Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer

Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55-73 years). Patients received the combination of amrubicin (30 mg/m² on days 1-3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0-57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7-84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9-15.4%; p = 0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1-42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p = 0.004). The median progression-free survival (PFS) time was 3 months (range: 1-14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p = 0.01). The most frequent grade 3-4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3-4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC.     

Phase I study of green tea extract in patients with advanced lung cancer

Purpose Epidemiologic studies suggest that consumption of green tea may have a protective effect against the development of several cancers. Preclinical studies of green tea and its polyphenolic components have demonstrated antimutagenic and anticarcinogenic activity, and inhibition of growth of tumor cell lines and animal tumor models, including lung cancer. Green tea may also have chemopreventive properties, and enhancement of cytotoxicity of chemotherapeutic agents has been demonstrated. This trial was designed to determine the maximum tolerated dose (MTD) of green tea extract (GTE) in patients with advanced lung cancer.Methods A total of 17 patients with advanced lung cancer were registered to receive once-daily oral dosing of GTE at a starting dose of 0.5 g/m² per day, with an accelerated dose-escalation scheme.Results On this schedule, the MTD of GTE was 3 g/m² per day, and at this dose, GTE was well tolerated with no grade 3 or 4 toxicity seen. Dose-limiting toxicities were diarrhea, nausea and hypertension. No objective responses were seen in this trial. Seven patients had stable disease ranging from 4 to 16 weeks; no patient remained on therapy longer than 16 weeks due to the development of progressive disease.Conclusions This study suggests that while relatively nontoxic at a dose of 3 g/m² per day, GTE likely has limited activity as a cytotoxic agent, and further study of GTE as a single-agent in established malignancies may not be warranted. Further studies should focus on the potential chemopreventive and chemotherapy-enhancing properties of GTE.     

Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

Purpose We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer. Patients and methods Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1–3) plus 60 mg/m² of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m², and it was escalated in 5 mg/m² increments until the maximum tolerated dose was reached. Results The 30 mg/m² of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid E _max model. There were five partial responses among 11 patients for an overall response rate of 45%. Conclusion The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m² of CPT-11 (days 1 and 8) and 25 mg/m² of amrubicin (days 1–3) administered every 21 days. This work was presented in part at the 41st Annual Meetings of the American Society of Clinical Oncology, Orlando, FL, USA May 13–17, 2005.     

Retrospective analysis of efficacy and safety of amrubicin in refractory and relapsed small-cell lung cancer

Background  Amrubicin, a totally synthetic 9-aminoanthracycline, was evaluated retrospectively for the treatment of refractory and relapsed small-cell lung cancer (SCLC). Methods  Retrospective analysis was performed in 32 patients. Amrubicin was infused over 5 min on days 1–3, with courses repeated at 3- or 4-week intervals. Amrubicin was given at a dose of 45 mg/m² per day, 40 mg/m² per day, 35 mg/m² per day, 30 mg/m² per day, or 25 mg/m² per day depending on medical conditions (patients’ age and performance status [PS]), and the dose was modulated according to myelosuppression. Results  The median number of treatment cycles was 3 (range, 1–6). Seventeen patients (53.1%) had a partial response. Median progression-free survival time for all patients was 96 days, and median survival time was 166 days. Grade 3 or 4 hematologic toxicities comprised neutropenia (78.1%), anemia (65.6%), and thrombocytopenia (50.0%). Febrile neutropenia was observed in 8 patients (25.0%). Nonhematologic toxicities were mild. Treatment-related death was observed in 1 patient. Conclusion  Treatment with amrubicin appeared effective in SCLC patients previously treated with chemotherapy, although it was not necessarily safe, because of myelosuppression. Further research is warranted to investigate amrubicin treatment for patients with SCLC.     

Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia

Purpose: Topoisomerase I inhibitors have shown promising anti leukemic activity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase I study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal dispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with acute leukemia.Patients and methods: Patients with refractory or relapsed AML, acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia in blastic phase (CML-BP) were included in the study. Eligibility criteria were age greater than 15 years, performance status of 2 or better, creatinine <1.5 mg/dl, and bilirubin <1.5 mg/dl.9-AC/CD was given as a continuous intravenous infusion over seven days every three to four weeks. The starting dose was 0.2 mg/m2/d (1.4 mg/m2/course). Courses were given every three to four weeks according to toxicity and anti leukemic efficacy. This phase I study used the classical 3 + 3 design. The dose was escalated by 50% until grade 1 toxicity was observed, and then by 30% to 35% until the dose limiting toxicity was defined. At the maximal tolerated dose (MTD), 8 to 10 patients were planned to be treated to better define the toxicity and early-activity profiles.Results: Thirty-nine patients (AML thirty-six patients; ALL two patients; CML-BP one patient), median age 56 years, were treated. Severe mucositis was the dose limiting toxicity; it occurred in three of six patients treated at a dose of 1.6 mg/m2/d. The MTD was defined as 1.4 mg/m2/day by the phase I design. Upon expansion of the number of patients, 3 of 10 patients had grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady-state concentration of 9-AC lactone was close to 10 nmol/l, and the of 9-AC lactone area under curve (AUC) was 1409 ± 705 nmol/l·hr.Conclusion: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m2/d (9.8 mg/m2/course) in patients with acute leukemia. This represents three to fourfold dose escalation compared with the MTD of 9-AC given as shorter continuous infusion (three days) in patients with solid tumors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia.     

A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401

Backgrounds

Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients.

Methods

Amrubicin (35 mg/m²) and topotecan (0.75 mg/m²) were administered on days 3–5 and 1–5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases.

Results

Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths.

Conclusion

This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.     

Phase I study of amrubicin and vinorelbine in non-small cell lung cancer previously treated with platinum-based chemotherapy

Background  Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC. Methods  The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0–1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions. Treatment consisted of five dose levels, with amrubicin 35–45 mg/m² administered as a 5-min intravenous infusion on days 1–3 and vinorelbine 15–25 mg/m² given as a 1-h intravenous infusion on days 1 and 8, every 3 weeks. Results  All patients had received carboplatin and paclitaxel as first-line therapy. Dose-limiting toxicity (DLT) was seen in two of six patients (febrile neutropenia and deep vein thrombosis ) at level 1, allowing us to conduct level 2. At level 2, all three patients experienced DLT (leucopenia ≥4 days in one patient; febrile neutropenia in three patients; and infection in two patients), and this level was determined as the MTD. Subsequently, level 1 (amrubicin 35 mg/m² and vinorelbine 15 mg/m²) was defined as the RD. Responses in the nine patients included a partial response in one patient and stable disease in four patients. Conclusion  As second-line therapy, the RD of the combination of amrubicin and vinorelbine is 35 mg/m² and 15 mg/m², respectively. Further study should proceed to clarify the efficacy of this regimen.     

Phase I and pharmacokinetic study of KW-2170, a novel pyrazoloacridone compound,in patients with malignant tumors

Purpose The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170.Experimental design KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m² according to a modified Fibonacci method.Results A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m². The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m² and in two of two patients treated at 53.0 mg/m²; therefore, the MTD was 53.0 mg/m². Although no patients showed a complete response (CR) or partial response (PR), 15 patients were evaluated as having freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CL_tot) and volume of distribution (V_dss) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (C_max) and area under the concentration–time curve (AUC_0–). In addition, there was a good correlation between neutropenia and AUC_0–. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxidative metabolites were observed in the patients plasma and urine.Conclusions The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m². A significant linear relationship was observed between neutropenia and AUC_0–. We estimate the recommended dose for phase II studies to be 41.0 mg/m².     

A single-arm confirmatory study of amrubicin therapy in patients with refractory small-cell lung cancer: Japan Clinical Oncology Group Study (JCOG0901)

Objectives

We conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC).

Patients and methods

Patients with chemotherapy-refractory SCLC received 40 mg/m² AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results

Between November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1–22 cycles). ORR was 32.9% [P < 0.0001 by the exact binomial test for the null hypothesis that ORR ≤ 10%; 95% confidence interval (CI), 22.9–44.2%]. The median PFS and OS periods were 3.5 months (95% CI, 3.0–4.3 months) and 8.9 months (95% CI, 7.6–11.3 months), respectively. Significant differences in ORR (21.4% v 45.0%; P = 0.034), PFS (median, 2.9 v 5.1 months; P = 0.0009), and OS (median, 7.9 v 13.1 months; P = 0.0128) were observed between patients previously treated with etoposide and others. Neutropenia was the most common grade 3 or 4 adverse events (93.9%), and febrile neutropenia developed in 26.8% patients. No treatment-related death occurred.

Conclusions

AMR monotherapy can be considered an effective and safe treatment option for refractory SCLC. Previous chemotherapy with etoposide may influence AMR efficacy.     

