Maximum Tolerated Dose Of Paclitaxel Research Articles

Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity.

A Phase I Study of Concurrent Weekly Carboplatin and Paclitaxel Combined With Intensity-Modulated Pelvic Radiotherapy as an Adjuvant Treatment for Early-Stage Cervical Cancer Patients With Positive Pelvic Lymph Nodes

The objective of this study was to determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLTs) of intravenous carboplatin plus paclitaxel combined with intensity-modulated pelvic radiotherapy (pelvic IMRT) as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes. Women with uterine cervical cancer who were treated with radical hysterectomy and pelvic lymphadenectomy and displayed positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic IMRT (50.4 Gy). The concurrent weekly chemotherapy consisted of carboplatin (area under the curve [AUC], 2) and paclitaxel (starting at 35 mg/m² and escalating by 5 mg/m² in 3 patient cohorts). The primary end point of the escalation study was acute DLT that occurred within 30 days of the completion of radiation therapy. Nine patients were enrolled and treated at 2 dose levels until DLT occurred. The median age of the patients was 47 years (range, 28-66 years). The median radiotherapy treatment time was 39.5 days (range, 38-64 days). At dose level I (35 mg/m² paclitaxel), 2 grade 3 leukopenia and a neutropenia were observed, but no DLT occurred. At dose level II (40 mg/m² paclitaxel), the first patient experienced a grade 2 hypersensitive reaction, which resulted in discontinuation of planned treatment. Thus, 2 more patients were evaluated at this dose level. Of these, 1 patient experienced febrile neutropenia, which was considered to be a DLT, and the other patient experienced long-lasting grade 3 leukopenia and grade 3 neutropenia, which resulted in the discontinuation of chemotherapy for 2 weeks (a DLT). We then evaluated 3 more patients at dose level 1, but no DLT occurred. The MTD of paclitaxel and carboplatin was thus defined as 35 mg/m² and an AUC of 2.0, respectively. Weekly paclitaxel/carboplatin and pelvic IMRT is a reasonable adjuvant treatment regimen for cervical cancer patients after radical hysterectomy. The MTD of paclitaxel and carboplatin for future phase II trials of this regimen is 35 mg/m² and an AUC of 2.0, respectively.

Maximum Tolerated Dose and Early Response — Results of a Phase I Trial of Paclitaxel and Cisplatin with Radiation Therapy in Carcinoma of the Cervix 1

Aims Cisplatin-based chemotherapy with radiotherapy is currently the standard treatment for locally advanced carcinoma of the cervix. Recent studies have shown a better response with the addition of newer chemotherapeutic agents. The aim of this phase I study was to establish the maximum tolerated dose (MTD) of paclitaxel in combination with cisplatin as a radiosensitiser along with radiation therapy in the treatment of carcinoma of the cervix and to analyse the toxicity profile of the combination regimen. Materials and methods In total, 21 newly diagnosed patients with squamous cell carcinoma of the cervix, International Federation of Gynecology and Obstetrics stage IB to IIIB were included in this trial. All patients received external beam radiation therapy to the pelvis (50 Gy in 25 fractions) delivered by conventional four-field box technique followed by low dose rate brachytherapy. Concurrent chemotherapy was administered with weekly cisplatin (30 mg/m 2) and an escalating dose of weekly paclitaxel starting at 10 mg/m 2 up to 50 mg/m 2 (according to the modified Fibonacci series). Results The MTD of weekly paclitaxel was found to be 40 mg/m 2. The dose-limiting toxicity that occurred in our patients at a dose of 50 mg/m 2 weekly paclitaxel was grade 3 proctitis and vaginitis. Conclusion In this phase I trial of concurrent radiation and combination chemotherapy with weekly paclitaxel and cisplatin (30 mg/m 2/week), the MTD of paclitaxel was found to be 40 mg/m 2. This combination was feasible, with an acceptable toxicity profile.

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m(2)) was given orally on days 1-21 every 35-day cycle (rest on days 22-35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m(2), stepping up to 70 mg/m(2) in 10-mg/m(2) increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. The MTD of paclitaxel was estimated to be 60 mg/m(2), because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m(2). In the phase II portion, 22 patients were evaluated with 50 mg/m(2) paclitaxel and 80 mg/m(2) S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2-75.6%). The median survival time was 283 days (95% CI, 218-508 days). The median number of treatment courses was 4 (range 1-10), indicating that this regimen could be given repeatedly. This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.

