A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

Summary The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received ≤2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m² and BMS-247550 20 mg/m². Grade 4 neutropenia lasting ≥7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m² plus BMS-247550 30 mg/m²) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m² plus BMS-247550 30 mg/m²), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m² plus BMS-247550 25 mg/m²), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicites included neutropenia, thrombocytopenia, neutropenic fever, hypophosphotemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m² over 90 min days 1 and 8 plus BMS-247550 20 mg/m² on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.     

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.     

Early evaluation of liposomal daunorubicin (DaunoXome®, Nexstar) in the treatment of relapsed and refractory lymphoma

We have treated 19 patients with relapsed or refractory lymphoma with liposomally encapsulated daunorubicin (DaunoXome) at two dose schedules; 40 mg/m² repeated every 14 days and 120 mg/m² repeated every 21 days. Non-haematological toxicity was mild, in particular, no patient treated with the higher dose schedule showed clinical deterioration in cardiac function. At the lower dose (10 patients) no objective responses were seen but at the higher dose (9 patients) one complete response and two partial responses were achieved. Liposomal daunorubicin at 120 mg/m² appears to have some activity against refractory lymphoma and we suggest that further studies with this agent are required.     

nab-Paclitaxel in patients with advanced solid tumors and hepatic dysfunction: a pilot study

Objective: This pilot open-label clinical study evaluated the safety and pharmacokinetics of albumin-bound paclitaxel (nab-paclitaxel) in patients with advanced solid tumors and hepatic dysfunction.

Research design/methods: Dosing was determined according to baseline bilirubin levels as described in the package insert for Taxol^® (paclitaxel), and patients received 130, 200 or 260 mg/m² nab-paclitaxel every 3 weeks.

Results: Thirty patients with elevated baseline bilirubin and aspartate aminotransferase levels received nab-paclitaxel. The most commonly-occurring grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 neutropenia occurred in 10, 30 and 30% of patients receiving 130, 200 and 260 mg/m² nab-paclitaxel, respectively. Grade 3 fatigue presented in 50 and 30% patients receiving 130 and 200 mg/m² nab-paclitaxel, respectively (no grade 4 event). Only one (10%) patient had a grade 3 sensory neuropathy in the 260 mg/m² nab-paclitaxel arm. Treatment-related grade 3 bilirubinemia and elevated aspartate aminotransferase was observed in patients receiving 130 mg/m² (30 and 10%, respectively) and 260 mg/m² nab-paclitaxel (20 and 10%, respectively). One patient had a grade 4 bilirubinemia in the 200 mg/m² nab-paclitaxel arm. Total bilirubin levels were inversely correlated to paclitaxel clearance (p < 0001).

Conclusions: nab-Paclitaxel has an acceptable tolerability profile in patients with solid tumors and hepatic dysfunction. The safety and pharmacokinetic results support the same dose modification scheme recommended for cremophor-based paclitaxel.     

Phase I trial of vinflunine and pemetrexed in refractory solid tumors

Background Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors. Methods A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m² was given with vinflunine 280 mg/m² (cohort 1), 300 mg/m² (cohort 2) or 320 mg/m² (cohort 3) on day 1 of a 21-day cycle. Results 19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1–6) prior therapies. DLT occured 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively. Conclusions Based on this experience we recommend vinflunine 300 mg/m² and pemetrexed 500 mg/m² in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.     

A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors

Summary CS-682 (1-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)-N⁴-palmitoylcytosine) is a novel orally administered 2’-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m²/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3–4) were seen more frequently with 10 patients experiencing grade 3–4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m²/day. The maximum tolerated dose was determined to be 160 mg/m²/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 ± 0.9 h after drug administration and the terminal elimination half-life was 1.7 ± 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 ± 0.31 h, peak plasma concentrations were achieved 3.1 ± 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 ± 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m²/day for 4 weeks repeated after a 2-week rest period. Supported by Sankyo Co., Ltd, and Cyclacel Ltd.     

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors

Purpose: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Patients and methods: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m². Pharmacokinetic studies were performed in patients at all dose levels. Result: Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m². One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m², and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m². Six patients were treated at the 18 mg/m² dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t_1/2) for TTI-237 was 25–29 h, and the mean area under the concentration time curve at 31.5 mg/m² was 2,768 ng•h/mL. Conclusion: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m² may be a tolerable dose of TTI-237.     

