A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.     

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

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

Phase I study of paclitaxel administered by ten-day continuous infusion

PURPOSE: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration. PATIENTS AND METHODS: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC < or = 500 or platelet count < or = 25,000 for > or = 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used. RESULTS: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level. CONCLUSION: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.     

Phase I study of liposomal doxorubicin and oxaliplatin as salvage chemotherapy in advanced ovarian cancer

Oxaliplatin (L-OHP) and stealth pegylated liposomal doxorubicin (PLD) have been shown to be active in pre-treated advanced ovarian cancer (PAOC). The aim of this phase I study was to determine the maximum tolerated dose (MTD) of L-OHP, combined with fixed doses of PLD as salvage treatment of PAOC. Twenty patients with recurrent ovarian cancer previously treated with two (30%) or three lines (70%) of chemotherapy were entered into the trial. Patients had a median age of 64 years (52-77) and a median platinum-free interval of 13 months (range 6-35). Patients received a fixed dose of PLD 40 mg/m2, combined with escalating doses of L-OHP from 80 to 130 mg/m2 administered in 1 day, every 3 weeks. Dose escalation was interrupted if 30% or more patients of a given cohort (three patients) exhibited dose-limiting toxicity in the first treatment cycle. The MTD of L-OHP was 130 mg/m2 as two out of three patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia during the first cycle of treatment. Amongst 20 evaluable patients, we observed an overall response rate of 55% (95% confidence interval 31.5-76.9%). With a median follow-up of 12 months (3.4+/-19.2), median time to progression was 9.7 months, while median survival was not reached yet. We conclude that a combination of PLD and L-OHP has a manageable toxicity profile, and can be safely administered as outpatient chemotherapy for heavily pre-treated patients with relapsed ovarian cancer. Promising anti-tumor activity was observed.     

Phase I study of paclitaxel administered by ten-day continuous infusion

Purpose: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration.Patients and methods: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC 500 or platelet count 25,000 for 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used.Results: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level.Conclusion: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.     

Dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer

This dose-finding study was designed to determine the maximum tolerated dose (MTD), efficacy and toxicity of combined paclitaxel and carboplatin in 35 previously untreated patients with advanced non-small cell lung cancer (NSCLC). Paclitaxel was given as a 3-h infusion at escalating dose levels (100-250 mg/m2) immediately followed by carboplatin as a 30-min infusion (325 or 350 mg/m2) every 3 weeks. The dose-limiting toxicity, paresthesia, occurred at the highest dose level, therefore the recommended dose was established one level below (paclitaxel 225 mg/m2 with carboplatin 325 mg/m2). Neutropenia was the most common hematotoxicity; dose dependency was not apparent. Two patients, at different dose levels, had febrile neutropenia. Thrombocytopenia was rare. Non-hematological toxicities grade 3 or higher included infection, anorexia, alopecia and paresthesia. One patient had a hypersensitivity reaction (transient hypotension). The overall response rate was 23% and median survival time was 7.5 months. Promising activity and acceptable toxicity supports the development of this combination as a useful chemotherapeutic option in advanced NSCLC.     

Escalating doses of paclitaxel and epirubicin in combination with cisplatin in advanced ovarian epithelial carcinoma: a phase I-II study

Our objective was to identify a new active three-drug combination regimen consisting of paclitaxel (PTX), epirubicin (EPI) and cisplatin as first-line line chemotherapy for advanced ovarian carcinoma. A phase I study was carried out to evaluate the dose-limiting toxicity (DLT) and the maximally tolerated dose (MTD) of PXT and EPI in combination with a fixed dose of cisplatin every 4 weeks. Side-effects were recorded according to the NCI Common Toxicity Criteria. Patients were treated in cohorts of three with fixed-dose cisplatin 80 mg/m2 and EPI 80-->100 mg/m2 and PXT 100-->160 mg/m2 until DLT was reached. Once MTD was identified, a single-step phase II study was therefore carried out to test the clinical activity and panel of toxicity of such regimen. Objective responses were recorded according to the WHO criteria. Time to progression and overall survival (OS) were secondary endpoints. The DLT was myelosuppression and, in more detail, febrile neutropenia, which occurred at the fifth dose level (PTX 140 mg/m2, EPI 100 mg/m2 and cisplatin 80 mg/m2) in two out of three patients. Other side-effects were grade 3 mucositis in two out of three patients and grade 3 anemia in one case. The combination of cisplatin 80 mg/m2 plus EPI 80 mg/m2 and PCT 140 mg/m2 every 4 weeks was considered as the MTD. In the phase II study a complete response was observed in six patients (33%) and a partial response in nine cases (50%) for an overall response rate of 83% [95% confidence limits (CL) 59-96%]. Median time to progression of patients with measurable disease was 16.4 months. Median OS was not reached after a follow-up of 42 months. This study demonstrated that PTX and EPI can be safely administered in combination with cisplatin to fit patients with advanced epithelial ovarian carcinoma. The three-drug regimen of cisplatin 80 mg/m2, EPI 80 mg/m2 and PTX 140 mg/m2 every 4 weeks is very active, at least in terms of objective response rate. This level of activity overlaps with the 95% CL of the activity of cisplatin alone; however, it does encourage future trials of the combination.     

