose was conductedin 14 patients with refractory ovarian cancer, all of whom hadpreviously received systemic platinum based therapy. Five ofthe 14 had also previously been treated with intraperitonealcarboplatin. Fifty-one cycles were administered. RESULTS:: The dose limiting toxicity in the phase I study was peritonealirritation and pain. Leucopenia was frequent at doses equalor greater than 30 mg/m². Three complete remissions were documentedin the phase I study (2 breast cancer and 1 ovarian cancer).There was no significant haematological toxicity in the phaseII assessment, though local toxicity precluded further therapyin 2 patients. No objective responses were seen in the phaseII evaluation. CONCLUSIONS:: These studies demonstrate the feasibility of intra-peritonealmitoxantrone therapy in patients with peritoneal disease, butdo not support its routine use in ovarian cancer. ovarian cancer, mitoxantrone, intraperitoneal therapy, phase I, phase II     

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     

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     

Multi-day fractionated administration schedule for paclitaxel

PURPOSE: To establish the feasibility of fractionating paclitaxel administrationby utilizing daily one-hour infusions for three, four or fivedays with dose escalating to determine the patterns of hematologicand non hematologic toxicities. PATIENTS AND METHODS: Forty patients received 87 courses of daily fractionated paclitaxelfor three, four or five days; cycles were repeated every 21days. Six patients received concomitant daily cisplatin. Themedian number of cycles delivered per patient was two with arange of one to six. RESULTS: Cumulative doses per cycle ranged from 120 mg/m² to 250 mg/m²with 25% of the cycles delivering 200 mg/m² or more. Ten cycles(11.5%) were associated with dose limiting neutropenia (grade3 [7 cycles]; grade 4 [3 cycles]). No hypersensitivity reactionswere observed and no patient required cytokine support. No patientrequired hos-pitalization. CONCLUSION: Administering paclitaxel on a daily fractioned schedule in anambulatory setting is logistically feasible; does not requirepremedication; is associated with a toxicity pattern similarto single day schedules (e.g. 24-hour or three-hour infusion);is capable of delivering a higher dose per cycle than published96- or 120-hour infusion schedules; and could possibly be escalatedto doses higher than 250 mg/m² in carefully selected patients.The optimal dose rate for five-day multifrac-tionated administrationof paclitaxel is 40 to 50 mg/m²/d or a cumulative cycle doseof 200 to 250 mg/m² and does not require cytokine usage. Addingcisplatin on a fractionated daily schedule may accentuate theneurotoxicity associated with both agents. A prospective comparisonof four-day fractionated vs. four-day continuous infusionalpaclitaxel has been proposed as a randomized study to determineclinical differences in response, dose intensity and toxicity. paclitaxel, schedule-dependent administration     

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     

A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors

Purpose: The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. Methods: The starting dose was pralatrexate 40 mg/m² intravenously and probenecid 70 mg/m² intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1. Results: Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m² and probenecid 233 mg/m². Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen. Conclusion: For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m² and probenecid 140 mg/m². Vitamin B₁₂ and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.     

FILM (5-fluorouracil, ifosfamide, leucovorin and mitomycin C), an alternative chemotherapy regimen suitable for the treatment of advanced breast cancer in the `out-patient'' setting

FILM, a combination of 5-fluorouracil (5-FU) 750 mg/m², ifosfamide 1 g/m², leucovorin 200 mg/m² and mitomycin C 6 mg/m² (alternate cycles), was administered to 24 chemo-naive patients with inoperable disease, locally advanced or metastatic. Up to 6 2 3-weekly cycles of FILM were administered on an out-patient basis. Responses included 8 patients in complete remission (CR) and 12 showing a partial response (PR) (83%). Following analysis of these results, the FILM regimen was introduced as a standard out-patient protocol at the North Middlesex Hospital, United Kingdom. A further 66 patients have been treated in this setting. Retrospective analysis of these data confirm the trial results and allow conclusions regarding tolerability, toxicity, duration of response and survival to be drawn from a total cohort of 90 patients. A total of 524 cycles have been administered. Nineteen cycles (4%) were delayed owing to slow recovery of white blood cells (WBC), but no dose reductions were necessary. Five blood transfusions were required for anaemia. The most frequent non-haematological toxicities included nausea, vomiting and fatigue. Of 80 patients treated for inoperable or locally advanced disease, 56 (70%) remain in remission, and 69 (86%) remain alive after 5 years.     

