Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Can mass media campaigns change antimicrobial prescribing? A regional evaluation study.

BACKGROUND: Antimicrobial drug resistance is a significant cause of avoidable morbidity and mortality. Inappropriate prescribing of antimicrobials is acknowledged as a key determinant of this phenomenon. Many approaches are advocated for reducing this inappropriate prescribing, including regulatory, professional and educational interventions. Mass media campaigns are often suggested as a useful tool in managing public expectations, but the evidence to support this is weak, as no controlled studies of such campaigns exist. Evaluating such campaigns is problematic, and uncontrolled observations are misleading. We report here the first controlled study of such an intervention in the use of antimicrobials. METHODS: Two sequential mass media campaigns, providing information on the appropriate use of antimicrobials, were conducted during early 2004 and 2005 in the North East of England. These messages were articulated in the campaign by the cartoon character 'Moxy Malone'. The campaigns were supported by printed materials, and in parts of this area, with professional education and prescribing support. A retrospective controlled before-after study was conducted, examining the effects on observed prescribing of antimicrobials for the populations covered by these two cycles of mass media campaigns. These populations were controlled with matched populations in the North of England. The primary outcome examined was prescribing rates (items) for all microbial agents for these populations, corrected for population structure (STAR-PU). A repeated measures analysis of variance (ANOVA) was used to analyse factors that had a possible effect on the prescribing of antibacterial drugs. This was supported by a survey of primary care organizations (PCOs) of all interventions undertaken around antimicrobial use in the intervention and comparison populations. RESULTS: In this retrospective study, there was incomplete reporting of adjuvant interventions undertaken by the PCOs intervention and comparison areas, so isolating the intervention, and attributing cause and effect is difficult. In this pragmatic evaluation the campaign was found to significantly reduce the volume of antibacterial drugs during the winter months of the intervention years. There were 21.7 fewer items prescribed per 1000 population (P < 0.0005), for the intervention populations over these winter months, equivalent to a 5.8% absolute reduction in prescribing. CONCLUSIONS: Mass media campaigns have a role in changing antimicrobial prescribing practice.

Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer.

BACKGROUND: Lymph node metastases are the most significant prognostic factor in localized non-small cell lung cancer (NSCLC). Nodal micrometastases may not be detected. Identification of the first nodal drainage site (sentinel node) may improve detection of metastatic nodes. We performed intraoperative Technetium 99m sentinel lymph node (SN) mapping in patients with resectable NSCLC. METHODS: Fifty-two patients (31 men, 21 women) with resectable suspected NSCLC were enrolled. At thoracotomy, the primary tumor was injected with 2 mCi Tc-99. After dissection, scintographic readings of both the primary tumor and lymph nodes were obtained with a handheld gamma counter. Resection with mediastinal node dissection was performed and findings were correlated with histologic examination. RESULTS: Seven of the 52 patients did not have NSCLC (5 benign lesions, and 2 metastatic tumors) and were excluded. Forty-five patients had NSCLC completely resected. Mean time from injection of the radionucleide to identification of sentinel nodes was 63 minutes (range 23 to 170). Thirty-seven patients (82%) had a SN identified; 12 (32%) had metastatic disease. 35 of the 37 SNs (94%) were classified as true positive with no metastases found in other intrathoracic lymph nodes without concurrent SN involvement. Two inaccurately identified SNs were encountered (5%). SNs were mediastinal (N2) in 8 patients (22%). CONCLUSIONS: Intraoperative SN mapping with Tc-99 is an accurate way to identify the first site of potential nodal metastases of NSCLC. This method may improve the precision of pathologic staging and limit the need for mediastinal node dissection in selected patients.

Sex-associated differences in survival of patients undergoing resection for lung cancer.

BACKGROUND: The increasing incidence of lung cancer among women prompted us to assess whether sex-associated differences exist in the presentation and survival of patients who undergo major lung resection for lung cancer. METHODS: We performed a retrospective review of patients who had major lung resection for lung cancer from January 1980 to June 1998. RESULTS: There were 265 men and 186 women. Women were younger (60.7+/-0.8 versus 63.6+/-0.6 years; p = 0.005). Adenocarcinoma was more common among women (48% versus 40%; p = 0.001). Pathologic stages for men were: I = 43%, II = 26%, IIIA = 25%, IIIB or IV = 6%, and for women: I = 52%, II = 20%, IIIA = 22%, IIIB or IV = 6% (p = 0.146). Median survival was better for women (41.8 versus 26.9 months; p = 0.006). This was due both to a difference in stage at presentation and to a better median survival rate for adenocarcinoma compared with squamous cell cancer. The data suggest an association between sex and survival, although this failed to reach statistical significance. Sex influenced survival with a relative risk for women of 0.67 (95% confidence interval 0.35 to 1.29; p = 0.231 adjusted for stage, cell type, age, and spirometry). CONCLUSIONS: There are sex-associated differences in the presentation and possibly in the survival of patients with lung cancer. This finding has possible implications regarding the selection of patients for therapy and for the design of randomized therapeutic trials.