Phase I Study of Biweekly Paclitaxel and Carboplatin for Frail Patients With Advanced Non-Small Cell Lung Cancer

The aim of this phase I study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity of the biweekly paclitaxel and carboplatin combination chemotherapy in frail patients with advanced non-small cell lung cancer (NSCLC). Seventeen unresectable and previously untreated NSCLC patients participated in this study. Frail patients (>80 years old with PS 0-1 and adequate organ functions, or <80 years old with PS 2 or <80 with PS 0-1 and one inadequate organ function of bone marrow, liver, or kidney) of NSCLC were enrolled in this study. Both paclitaxel and carboplatin were administered on day 1 and repeated biweekly. The starting dose of paclitaxel 120 mg/m2 and carboplatin was AUC 3 /d on day 1 every 2 weeks for 4 to 8 cycles. Seventeen frail patients received a total of 1 to 10 cycles. The major hematologic toxicity was neutropenia. Nonhematologic toxicities, including numbness and constipation, were generally mild and reversible. The MTD of paclitaxel were determined as 140 mg/m2. The recommended phase II study dose of paclitaxel was determined as 120 mg/m2 with area under the curve 3 biweekly for 1 day. An objective response was observed in 8 of 17 patients (47%) with frail patients. The combination chemotherapy of biweekly paclitaxel and carboplatin appears to be tolerable and sufficiently effective in frail patients with NSCLC. A phase II trial is underway.

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m−2 day−1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m−2 day−1. The dose was increased in a stepwise manner to 70 mg m−2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m−2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m−2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1–17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.

Phase I and Pharmacokinetic Study of S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer

Objective: A dose-escalation study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the dose-limiting toxicities (DLTs) in advanced gastric cancer. Patients and Methods: Twelve patients were enrolled. S-1 was given orally at a fixed dosage of 40 mg/m² b.i.d. for 14 consecutive days, followed by a 1-week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8 at a dose of 50, 60, 70 or 80 mg/m², depending on the DLTs. Treatment was repeated every 3 weeks. A pharmacokinetic study was conducted in an additional 5 patients on days 7 and 8 during the first course given at the RD. Results: The MTD of paclitaxel was presumed to be 60 mg/m², because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). DLT was observed in 1 out of 8 patients at a dose of 50 mg/m². Therefore, the RD of paclitaxel was estimated to be 50 mg/m². The preliminary response rate was 62.5% (5/8) at the RD. There were no significant pharmacokinetic interactions between S-1 and paclitaxel. An adequate plasma paclitaxel concentration for an antineoplastic effect was achieved with weekly doses of 50 mg/m². Conclusion: Weekly paclitaxel combined with S-1 was demonstrated to exhibit a tolerable toxicity profile with therapeutic plasma concentration at the dose of 50 mg/m². This regimen could represent a novel and low toxic combination for advanced gastric cancer.

Phase I Study of 90Y-CC49 Monoclonal Antibody Therapy in Patients with Advanced Non-Small Cell Lung Cancer: Effect of Chelating Agents and Paclitaxel Co-Administration

This trial was designed to evaluate strategies to improve the efficacy of a radiolabeled monoclonal antibody (mCC49) against tumor-associated glycoprotein-72 (TAG-72) in patients with non-small cell lung cancer (NSCLC). The aims of this study were to determine: safety and maximum tolerated dose (MTD) of (90)Y-mCC49 in combination with interferon alpha2beta (IFN); whether calcium disodium versonate (EDTA) or diethylenetriamine penta-acetic acid (DTPA) could reduce myelosuppression; and safety and MTD of paclitaxel (Taxol) in combination with (90)Y-mCC49. Patients with advanced (TAG-72 positive) non-small cell lung cancer were entered in three phases; the first was the dose escalation of a single agent (90)Y-mCC49. In the second phase, the dose escalation of (90)Y-mCC49 was attempted with concurrent EDTA or DTPA chelator therapy. In the third phase, radiosensitization with a continuous infusion of paclitaxel (96-hour) was administered with (90)Y-mCC49. All patients received IFN for TAG-72 up-regulation. Thirty-four patients were evaluable. Reversible Grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs). The MTD of (90)Y-mCC49/IFN was 14 mCi/m(2). EDTA did not alter toxicity, while there was a modest reduction of myelosuppression with DTPA. The MTD of continuous infusion paclitaxel in combination with 14 mCi/m(2) of (90)Y-CC49 was 60 mg/m(2). There were no objective tumor responses. (90)Y-mCC49/IFN was well tolerated at a dose of 14 mCi/m(2). The clinical effect of adjunctive chelating therapy with DTPA was modest. The MTD of coadministered continuous infusion (96-hour) paclitaxel was 60 mg/m(2). Because of the immunogenicity of the murine compound, future studies are planned using a humanized version of CC49.