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors

BACKGROUND: Paclitaxel is a novel agent with significant activity in severalsolid tumors. Preclinical data suggested that methotrexate priorto pacitaxel would be synergistic. To determine the qualitativeand quantitative toxicity of this regimen we performed a phaseI study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more thantwo prior chemotherapy regimens were given methotrexate intravenouslyon day 1, followed by pacitaxel, as a 24-hour infusion on day2. The starting dose (level ‘0’) was 40 mg/m formethotrexate and 135 mg/m for paditaxel. RESULTS: After achieving a maximum tolerated dose, additional patientswere enrolled with the addition of G-CSF 5 µg/kg/d ondays 4–13. At the starting dose level, dose-limit ingtoxicity consisting of neutropenic fever occurred in 3 of 4patients. At dose level–1, methotrexate 30 mg/m² and paclitaxel110 mg/m² neutropenic fever occurred in 7 of 10 patients duringthe first course. At dose level–2, methotrexate 23 mg/m²and paclitaxel 85 mg/m² neutropenic fever occurred in 1 of 7patients. To abrogate the neutropenia we explored the same combinationwith the addition of G-CSF. Neutropenic fever remained the onlydose-limiting toxicity. At dose level ‘0’ with G-CSF,1 of 7 patients developed doselimiting toxicity. At dose level1 plus G—CSF, methotrexate 40 mg/m² and pacitaxel 170mg/m² dose-limiting neutropenic fever occurred in 4 of 6 patients.Partial responses occurred in 4 of 41 patients entered on thisstudy. Pharmacokinetic data suggested that methotrexate didnot increase pacitaxel levels. CONCLUSION: The combination of methotrexate and paci taxel is feasible,but neutropenic fever, even with the addition of G—CSFprevents further escalations of paclitaxel beyond 135 mg/m²following methotrexate. phase I, methotrexate, paclitaxel, solid tumors     

Antitumor Activity of Ifosfamide against Nude Mice Xenograft and Results of Clinical Investigation

An evaluation of the effectiveness of ifosfamide against a xenograftof a mammary breast carcinoma and clinical evaluation in patientswith advanced malignant tumors refractory to previous chemo-and radiotherapy was performed. Ifosfamide showed high antitumoractivity against the xenograft of mammary breast carcinoma MX-1,but the antitumor activity of cyclophosphamide was higher. Combination chemotherapy with ifosfamide was investigated in26 patients. Except in one case, ifosfamide was given in combinationwith other anticancer agents as follows: regimen 1 (vincristineat 1 mg/body weekly, ifosfamide at 1.2g/m²/d and prednisoloneat 40 mg/m²/d on days 1 to 5); regimen II (vincristine at 1to 1.5 mg/body weekly, ifosfamide at 2.0 g/m²/d and prednisoloneat 40 mg/m²/d on days 1 to 5); and regimen III (Bischlorethylnitrosourea, BCNU at 100mg/m² at six-week intervals, ifosfamideat 2.0 g/m²/d and prednisolone at 60 mg/m²/d on days 1 to 5).For four patients, ifosfamide at 1.2 g/m²/d on days 1 to 5 wasgiven with vinblastine, actinomycin-D, Cis-dichloro-diammineplatinum (cis-DDP) or bleomycin. In patients with advanced malignanttumors refractory to previous chemo-and radiotherapy, the responseto all regimens was minimal. In regimen II and III, there wasincreased hematological, genitourinary and central nervous systemtoxicity due to dose escalation of ifosfamide, as compared withregimen I. Therefore, dose escalation of more than 1.2g/m²/dis not recommended.     

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.     

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.