Gemcitabine and carboplatin in advanced non small-cell lung cancer: a review.

Both gemcitabine and carboplatin have demonstrated activity in advanced non small-cell lung cancer. The combination of gemcitabine and cisplatin has demonstrated equivalent or superior efficacy to other commonly used agents and two-drug combinations, and a recent Eastern Cooperative Oncology Group trial suggested that this regimen may have a slight advantage over other regimens in time to progression. The substitution of carboplatin for cisplatin offers the opportunity for a more well-tolerated regimen, and the combination of gemcitabine with carboplatin has now been studied in various clinical phase I and II trials. The administration of gemcitabine on a day-1-and-8 regimen with carboplatin appears to have a more favorable toxicity profile, especially with regard to platelet toxicity. Therefore, a number of ongoing trials, both phase II and phase III, are investigating the activity of this combination in locally advanced and metastatic non small-cell lung cancer. These trials will help define the role of this active and well-tolerated new regimen and, ultimately, its ability to be incorporated into multimodality therapy as well as with the new biologic agents for the treatment of non small-cell lung cancer.

A phase II study of 9-aminocamptothecin in advanced non-small-cell lung cancer.

BACKGROUND: 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 micrograms/m2/day x 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia. PATIENTS AND METHODS: Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 micrograms/m2/d x 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 micrograms/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression. RESULTS: Fifty-eight patients were treated, thirteen at 1416 micrograms/m2/d and 45 at 1100 micrograms/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9-28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%-19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 micrograms/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 micrograms/m2/d these toxicities were observed in 12 and three of 45 patients, respectively. CONCLUSION: 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer.

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies.

PURPOSE: The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS: Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS: Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION: Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

A review of ifosfamide and vinorelbine in advanced non-small cell carcinoma of the lung.

Ifosfamide and vinorelbine have demonstrated single-agent activity against advanced non-small cell lung cancer. The dose-limiting toxicity of each agent is myelosuppression. Several trials have studied this combination to determine its toxicity and efficacy in non-small cell lung cancer. We conducted a dose-escalation study of vinorelbine in a novel (daily x 3) schedule with ifosfamide and granulocyte colony-stimulating factor support to define the dose-limiting toxicities and maximum tolerated dose of vinorelbine in this combination. Other investigators have studied this combination in the phase II setting. In our phase I study involving 42 patients, the recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2, each given on 3 consecutive days, followed by granulocyte colony-stimulating factor. The overall response rate was 40%, with a median survival of 50 weeks. Myelosuppression proved to be dose limiting for this regimen, without other major toxicities. Other groups have studied the ifosfamide/vinorelbine combination, and studies adding cisplatin to this regimen have been conducted as well. Given the tolerable toxicity and encouraging response rates and 1-year survival rate seen with this regimen, further investigation of the ifosfamide/vinorelbine regimen has continued in a phase II Cancer and Leukemia Group B trial. Further study of the potential application of the combination as induction therapy for stage III disease is warranted.

Ifosfamide-based three-drug combination regimens in non-small cell lung cancer.

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has expanded in recent years, resulting in increased median survival and higher 5-year survival rates in some studies. Few patients with NSCLC can be cured, however, and the median survival time is still modest. Research strategies are aimed at identifying new active single agents, testing their combination in non-cisplatin- and non-carboplatin-containing regimens, and their incorporation into regimens containing more than two drugs, in efforts to improve response and survival and/or reduce toxicity. Several trials of triplet chemotherapy combinations for the treatment of NSCLC have been conducted at the University of Chicago. The three-drug regimen of vinorelbine, paclitaxel, and ifosfamide with granulocyte colony-stimulating factor was evaluated in a phase I trial. Doses of all three drugs were reduced from their standard doses so that toxicity would be manageable, although toxicity was still high. The low response rate (<20%) at the recommended phase II doses led to early closure of this trial. The University of Chicago is also assessing the three-drug combination of carboplatin, paclitaxel, and ifosfamide in patients with stage IIIB and IV NSCLC. The carboplatin and paclitaxel doses are being maintained within their active single-agent range, with the goal of identifying the maximum tolerated dose of ifosfamide when added to this combination. Additional end points include response rates, survival time, and dose-limiting toxicities. This study is ongoing.