Gemcitabine plus dose-escalated epirubicin in advanced breast cancer: results of a phase I study

Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle.     

Phase I trial of weekly cisplatin,irinotecan and paclitaxel in patients with advanced gastrointestinal cancer

Summary   Objectives: To determine the maximum tolerated dose (MTD), toxicities, and suitable dose for weekly 1-h paclitaxel combined with weekly cisplatin and irinotecan to treat advanced gastrointestinal malignancies. Methods: Thirty patients with metastatic or locally advanced (unresectable or recurrent) gastrointestinal solid tumors were enrolled on this single-center, phase I study. Patients were treated with paclitaxel given over 1h at 1 of 4 dose levels (40, 50, 65, or 80 mg/m²). Paclitaxel was followed by fixed doses of cisplatin (30 mg/m²) and irinotecan (50 mg/m²). All treatment was administered sequentially, once a week, in 6-week cycles (4 weeks on, 2 weeks off). Dose-limiting toxicity (DLT) was defined as a 2-week delay in treatment for grade 3 or 4 non-hematologic toxicity, neutropenic fever, a 1-week delay for grade 4 hematologic toxicity, or a 2-week delay for grade 3 hematologic toxicity. Results: Thirty patients were recruited; 28 patients were assessable for safety. Most of the patients (70%) had no prior chemotherapy. The primary first-cycle DLTs were neutropenia, diarrhea, and nausea. Paclitaxel at 65 mg/m² was defined as the MTD. The most common grade 3–4 toxicities observed during all cycles were neutropenia (57%), febrile neutropenia (11%), diarrhea (29%), fatigue (29%), and nausea (18%). No patients had G-CSF (Neupogen, Amgen Inc., Thousand Oaks, CA) support. Responses were observed in gastric, esophageal, and pancreatic cancers. Conclusion: Paclitaxel at 65 mg/m², cisplatin (30 mg/m²), and irinotecan (50 mg/m²) given weekly can be safely administered to patients with solid tumor malignancies. To improve cumulative toxicities, a schedule modification was required (3-week cycle; 2-on, 1-off) Neutropenia was the most common DLT. This combination showed substantial activity, particularly in patients with gastric and esophageal adenocarcinoma, and phase II evaluation could be considered.     

A phase I study of paclitaxel,estramustine phosphate and vinorelbine (Pacl-E-Vin) in advanced malignancies: triple tubulin targeting

Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.     

Neoadjuvant chemotherapy with low dose of pegylated liposomal doxorubicin plus weekly paclitaxel in operable and locally advanced breast cancer

To determine the activity and safety of a schedule with a low dose of pegylated liposomal doxorubicin (PLD) and weekly paclitaxel in operable and locally advanced breast cancer patients. Thirty-five patients with histologically confirmed, operable, and locally advanced breast cancer entered the study. The median age was 59 years (range 31-74 years). The schedule was biweekly PLD at the dose of 15 mg/m for four administrations and weekly paclitaxel at the dose of 80 mg/m for eight administrations. All patients were evaluable for response and toxicity. Twenty-six patients responded (74%): three (8%) had a complete response and 23 (66%) had a partial response, seven (23%) remained stable, and one experienced progression (3%). Fifteen of 27 operable patients (55%) underwent conservative surgery. Three patients (9%) had a pathological complete response and the disappearance of infiltrating disease was documented in three other patients. The main toxicity was hand-foot syndrome (grade 3 in four patients; 11%). Other nonhematological grade 3 toxicities included stomatitis in three patients (8%) and liver toxicity in one patient (3%). Grade 3-4 neutropenia was documented in another three patients and dose reduction was necessary in two patients. The fourth administration of PLD was suspended in four patients for grade 2-3 hand-foot syndrome. No symptoms were related to impairment of cardiac function and no death related to toxicity occurred. The combination of biweekly PLD and weekly paclitaxel was active in operable and locally advanced breast cancer with a manageable safety profile.     