A combination phase I study of weekly paclitaxel and 5'-DFUR in patients with unresectable or recurrent gastric cancer in an outpatient setting

4228 Background: Paclitaxel (PTX) and 5'-DFUR have single-agent activity in gastric cancer and have distinct mechanisms of action and no overlap of key toxicities. Synergistic interaction between PTX and 5'-DFUR is mediated by taxane-induced up-regulation of thymidine phosphorylase. Objectives: To determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD). The DLT was set in low grade to treat the patients in the outpatient clinic. Patients and methods: Eligibility criteria included patients with histologically proven unresectable or recurrent gastric cancer, no requirement of prior chemotherapy, a performance status of 0–2, adequate organ function and written informed consent. PTX was administered by 1-hour intravenous infusion (level 1, 2, 3, 4: 50, 60, 70, 80 mg/m2) weekly for 3 consecutive weeks every 4 weeks. 5'-DFUR was administered orally at a fixed dose of 600mg/body everyday. Toxicity and efficacy were evaluated during the 2 cycles for 8 weeks. Three or 6 patients were enrolled at each dose level. DLT was defined as grade 3 hematologic toxicity, grade 2 non-hematologic toxicity and treatment delay because of grade 2 hematologic toxicity for more than 8 days of the schedule. The MTD was defined as the dose level at which at least two of three patients or three of six patients presented with DLT. Results: Twenty-one patients with a median age of 66 years (range, 39 to 74) were enrolled in this study. Nine patients have received prior chemotherapy. Seven patients were unresectable and 14 had recurrent tumors. At level 1(n=3), no patients developed DLT. One, 2 and 3 patients developed DLT at level 2(n=6), 3(n=6) and 4(n=6), respectively. All DLT was neutropenia. Only 1 developed grade 4 neutropenia at level 4. Non-hematological toxicity was uncommon. Level 4 was determined as the MTD. Of 16 evaluable patients, responses included 1 CR, 7 PR, 6 SD and 2 PD for an overall response rate of 50%. Conclusion: The MTD of PTX in this combination is 80 mg/m2 and the RD is 70 mg/m2. This regimen is well-tolerated with high response rate in outpatient setting. A phase II study is conducted. No significant financial relationships to disclose.

A combination phase I study of weekly paclitaxel and 5'-DFUR in patients with unresectable or recurrent gastric cancer in an outpatient setting