Phase I study of docetaxel with concomitant thoracic radiation therapy.

PURPOSE: The taxanes have demonstrated activity as radiation sensitizers in preclinical studies. This study was designed to determine the maximum-tolerated dose (MTD), optimal schedule, and toxicities of docetaxel in combination with concomitant standard chest radiotherapy. PATIENTS AND METHODS: Twenty-nine patients with advanced non-small-cell lung or esophageal cancer enrolled in this phase I study to evaluate escalating docetaxel doses at three schedules. Docetaxel was administered as two 21-day cycles at doses of 40, 60, and 75 mg/m2 per cycle. Docetaxel administration schedules were as follows: schedule A, once every 3 weeks; schedule B, 2 of 3 weeks; or schedule C, weekly. Six weeks of concomitant standard chest radiotherapy in 1.8- to 2.0-Gy daily fractions was delivered to 60 Gy total. RESULTS: Dose-limiting esophagitis and neutropenia were encountered with schedules A and B at docetaxel doses of 60 mg/m2 per cycle. The docetaxel MTD for schedules A and B was 40 mg/m2 per cycle. Dose-limiting esophagitis was also observed with schedule C; however, there was no neutropenia. For schedule C, we identified the MTD as 60 mg/m2 per cycle (20 mg/m2/wk). Other toxicities encountered included thrombocytopenia, hypersensitivity reaction, and pulmonary infiltrates (fatal in two patients). Late toxicity of esophageal stricture occurred in five patients. CONCLUSION: Esophagitis and neutropenia are the dose-limiting toxicities of docetaxel administered with concomitant chest radiotherapy. Weekly administration of docetaxel allows for the highest total docetaxel dose during chest radiotherapy. We identified the recommended phase II docetaxel dose as 20 mg/m2 administered weekly with concomitant chest radiotherapy for 6 weeks.

Clinical studies of docetaxel (Taxotere) and concomitant chest therapy.

The administration of concomitant chemoradiotherapy has been shown to increase local and regional control of non-small cell lung cancer. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) has single-agent activity in non-small cell lung cancer, as well as radiation-enhancing potential in preclinical studies. Therefore, its investigation with concomitant radiotherapy in the clinical setting is justified. Since the clinical interactions of docetaxel and concomitant chest radiotherapy have not been previously described, we initiated a phase I study with the goal of determining the maximum tolerated dose of docetaxel and the optimal schedule for its administration during a standard course of radiation therapy to the chest, in addition to defining the dose-limiting toxicities of this regimen. This report describes the design and preliminary results of this study.

Phase I study of vinorelbine and ifosfamide in advanced non-small-cell lung cancer.

PURPOSE: We designed a phase I dose-escalation study of vinorelbine on a novel (daily-times-three) schedule with ifosfamide with granulocyte colony-stimulating factor (G-CSF) support to define the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of vinorelbine in this combination. PATIENTS AND METHODS: Cohorts of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) and no prior chemotherapy received vinorelbine starting at 15 mg/m2 on days 1, 2, and 3, and ifosfamide starting at 2.0 g/m2 on days 1, 2, and 3 with G-CSF support for all patients. Cycles were repeated every 21 days. Plasma vinorelbine concentrations were also analyzed. RESULTS: Forty-two patients were treated. The median age was 58 years (range, 34 to 75) and 41 had a performance status of 0 or 1. The DLT was neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days. The recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2 both given on 3 consecutive days. The overall response rate was 40% (17 of 42; all partial responders). The median survival duration was 50 weeks, with a 1-year survival rate of 48%. Pharmacokinetic analysis showed that vinorelbine in this combination and on this schedule is cleared 1.5 to two times faster than in single-agent once-weekly studies. CONCLUSION: Myelosuppression is the DLT of this regimen with no major subjective toxicities. With tolerable toxicity and an encouraging 1-year survival rate of 48%, further investigation of this new vinorelbine schedule is warranted in this and other combination regimens.

Ifosfamide-based chemotherapy for non-small cell lung cancer: phase I/II studies at the University of Chicago.

Current clinical investigations in the palliative care setting for patients with non-small cell lung cancer are focused on new drugs and combinations. The goal of these studies is to identify more effective and/or less toxic therapy. At the University of Chicago, we have conducted phase I and II studies to integrate new single agents into novel combination chemotherapy regimens. Two such studies have combined the use of ifosfamide with either vinorelbine or paclitaxel. All these drugs have established single-agent activity in non-small cell lung cancer and a favorable toxicity spectrum. We describe the study rationale and design, and the preliminary data of these trials.