Phase I study of carboplatin,irinotecan and docetaxel on a divided schedule with recombinant human granulocyte colony stimulating factor support in patients with stage IIIB or IV non-small cell lung cancer

A phase I study was conducted to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of carboplatin combined with irinotecan and docetaxel on a divided schedule with recombinant human granulocyte colony stimulating factor (rhG-CSF) support in patients with stage IIIB or IV non-small cell lung cancer. Carboplatin was given at the dose of AUC5 on day 1. Irinotecan and docetaxel on days 1 and 8 were administered at a starting dose of 40 and 30 mg/m2 as level 1. Subsequent levels were: irinotecan/docetaxel (in mg/m2), 50/30 (level 2), 60/30 (level 3) and 60/35 (level 4). rhG-CSF was given at 50 mg/m2 on days 5-15. Cycles were repeated every 3 weeks. Between May 1999 and April 2001, 31 patients were registered in this phase I study. Level 4 was judged as the MTD. The DLTs were considered diarrhea and febrile neutropenia. The overall response rate was 32.3% and median survival was 490 days with 1-year survival of 65.1%. We conclude that both irinotecan 60 mg/m2 and docetaxel 30 mg/m2 on days 1 and 8 in combination with an AUC5 of carboplatin on day 1 with rhG-CSF support is recommended for phase II study. The response rate and survival data in this phase I study are encouraging. We considered that the pathogenesis of diarrhea involved not only direct cytotoxic damage to the mucosa, but also bacterial overgrowth.     

Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium

Summary Objectives: Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P + G in patients with metastatic TCC. Methods: Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800–1,000 mg/m² on days 1 and 15; P 400–500 mg/m² on day 15; and C 50–70 mg/m² on day 1. All patients received folic acid, vitamin B₁₂, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. Results: Fifteen patients registered: 13/15 white males; median age 70 years (range, 53–82); 11/15 had KPS ≥ 90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed <1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3–4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). Conclusion: Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.     

Combined topoisomerase I inhibition for the treatment of metastatic colon cancer

The objective of this study was to define the maximally tolerated dose (MTD) and response rate of a combination of two topoisomerase I inhibitors, topotecan and irinotecan, in patients with metastatic colon cancer. Eleven patients, the majority with previously progressive disease on 5-fluorouracil-based regimens, were enrolled onto a phase I/II dose escalation trial utilizing continuous infusion topotecan for 2 weeks and weekly irinotecan x 3 with cycles repeated every 28 days. Dosages of topotecan utilized included 0.2 and 0.25mg/m2/day. Irinotecan was administered at a dose of 62 mg/m2 by i.v. bolus. Patients were followed for toxicity and response. The MTD of the combination of agents was found to be 0.25mg/m2/day for topotecan and 62 mg/m2 for irinotecan. The most common serious toxicities were diarrhea and nausea/vomiting. Only one patient experienced grade III neutropenia. There were no complete or partial responses. However, four patients had prolonged disease stabilization (SD) of up to 324 days and this group remained on protocol therapy for an average of 227 days (p=0.0005 versus patients not achieving SD). We concluded that the MTD for this combination of topoisomerase I inhibitors, given on this particular schedule, has been defined. This combination cannot be recommended as a first- or second-line therapy for patients with metastatic colon cancer based on the responses observed. However, approximately one-third of patients achieved prolonged disease stabilization. Topotecan with irinotecan may be useful as a palliative regimen for a subgroup of colon cancer patients.     

Increasing-dose gemcitabine plus low-dose cisplatin in metastatic non-small cell lung cancer

Gemcitabine, a pyrimidine analog active in non-small cell lung cancer (NSCLC), is widely used with cisplatin. The potential activity of the combination has not been fully assessed: gemcitabine is not used at its maximum tolerated dose (MTD) and cisplatin shows a clearly dose-related toxicity. This trial was designed to assess the MTD and dose-limiting toxicity (DLT) of low-dose cisplatin and increasing gemcitabine dose. CHEMOTHERAPY: cisplatin 50 mg/m2 on day 1, gemcitabine starting at 1400 mg/m on days 1 and 8 every 21 days. Subsequent levels were increased by 200 mg/m2. Forty-two patients with metastatic NSCLC were enrolled (37 males; median age 61 years; squamous cell carcinoma 19 patients; performance status 2, in 13 patients; 18 patients had significant weight loss). MTD was found to be 2600 mg/m2 because of DLT in three of six patients: two neutropenic fever and one massive bleeding. Overall toxicity was generally mild consisting mainly of neutropenia. Asthenia was the most common non-hematological effect. Overall response rate was 19 out of 41 patients (46.3%) and median survival was 31 weeks. We conclude that the recommended dose for a phase II dose is gemcitabine 2400 mg/m2 days 1 and 8 as a 30-min infusion when given with cisplatin 50 mg/m2.     