A phase I study of ispinesib,a kinesin spindle protein inhibitor,administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors

Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. Experimental Design Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1–8 mg/m²/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. Results The MTD was defined as 7 mg/m² administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m² due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3–7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. Conclusion The recommended dose of ispinesib is 7 mg/m² over 1 h weekly for three consecutive weeks of a 28 day treatment 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.     

Phase I trial of edatrexate plus carboplatin in advanced solid tumors: amelioration of dose-limiting mucositis by ice chip cryotherapy

Purpose: Edatrexate (10-Edam) is a methotrexate analog with improved intracellular transport, polyglutamation, and antitumor activity compared to the parent compound. Edatrexate shows schedule-dependent synergism with platinum compounds in preclinical studies. We performed a phase I trial to determine toxicities and establish the maximum tolerated dose (MTD) of edatrexate in combination with carboplatin. Based on the short initial plasma half-life of edatrexate, prophylactic ice chip cryotherapy was used to reduce the severity of mucositis. Patients and methods: Forty-six chemotherapy-naive patients with advanced solid tumors were treated. Edatrexate was given weekly for 5 doses (50% on day 8), and then every other week, followed by carboplatin at a fixed dose of 350 mg/m² on day 1 and then every 4 weeks for 8 cycles. Edatrexate dose was increased at increments of 10 mg/m²/dose level beginning at 60 mg/m²/week (range 60–120 mg/m²). Results: All patients were assessable for toxicity and response analysis. The median number of cycles administered per patients was 4. This combination chemotherapy regimen was well tolerated. Using ice chip cryotherapy, no grade IV mucositis was observed. Grade III mucositis occurred in only 7/46 pts and was not dose-related. Protocol-defined dose-limiting toxicity occurred at a edatrexate dose level of 120 mg/m², yielding an MTD of 110 mg/m². Responding tumor types included non-small cell and small lung cancer, head and neck cancer, and bladder cancer. Conclusions: 1) This phase I study demonstrated the safety and tolerability of this edatrexate and carboplatin combination. 2) Dose-limiting mucositis did not occur allowing escalation of edatrexate dose above levels previously achieved with this edatrexate dose schedule. This was most likely a result of prophylactic ice chip cryotherapy. 3) An edatrexate dose of 110 mg/m² with ice chip cryotherapy is recommended for Phase II trials of this combination.     

A phase I trial of recombinant alpha-2a Interferon (Roferon-A) with weekly cisplatinum

Eighteen patients with advanced solid tumors were treated in a phase I study of cisplatinum in combination with recombinant alpha-2a Interferon (Roferon-A, Hoffman-LaRoche, Inc, Nutley, NJ). Roferon-A was administered at a dose of 5 MU/m² S.C. three times a week and the dose levels of cisplatinum were 15, 20, 25, 33, and 42 mg/m²/week given intravenously. All patients experienced grade I/II fatigue, nausea and vomiting. Grade III toxicity occurred in 4/6 patients at dose level 4. The dose limiting toxicities were myelosuppression [leukopenia (two patients), neutropenia (one patient), thrombocytopenia (one patient)], vomiting (one patient) and severe fatigue leading to a decrease in performance status (one patient). One patient with non-small cell lung carcinoma had a mixed response and another a minor response. The recommended dose level of this combination for phase II studies is cisplatinum 25 mg/m²/week and Roferon-A 5 MU/m² three times a week.     