4228 Background: Paclitaxel (PTX) and 5'-DFUR have single-agent activity in gastric cancer and have distinct mechanisms of action and no overlap of key toxicities. Synergistic interaction between PTX and 5'-DFUR is mediated by taxane-induced up-regulation of thymidine phosphorylase. Objectives: To determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD). The DLT was set in low grade to treat the patients in the outpatient clinic. Patients and methods: Eligibility criteria included patients with histologically proven unresectable or recurrent gastric cancer, no requirement of prior chemotherapy, a performance status of 0–2, adequate organ function and written informed consent. PTX was administered by 1-hour intravenous infusion (level 1, 2, 3, 4: 50, 60, 70, 80 mg/m2) weekly for 3 consecutive weeks every 4 weeks. 5'-DFUR was administered orally at a fixed dose of 600mg/body everyday. Toxicity and efficacy were evaluated during the 2 cycles for 8 weeks. Three or 6 patients were enrolled at each dose level. DLT was defined as grade 3 hematologic toxicity, grade 2 non-hematologic toxicity and treatment delay because of grade 2 hematologic toxicity for more than 8 days of the schedule. The MTD was defined as the dose level at which at least two of three patients or three of six patients presented with DLT. Results: Twenty-one patients with a median age of 66 years (range, 39 to 74) were enrolled in this study. Nine patients have received prior chemotherapy. Seven patients were unresectable and 14 had recurrent tumors. At level 1(n=3), no patients developed DLT. One, 2 and 3 patients developed DLT at level 2(n=6), 3(n=6) and 4(n=6), respectively. All DLT was neutropenia. Only 1 developed grade 4 neutropenia at level 4. Non-hematological toxicity was uncommon. Level 4 was determined as the MTD. Of 16 evaluable patients, responses included 1 CR, 7 PR, 6 SD and 2 PD for an overall response rate of 50%. Conclusion: The MTD of PTX in this combination is 80 mg/m2 and the RD is 70 mg/m2. This regimen is well-tolerated with high response rate in outpatient setting. A phase II study is conducted. No significant financial relationships to disclose.

Phase I study with weekly cisplatin-paclitaxel and concurrent radiotherapy in patients with carcinoma of the cervix uteri

Cisplatin and paclitaxel are active in cervical cancer and both are able to potentiate the effects of radiotherapy. In this study we evaluated the maximum-tolerated dose (MTD) of paclitaxel in combination with a fixed dose of cisplatin when given weekly concurrently with pelvic radiotherapy to patients with carcinoma of the cervix uteri. Eighteen patients with cervical cancer were enrolled in this study. Cisplatin (30 mg/m2) and paclitaxel (starting dose 40 mg/m2; 5 mg/m2 escalation per level) were given on day 1 of radiotherapy and then weekly for six times. Radiotherapy was given to the pelvis with a four-field box technique for five days each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of three patients were enrolled at each level and three further patients were included if one or two dose-limiting severe adverse events (SAE) were recorded. SAE was defined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomiting and alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (> 1 week) neutropenia or thrombocytopenia. Four levels were studied (paclitaxel 40, 45, 50, 55 mg/m2) with three, five, four and six patients enrolled, respectively. The MTD of paclitaxel was found at 50 mg/m2/wk and cisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity. Thirteen patients were evaluable for response: seven complete and five partial responses were obtained with an overall response rate of 92.3%. The MTD of paclitaxel is 50 mg/m2/wk when associated to cisplatin 30 mg/m2/wk and concurrent pelvic radiotherapy. Diarrhea is the dose limiting side effect. Preliminary data suggest that concurrent chemoradiotherapy with paclitaxel and cisplatin could be a very active treatment for patients with locally advanced carcinoma of the cervix.

A phase I trial of 96-hour padlitaxel infusion plus accelerated radiotherapy of unrespectable head and neck cancer

Purpose: To determine the maximum tolerated dose (MTD) of paclitaxel given as a 96-hour continuous infusion during Weeks 1 and 5 of an accelerated radiotherapy schedule for the definitive treatment of advanced (nonmetastatic) unresectable squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials: Thirteen patients with Stage IV SCCHN were enrolled. Radiotherapy consisted of 70–72 Gy over 6 weeks, with a fractionation scheme of 2 Gy q.d. for 4 weeks followed by 1.6 Gy b.i.d. for 2 weeks, with no planned interruptions. Paclitaxel was administered over a 96-hour continuous infusion during Weeks 1 and 5 of radiotherapy at the following dose levels: Dose Level 1: 40 mg/m 2/96-hours (3 patients); Dose Level 2: 80 mg/m 2/96-hrs (5 patients); Dose Level 3: 120 mg/m 2/96-hours (2 patients); and Dose Level 2A: 100 mg/m 2/96-hours (3 patients). Results: The MTD of Paclitaxel was 100 mg/m 2/96-hours. All but one patient (who experienced progressive disease after receiving 61 Gy and both cycles of paclitaxel) completed therapy as planned. Dose-limiting toxicity occurred in both patients enrolled at Dose Level 3, with one patient experiencing Grade 4 diffuse moist desquamation and the other patient experiencing Grade 4 mucositis and febrile neutropenia. Thus, Dose Level 2A was opened and no dose limiting toxicity was noted. Grade 3 non-dose limiting mucositis and dermatitis occurred at all paclitaxel dose levels. There were no treatment-related deaths. All Grade 3 and 4 toxicities were reversible. Complete responses were seen in 8 of 13 patients, 4 patients achieved partial responses, and 1 patient had no response/progressive disease. Conclusions: Infusional paclitaxel over 96 hours during Weeks 1 and 5 of this accelerated radiotherapy schedule is feasible. The MTD of paclitaxel in this protocol was 100 mg/m 2/96-hours. Dose-limiting toxicities were primarily enhanced epithelial reactions, but febrile neutropenia also occurred. All patients develop non-dose limiting Grade 3 skin and mucosal reactions, reflecting the high treatment intensity. This regimen merits further investigation.