Phase I study of Tomudex and Doxorubicin in patients with locally advanced, inoperable or metastatic cancer (IND.98)

BACKGROUND: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and Doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. PATIENTS AND METHODS: Starting doses were Tomudex 2.5 mg/m2 i.v. bolus day 1 and Doxorubicin 30 mg/m2 i.v. bolus day 1, repeated every 3 weeks. Doxorubicin was escalated in increments of 10 mg/m2 to 60 mg/m2, followed by escalation of Tomudex in increments of 0.5 mg/m2 to 3.5 mg/m2, on six dose levels. Twenty-five patients received 127 cycles of therapy, with at least 3 patients treated at each dose level. RESULTS: There was no dose limiting toxicity (DLT) observed in the first five dose levels. Three of six patients on dose level six had DLT. Further dose escalation was not warranted and this was declared the MTD. Grade 3 or 4 granulocytopenia was observed in 16/25 patients, with associated fever in 3/25 patients. Responses were seen in this study with one complete response (duration 12.8 months) and 3 partial responses (median duration 8 months) in 21 evaluable patients. Fourteen patients had stable disease (median duration 2.5 months). All 4 responding patients and 10 patients with stable disease had gastric cancer. CONCLUSIONS: The recommended phase-II dose for this combination in future studies is Tomudex 3 mg/m2 and Doxorubicin 60 mg/m2 given every 3 weeks.     

Multifractionated paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin in patients with metastatic or recurrent esophageal squamous cell carcinoma

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.     

Prolonged administration of infusional cisplatin and oral etoposide in advanced non-small cell lung cancer

We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and the efficacy of prolonged infusion of cisplatin and oral etoposide in the treatment of advanced non-small cell lung cancer (NSCLC). Cisplatin was given via an infuser in escalating doses of 5, 6.5, 8, 9 and 10 mg/m(2)/day for 14 days along with etoposide at a fixed dose of 50 mg/m(2)/day orally followed by a 2-week rest period. All patients had stage IIIB or IV NSCLC. A cisplatin dose of 8 mg/m(2)/day was determined as the MTD. In the 13 patients treated at this dose level, grade III and IV toxicities were mainly hematologic including neutropenia (n = 5), febrile neutropenia (n = 4), thrombocytopenia (n = 3) and anemia (n = 6). Grade III/IV renal toxicity occurred in one patient. There were no treatment-related deaths. One patient had a partial response and three patients had stable disease. Thus, although the described regimen of cisplatin/etoposide is reasonably well tolerated, it does not appear to be better than the same combination administered over a shorter duration, in spite of a cumulative dose of 112 mg/ m(2) of cisplatin and 700 mg/ m(2) of etoposide per cycle.     

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

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

Eribulin mesylate in patients with refractory cancers: a Phase I study

Eribulin mesylate (Halaven?, E7389) is a synthetic analog of the marine natural product halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This Phase I study (clinicaltrials.gov identifier: NCT00326950) was the first to investigate eribulin mesylate in Japanese patients. The study determined the recommended dose, MTD, DLTs, safety, pharmacokinetics, and antitumor activity of eribulin administered on Days 1 and 8 of a 21-day cycle in Japanese patients with advanced solid tumors. Fifteen patients received eribulin mesylate 0.7-2.0 mg/m(2) as a 2- to 10-min intravenous injection. Neutropenia was the principal DLT. DLTs were observed in two of six patients treated at 1.4 mg/m(2), and in all three patients at 2.0 mg/m(2). The recommended dose was 1.4 mg/m(2) and the MTD was 2.0 mg/m(2). Neutropenia (67%), lymphocytopenia (20%), febrile neutropenia (33%), and fatigue (13%) were the most common grade 3 or 4 toxicities. Eribulin exhibited triphasic pharmacokinetics with a long terminal half-life, high volume of distribution, and low urinary clearance. Three patients achieved partial responses (two with NSCLC, one with head and neck cancer) at 1.4 mg/m(2) dose level. Eribulin mesylate, administered on Days 1 and 8 of a 21-day cycle, exhibits manageable tolerability at 1.4 mg/m(2). DLT was neutropenia.