Prolonged infusion gemcitabine: a clinical phase I study at low- (300 mg/m2) and high-dose (875 mg/m2) levels

Gemcitabine (GEM) is a novel nucleoside analogue with a unique mechanism of action. Preliminary studies have shown a mild, schedule-dependent toxic profile with a broad range of MTDs and promising antitumor activity in various solid tumors. This phase I study describes the infusion length-effect relationships of low(300 mg/m²) and high-dose (875 mg/m²) GEM, administered on days 1, 8 and 15 at 4-week intervals in a step-wise escalation of duration (> 33%) at a starting level of 60 minutes. At least 3 patients entered each infusion-level step and 3 more cases were treated in the presence of significant toxicity. Conservative criteria for toxicity were employed, including treatment delay until recovery with infusion de-escalation in the subsequent course. Forty seven patients (29 at low- and 18 at high-dose GEM levels) with various solid tumors, including 9 (taken as a reference) who had received the same dose-levels over 30 min. entered the study. All but 9 patients (with pancreatic cancer) had been previously treated with chemotherapy and all had extensive visceral disease. A striking infusional-effect relationship was observed at both GEM dose levels. Four escalation steps were required to define the maximum tolerated infusion time (MTIT) at 6 hours for 300 mg/m² GEM, with leucopenia being dose-limiting. At 875 mg/m², although no limiting toxicity was observed (in spite of increased severity of leucopenia), no escalation was attempted following the 1 hour infusion, due to the limiting rate (58% of 12 patients) of toxic delay requiring shorter infusions. Toxicity was usually mild (no grade 4 event was recorded) showing the usual profile, although there was a trend towards increased non-hematologic toxicity (i.e. LFT abnormalities) as compared with the MTD previously defined using 30-min. infusion schedule (1,370 mg/m²). Eight patients achieved a PR: 1 with NSCLC, 1 with gastric and 2 with bladder cancer at 300 mg/m² (1 with a 3- and 3 with a 6-hour infusion) and 2 with pancreatic, 1 with cervical and another with bladder cancer at 875 mg/m² (all but one with a 1-hour infusion). These data clearly suggest that the infusion duration is an important independent factor that influences the clinical effects of GEM. The present study not only defined the toxic profiles and the MTITs of the selected dose-levels but demonstrated that GEM retained the antitumor activity at doses as small as 300 mg/m² when given as a prolonged infusion. Further studies should clarify the underlying mechanism(s) responsible for the erratic dose-effect relationships of GEM and establish the optimal dose-infusion level in the treatment of solid tumors.     

Phase I/II study of amrubicin,a novel 9-aminoanthracycline,in patients with advanced non-small-cell lung cancer

Purpose: Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks. Results: In a phase I study, four patients were enrolled at dose level 1 (40 mg/m²/day) and four at dose level 2 (45 mg/m²/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m²/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m²/day and 45 mg/m²/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%. Conclusion: Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.     

Phase II trial of ICRF-187 in patients with acquired immune deficiency related Kaposi's Sarcoma (AIDS-KS)

Summary Thirteen patients with AIDS related Kaposi's Sarcoma were entered on a phase II trial of ICRF-187, 1000 mg/m² IV daily for 3 days every 3 weeks. Eight patients had received prior chemotherapy for AIDS-KS. Six patients had prior opportunistic infection. There were no complete responses; one partial response lasting six months was seen. Toxicity was significant, and of the first 5 patients treated, 3 out of 5 had grade III or IV neutropenia. Because of this, subsequent patients received 800 mg/m² IV days 1–3 if previously untreated or 600 mg/m² if previously treated. Overall 4 of 13 patients had Grade IV neutropenia and 5 of 13 had Grade III neutropenia. One patient had Grade IV thrombocytopenia. ICRF-187 at a daily × 3 schedule has some efficacy in the treatment of AIDS related KS, future trials should evaluate lower doses or alternate schedules of administration.     

Phase I trial of edatrexate plus carboplatin in advanced solid tumors: amelioration of dose-limiting mucositis by ice chip cryotherapy