A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors

PURPOSE: We conducted a phase I study to determine the recommended dose of selenomethionine (SLM) in combination with irinotecan that consistently results in a protective plasma selenium (Se) concentrations > 15 microM after 1 week of SLM loading. EXPERIMENTAL DESIGN: A 3-3 standard escalation design was followed. SLM was given orally twice daily (BID) for one week (loading) followed by continuous once daily (QD) dosing (maintenance). Seven dose levels of selenomethionine were investigated. Irinotecan was given intravenously at a fixed standard weekly dose, starting on the first day of maintenance SLM. RESULTS: Thirty-one patients were treated on study. Dose limiting diarrhea complicated by sepsis was noted in one of six patients at each of the dose-levels 1 and 7. Dose-levels > or = 5 (4,800 mcg/dose loading maintenance) resulted in day 8 Se concentrations >15 microM while dose-level 7 (7,200 mcg/dose loading and maintenance) resulted in day 8 Se concentrations > 20 muM. No significant variations in SN-38 or biliary index were noted between weeks 1 and 4 of treatment. Despite achieving target Se concentrations, gastrointestinal and bone marrow toxicities were common and irinotecan dose modification was prevalent. Objective responses were seen in two patients and nine patients had disease control for 6 months or longer. CONCLUSIONS: Selenomethionine can be escalated safely to 7,200 mcg BID x 1 week followed by 7,200 mcg QD in combination with a standard dose of irinotecan. No major protection against irinotecan toxicity was established; however, interesting clinical benefits were noted-supporting the investigation of this combination in future efficacy trials.     

Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer

Purpose R115777 is a selective, nonpeptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational modification of several proteins, including Ras. Given the high frequency of K-Ras mutations in malignancies commonly treated with irinotecan, the broad preclinical antiproliferative activity of R115777 and its largely non-overlapping toxicity profile with irinotecan, this phase I study of the combination of R115777 and irinotecan in patients with advanced cancer was undertaken.Patients and methods Enrolled onto the study were 14 patients (eight male, six female; median age 63 years, range 48–72 years). Five patients had an ECOG performance status (PS) of 0, eight patients PS 1, and one patient PS 2. The patients were treated with R115777 orally twice daily for 28 days and irinotecan 100 mg/m² as an intravenous infusion on days 1, 8, 15, and 22 of each 42-day cycle. Seven patients received R115777 100 mg twice daily and seven received R115777 200 mg twice daily.Results Dose-limiting toxicity (DLT) was experienced by one of seven patients treated with R115777 100 mg (grade 3 fatigue), and two of seven patients treated with R115777 200 mg (grade 3 diarrhea, grade 4 neutropenia lasting >5 days). The maximum tolerated dose (MTD) was R115777 100 mg twice daily and irinotecan 100 mg/m² weekly. Non-DLTs were primarily rash, fatigue, diarrhea, and neutropenia. R115777 demonstrated linear pharmacokinetics without interaction with irinotecan and achieved serum levels required for antitumor activity in vitro.Conclusions Serum levels of R115777 exceeded those necessary for FTase inhibition in vitro without evidence of interaction with irinotecan. However, the MTD of R115777 in this study was lower than that obtained with an alternate schedule. Thus, further development of this schedule is not recommended.This work was supported by a grant from Johnson and Johnson Pharmaceutical Research and Development and NCI K12 CA01728.     

Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule

Background Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing.Methods Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m², respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay.Results A total of 35 patients were treated. The MTD was docetaxel 30 mg/m² plus irinotecan 65 mg/m². Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease.Conclusions The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.     

Phase I study of daily S-1 combined with weekly irinotecan in patients with advanced non-small cell lung cancer

Background  S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan. Methods  Patients with advanced NSCLC received S-1 (80 mg/m²) on days 1–14 and irinotecan (50–80 mg/m²) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients. Results  At doses of 50–70 mg/m², no patients experienced any DLT, whereas, at a dose of 80 mg/m², two of four patients experienced DLTs. Two patients experienced grade 3 toxicities — neutropenia and diarrhea. Conclusion  The MTD of weekly irinotecan was 80 mg/m², making its RD for phase II trials 70 mg/m².     