A phase I study of paclitaxel in combination with etoposide in patients with stage IIIB/IV non-small cell lung cancer (NSCLC)

Paclitaxel is a new antineoplastic agent with activity in lung cancer. This phase I clinical trial was designed to determine the maximum tolerated dose (MTD) of paclitaxel in combination with etoposide in previously untreated patients with non-small cell lung cancer (NSCLC). Doses of paclitaxel were in the range of 150–225 mg/m 2 (d1) and of etoposide in the range of 100–120 mg/m 2 (d2–4). The drugs were administered by i.v. infusion over 3 h (paclitaxel) and 2 h (etoposide). The patients received four courses at 21-day intervals. Twenty-four patients (six female, 18 male) entered the trial. The characteristics of the patients were as follows: median age 64 (55–73) years; Karnofsky index 80% (70–90%); stage IIIB n=7, IV n=17; histology, 14 adenocarcinoma, 10 squamous carcinoma. Hypersensitivity reactions after paclitaxel were not observed. The most relevant toxic effect observed was neutropenia (WHO grade 3–4). Three episodes of febrile neutropenia, two episodes of absolute neutropenia (<100/ μl for >3 days), and one case of mucositis (WHO grade ≥3 for >7 days) occurred. It can be concluded that the MTD of paclitaxel in combination with etoposide was reached at doses of 200 mg/m 2 paclitaxel (d1) and 100 mg/m 2 etoposide (d2–4).

Phase I study of paclitaxel and topotecan in patients with advanced tumors: a cancer and leukemia group B study.

To define the dose-limiting toxicities (DLTs) and the recommended phase II doses of paclitaxel combined with topotecan, without and with filgrastim support. Patients with advanced solid tumors and a maximum of one prior chemotherapy regimen for metastatic disease were eligible if they had a performance status of 0 to 1 and normal renal, hepatic, and bone marrow function. Prior treatment with taxanes or comptothecin analogs, and prior pelvic irradiation were not allowed. Patients with a history of cardiac disease or on medications known to affect cardiac conduction were excluded. The dose of topotecan was fixed at 1.0 mg/m2/d for 5 days. The dose of paclitaxel was escalated until the maximum-tolerated dose (MTD), without and with filgrastim 5 micrograms/kg subcutaneously (SC) on days 6 to 14, was reached. Paclitaxel was administered over 3 hours on day 1 before topotecan. Treatment cycles were repeated every 21 days. Of 46 patients entered, 45 were assessable for toxicity and 34 for response. The principal toxicity was neutropenia. Without filgrastim, the MTD of paclitaxel was 80 mg/m2 on day 1 in combination with topotecan 1.0 mg/m2/d for 5 days. With filgrastim, the dose of paclitaxel was escalated to 230 mg/m2 in combination with the same dose of topotecan. At this dose level, one patient had hematologic DLT and a second patient developed neuromuscular DLT. Three patients had a partial response (PR): one with head and neck cancer, a second with non-small-cell lung cancer, and the third with colon cancer. We conclude that paclitaxel can be given at clinically relevant doses in combination with topotecan and filgrastim. The recommended dose for phase II studies is paclitaxel 230 mg/m2 on day 1 and topotecan 1.0 mg/m2/day for 5 days with filgrastim 5 micrograms/kg on days 6 to 14.

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.