Purpose: Edatrexate (10-Edam) is a methotrexate analog with improved intracellular transport, polyglutamation, and antitumor activity compared to the parent compound. Edatrexate shows schedule-dependent synergism with platinum compounds in preclinical studies. We performed a phase I trial to determine toxicities and establish the maximum tolerated dose (MTD) of edatrexate in combination with carboplatin. Based on the short initial plasma half-life of edatrexate, prophylactic ice chip cryotherapy was used to reduce the severity of mucositis. Patients and methods: Forty-six chemotherapy-naive patients with advanced solid tumors were treated. Edatrexate was given weekly for 5 doses (50% on day 8), and then every other week, followed by carboplatin at a fixed dose of 350 mg/m² on day 1 and then every 4 weeks for 8 cycles. Edatrexate dose was increased at increments of 10 mg/m²/dose level beginning at 60 mg/m²/week (range 60–120 mg/m²). Results: All patients were assessable for toxicity and response analysis. The median number of cycles administered per patients was 4. This combination chemotherapy regimen was well tolerated. Using ice chip cryotherapy, no grade IV mucositis was observed. Grade III mucositis occurred in only 7/46 pts and was not dose-related. Protocol-defined dose-limiting toxicity occurred at a edatrexate dose level of 120 mg/m², yielding an MTD of 110 mg/m². Responding tumor types included non-small cell and small lung cancer, head and neck cancer, and bladder cancer. Conclusions: 1) This phase I study demonstrated the safety and tolerability of this edatrexate and carboplatin combination. 2) Dose-limiting mucositis did not occur allowing escalation of edatrexate dose above levels previously achieved with this edatrexate dose schedule. This was most likely a result of prophylactic ice chip cryotherapy. 3) An edatrexate dose of 110 mg/m² with ice chip cryotherapy is recommended for Phase II trials of this combination.     

Phase I dose escalation study of pegylated liposomal doxorubicin (Caelyx®) in combination with topotecan in patients with advanced malignancies

Summary Aims of this study were to determine the toxicity profile and the recommended dose of pegylated liposomal doxorubicin (Caelyx) in combination with topotecan in patients with advanced malignancies. Caelyx: 35 (DLI) or 40 (DLII) mg/m²/d1 was followed by 0.5 mg/m²/d topotecan daily for 5 days, every 4 weeks. Twenty-three patients received a total of 82 cycles. At DLII, 2/6 patients experienced dose-limiting toxicity consisting of grade 4 neutropenia lasting for more than 7 days and febrile neutropenia. At DLI, 4/18 and 2/18 patients presented febrile neutropenia and grade 4 sustained neutropenia, respectively. Non-hematological toxicities were mild to moderate. One patient with ovarian cancer presented a complete response. The hematological toxicity was a dose limiting factor that led to the recommended dose of 35 mg/m² Caelyx on day 1 with 0.5 mg/m²/d topotecan on days 1–5. This study results suggest that alternative schedules of this combination are required. Comment: Hervé Ghesquières and Sandrine Faivre contributed equally to this work and shall be regarded as joint first authors.Conflicts of interest: None of the authors declared conflicts of interest.     

Phase I study of NK105, a nanomicellar paclitaxel formulation,administered on a weekly schedule in patients with solid tumors

Previous studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3 weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50–100 mg/m²; n = 16). At a dose level of 100 mg/m², predefined dose-limiting toxicity (DLT) manifested in only one out of six evaluable patients, whereas a dose delay due to neutropenia during the first course occurred two patients. None of the three patients given 80 mg/m² had a dose reduction, while a dose delay occurred in two. NK105 exhibited linear pharmacokinetics at doses of 50–100 mg/m², and approximately 5 % of total paclitaxel was released from micelles. Thus, the recommended dose was set at 80 mg/m², and an additional 10 advanced breast cancer (ABC) patients were given this dose in the dose-expansion phase. DLT manifested in two patients, and grade ≥ 3 neutropenia was found in eight patients. Among the nine patients who completed the first cycle, four had a dose reduction, mostly because of neutropenia. Of the 10 patients, six achieved partial response (PR), and four achieved stable disease (SD) status. Overall, weekly NK105 was well tolerated and had a desirable antitumor activity profile. Further investigations of NK105 in ABC patients are currently underway.     

Phase II trial of ixabepilone,an epothilone B analog,given daily for three days every three weeks,in metastatic breast cancer

Summary Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m²/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m²/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m², 8 mg/m² and 10 mg/m² dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8–10 mg/m² daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.     

Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients

Summary We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37–69)]. Dose levels were 35, 40 and 45 mg/m² with a total of 26 cycles administered. At 40 mg/m², 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m² developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m² in 1/6 pts WHO grade 4, at 40 mg/m² in 2/6 pts WHO grade 3 and at 45 mg/m² in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using 30 mg/m². Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m², the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m².     

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

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