Phase I and pharmacology study of flavone acetic acid administered two or three times weekly without alkalinization

Flavone acetic acid (FAA, NSC 347512) is a synthetic flavonoid compound with a unique form of preclinical antitumor activity, but its mechanism of action is still not known. In an attempt to exploit the remarkable preclinical activity of this compound in such a way as to allow its use as a clinically useful agent, we performed a phase I and pharmacology study with frequent administration and no hyperhydration or alkalinization. Sixteen patients (9 men, 7 women) were given FAA as 6-h i.v. infusions 2 or 3 times a week (10 and 6 patients, respectively), at doses ranging from 2.5 to 8.1 g/m². A total of 130 doses were administered during this study. Sedation, arterial hypotension, vomiting and diarrhea were the predominant toxicities observed at the highest dose (8.1 g/m²). One patient developed severe but reversible multiple organ failure. No treatment-related deaths occurred. Pharmacokinetics was linear for the doses studied, with peak plasma levels ranging from 39 to 449 g/ml and a mean terminal half-life of 3.1 h. No drug accumulation was observed with this frequent-administration schedule. No objective response was observed. Three FAA infusions per week at 8.1 g/m² could be recommended as an optimal and tolerable schedule.Dedicated to the memory of Dr. Marcel de Forni (deceased on 10 May 1994)     

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative, for the treatment of patients with non-small cell lung cancer

Purpose The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3–4 weeks. Methods Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2; adequate organ function; and age ≥20 and <75 years. The patients were administered TZT-1027 in escalating doses from 0.5 to 5.6 mg/m². Pharmacokinetic samples were collected during each treatment course. Results Forty-nine patients were enrolled. Three patients had DLTs, including neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The common toxicities included constipation, anorexia, alopecia, nausea, leukopenia, and neutropenia. One complete response and three partial responses were observed. The pharmacokinetic parameters (AUC and C _max) of TZT-1027 tended to increase linearly with dose. Conclusions DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m². The recommended phase II study dose of TZT-1027 is 4.8 mg/m² administered every 3–4 weeks.     

Phase I study of etoposide, cisplatin and irinotecan triplet in patients with advanced-stage small-cell lung cancer

Aim The irinotecan–cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan.Methods Successive cohorts of AS-SCLC patients were treated with irinotecan administered as a single 1-h infusion in combination with fixed doses of cisplatin (20 mg/m²) and etoposide (75 mg/m²), both given for three consecutive days (ECI regimen). Irinotecan dose was escalated from 60 mg/m² by 40-mg/m² increments. At mid-step between the maximum tolerated dose (MTD) and the previous dose level, patients were randomized for the day of administration of irinotecan (day 1 vs day 3).Results A total of 36 AS-SCLC patients received 166 courses of treatment at four dose levels. The MTD of irinotecan was 140 mg/m² (three dose-limiting toxicities, DLTs), and the recommended optimal dose (ROD) 120 mg/m² (two DLTs). DLTs were febrile neutropenia and grade 3 diarrhea. Other toxicities were mild. No difference in toxicity was seen between the two time schedules. A 77% (95% CI 63.25–90.75%) response rate was recorded among 31 evaluable patients and the median survival was 12 months.Conclusions The ECI regimen was well tolerated and showed considerable activity in patients with AS-SCLC. Phase II/III evaluation is ongoing.The results of this trial were presented at ECCO 12, Copenhagen, Denmark, September 2003.     

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer

BACKGROUND: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer. METHODS: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day. RESULTS: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks. CONCLUSION: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.     

Phase I clinical,pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies

Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.     

Phase I and pharmacokinetic study of vatalanib plus capecitabine in patients with advanced cancer

Angiogenesis inhibition is now a proven therapeutic strategy in treatment of several solid tumors. Vatalanib is a potent inhibitor of all known vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. In view of the effectiveness of angiogenesis inhibitor therapy when combined with chemotherapy and the established role of capecitabine in treatment of colorectal and breast cancer, we undertook a phase I clinical trial of the combination of capecitabine and vatalanib with the goal of developing a combination oral regimen. The study objectives were to determine the maximally tolerated dose of vatalanib that could be safely administered daily with capecitabine given orally for 14 out of 21 days to patients with advanced cancer; to characterize the safety, tolerability, and pharmacokinetic profile of vatalanib given in combination with capecitabine; and to describe any pharmacokinetic interactions between the drugs. The study had an initial dose escalation phase followed by a dose expansion phase. During the dose escalation phase, cohorts of at least three patients each were treated with capecitabine and escalating doses of vatalanib until the maximally tolerated dose of vatalanib was determined. Vatalanib given continuously at a dose of 1,250 mg/day could be safely combined with capecitabine at a dose of 2,000 mg/m²/day given for 14 of 21 days. Dose-limiting toxicities of the combination included fatigue, hypertension, dizziness, and proteinuria. Vatalanib did not alter the pharmacokinetics of 5-FU, the active metabolite of capecitabine. Vatalanib and capecitabine can be safely combined without unexpected toxicities or significant pharmacokinetic interactions.