Ifosfamide-based combination chemotherapy in advanced non-small cell lung cancer: two phase I studies.

Two studies were performed to determine the maximum tolerated dose (MTD) of paclitaxel and vinorelbine, respectively, in combination with a fixed dose of ifosfamide in previously untreated patients with stage IIIB or IV non-small cell lung cancer. Response rate and survival were also assessed. Both regimens were given with mesna and granulocyte colony-stimulating factor support. The maximum tolerated dose of paclitaxel in combination with 1.6 g/m2/d X 3 ifosfamide was 300 mg/m2, and the recommended dose for phase II study is 250 mg/m2. Among 31 patients treated with ifosfamide/paclitaxel, there were seven partial responses; additionally, 10 patients had either minor regression or stable disease. The maximum tolerated dose of vinorelbine in combination with 1.6 g/m2/d X 3 ifosfamide was 35 mg/m2/d X 3, and the recommended dose for phase II study is 30 mg/m2/d X 3. Among 42 patients treated with ifosfamide/vinorelbine, responses have been encouraging, and final analysis is pending. The dose-limiting toxicity for both regimens was neutropenia. These findings indicate that ifosfamide-containing combination chemotherapy regimens have activity in advanced non-small cell lung cancer and are well tolerated when administered with granulocyte colony-stimulating factor.

Preliminary report on a phase I study of ifosfamide and vinorelbine (navelbine) in advanced non-small cell lung cancer.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid, and ifosfamide have each shown activity as a single agent and in various combination-chemotherapy regimens against non-small cell lung cancer. Vinorelbine usually has been given on a once-weekly schedule. We designed a phase I study adding escalating doses of vinorelbine on a novel schedule of 3 consecutive days to ifosfamide in a dose-intensive regimen with granulocyte colony-stimulating factor. The goals were to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine and to document the toxicity profile and the overall response and survival rates observed. Eligibility criteria included histologically or cytologically documented stage IIIB or stage IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 15 mg/m2) on days 1, 2, and 3 and ifosfamide at 2 g/m2 and decreased to 1.6 g/m2 on days 1, 2, and 3. Granulocyte colony-stimulating factor was administered subcutaneously at 5 micrograms/kg on days 5 through 11 in all patients. Cycles were repeated every 21 days. Forty-two patients were treated. The median age was 58 years (age range, 34 to 75 years); 41 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in two of three patients at the initial dose level of ifosfamide 2 g/m2 and vinorelbine 15 mg/m2. Ifosfamide was therefore decreased to 1.6 g/m2, and vinorelbine was subsequently escalated, with a maximum administered dose of 35 mg/m2. The recommended phase II dose was ifosfamide 1.6 g/m2 on days 1, 2, and 3 with vinorelbine 30 mg/m2 on days 1, 2, and 3, given with granulocyte colony-stimulating factor support, on a 21-day cycle. At the recommended phase II dose myelosuppression remained the most common toxic effect, with grade 3 or 4 neutropenia of brief duration occurring in 20 patients. Final analysis has not yet been completed, but responses have been observed at several dose levels. The maximum tolerated dose of vinorelbine given on days 1, 2, and 3 is 30 mg/m2 when given with ifosfamide at 1.6 g/m2 on days 1, 2, and 3 and granulocyte colony-stimulating factor support. Myelosuppression is the dose-limiting toxic effect. Future analyses of the data will report the overall response and survival rates in these patients.

Vinorelbine (Navelbine), cisplatin, and concomitant radiation therapy for advanced malignancies of the chest: a Phase I study.

Most patients with advanced solid tumors of the chest will have local and/or distant disease progression despite standard therapy. Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France) is a new semisynthetic vinca alkaloid with single-agent activity in lung cancer that recently also has been shown to act as a radiosensitizer in vitro. This study aims to define the maximum tolerated dose and dose-limiting toxicity when vinorelbine is given with cisplatin and concomitant radiation therapy. To date, 25 patients with advanced malignancies of the chest have been treated in a dose-escalation trial of vinorelbine administered once weekly with cisplatin (100 mg/m2 every 21 days) and concomitant thoracic radiation therapy (2 Gy/d x 30 fractions for 60 Gy). Vinorelbine was initially given at 20 and 25 mg/m2/wk. Acute dose-limiting toxicity was myelosuppression, which was seen at a vinorelbine dose of 25/mg/m2/wk, with grade 4 neutropenia in two of three patients and one treatment-related death from neutropenic sepsis. At vinorelbine 20/mg/m2/wk, no acute dose-limiting toxicity was seen, but grade 3 or 4 esophagitis developed in three of six patients near the end or after completion of radiation therapy. We subsequently decreased the administration of vinorelbine to weeks 1, 2, 4, and 5. Tolerance appears to be greater with this schedule; however, severe or life-threatening esophagitis at the completion of therapy continues to be observed. Given these preliminary results, it appears feasible to treat patients with advanced chest malignancies with concomitant cisplatin, vinorelbine, and radiation therapy. The significant dose reduction of vinorelbine that is necessary with concomitant radiation therapy provides the first in vivo evidence of a strong radiosensitizing effect of vinorelbine. The schedule is currently being modified to reduce the incidence of esophagitis.

Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: a phase I study.

BACKGROUND: Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer. We have performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the dose-limiting toxicities of the combination at the recommended phase II dose of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recommended phase II dose. PATIENTS AND METHODS: Thirty-one patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m2 i.v. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administered as a 24-hour infusion at dose levels of 135, 170, 200, 250, and 300 mg/m2; six patients were treated with a one-hour infusion, at a dose of 250 mg/m2. G-CSF, 5 micrograms/kg, was administered subcutaneously on days 4 through 10, or until the absolute neutrophil count exceeded 4000/microliters. Cycles were repeated every 21 days. RESULTS: The dose-limiting toxicity was granulocytopenia, which increased with increasing dose levels of paclitaxel. The MTD was 300 mg/m2 of paclitaxel, and the recommended phase II dose 250 mg/m2 administered as a 24-hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%), all in the 18 patients who received dose levels of 250 mg/m2 or higher. CONCLUSIONS: Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase II study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survival.

A phase I-phase II study of vinorelbine with cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer.

PURPOSE: The combination of cisplatin, 5-fluorouracil, and leucovorin (PFL) has been reported to have a 29% response rate in advanced non-small cell lung cancer. Vinorelbine, a semi-synthetic vinca alkaloid, has also been reported to have single-agent activity in this disease. We designed a phase I-II study in which escalating doses of vinorelbine were added to PFL to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine, and to determine the response rate and survival at the recommended phase II dose. PATIENTS AND METHODS: This study enrolled patients between December 1991 and August 1993. Eligibility criteria included histologically or cytologically documented stage III or IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 20 mg/m2) on days 1 and 6, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil as a continuous infusion at 800 mg/m2/day for 4 days (days 2-5) with leucovorin 100 mg orally every 4 hours on days 1 through 5. Cycles were repeated every 21 days. RESULTS: Forty patients were treated during the study. The median age of the patients was 58 (range, 33-75) and 36 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in both patients treated with vinorelbine at 25 mg/m2. At the recommended phase II vinorelbine dose of 20 mg/m2 on days 1 and 6, myelosuppression remained the most common toxicity, with 22 patients (55%) having grade 4 neutropenia. Fifteen patients (38%) required hospital admission for neutropenic fever; two died of neutropenic sepsis. Of 33 patients evaluated, 2 patients achieved a complete response and 10 patients achieved a partial response (overall response rate, 30%; 36% of the evaluated patients). Median survival was 10.4 months for the entire cohort (16.4 months for those with stage III disease and 9.6 months for patients with stage IV disease) and 1-year survival was 45%. The overall median time to progression was 8.1 months. CONCLUSIONS: The maximum tolerated dose of vinorelbine given on days 1 and 6 with PFL is 20 mg/m2; myelosuppression is the dose-limited factor. The response rate is similar to rates observed in prior studies of combination chemotherapy, but the median survival of patients with stage IV disease exceeds that of many other regimens.

Paclitaxel and ifosfamide: a multicenter phase I study in advanced non-small cell lung cancer.

Both paclitaxel and ifosfamide have significant single-agent activity in non-small cell lung cancer. We designed a phase I study combining escalating doses of paclitaxel, administered by 24-hour infusion, with ifosfamide given at a dose of 1.6 g/m2 daily x 3. Paclitaxel dose levels were 135, 170, 200, 250, and 300 mg/m2. The goal of the study was to determine the maximum tolerated dose and dose-limiting toxicities of paclitaxel when used in this combination. Dose escalation was possible because of the use of filgrastim, a granulocyte colony-stimulating factor. Twenty-five patients at three institutions were treated. The dose-limiting toxicity of the combination was granulocytopenia, with other toxicities being generally mild to moderate. The maximum tolerated dose of paclitaxel was 300 mg/m2, and the recommended phase II dose is 250 mg/m2. There was a suggestion of a dose-response curve with paclitaxel as all three partial responses were seen at the 250 mg/m2 dose level. An additional II patients had objective regression or stable disease lasting for 9 to 30 weeks. A phase II study of this combination is currently being planned by the Cancer and Leukemia Group B.