Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.

BACKGROUND: R115777 (tipifarnib, Zarnestra) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment. RESULTS: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1-2 and included nausea (64%) and fatigue (60%). Grade 3-4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6-4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response. CONCLUSIONS: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Phase I trial of outpatient weekly docetaxel, carboplatin and concurrent thoracic radiation therapy for stage III unresectable non-small-cell lung cancer: a Vanderbilt cancer center affiliate network (VCCAN) trial.

PURPOSE: Docetaxel, an active agent for non-small cell lung cancer (NSCLC), has demonstrated activity as a radiosensitizer in numerous pre-clinical studies. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly Docetaxel, Carboplatin with concurrent thoracic radiation therapy (TRT) in patients with unresectable stage III NSCLC. PATIENTS AND METHODS: In this phase I clinical trial, Docetaxel was administered weekly as a 1-h intravenous infusion for 6 weeks with a starting dose of 20 mg/m(2). Docetaxel doses were escalated by 10 mg/m(2) increments in successive cohorts of three patients. DLT was defined as grade >or=3 nonhematologic and hematologic toxicity according to RTOG toxicity criteria. Once the DLT of Docetaxel alone was reached, weekly Carboplatin (AUC 2) was added at a DLT-2 dose of Docetaxel (two dose levels below that of dose limiting toxicity). Docetaxel doses were again escalated at 10 mg/m(2) increments in successive cohorts of three new patients to define further DLT and MTD of Docetaxel/Carboplatin with TRT. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Fifteen patients were entered onto this study with Docetaxel alone through three dose escalations (from 20 to 40 mg/m(2) weekly). The DLT of weekly Docetaxel/TRT was esophagitis and the MTD was 30 mg/m(2) per week for 6 weeks. Nine more patients were added with the Docetaxel/Carboplatin/TRT regimen. The DLT of weekly Docetaxel/Carboplatin with TRT was esophagitis and the MTD of Docetaxel was 20 mg/m(2) per week with weekly Carboplatin (AUC 2). There were 2 complete responses and 13 partial responses in 25 evaluable patients (RR 60%). CONCLUSIONS: This combination regimen has activity with manageable toxicity in patients with stage III NSCLC. A phase II study is planned to define activity.

A phase II trial of 6-hydroxymethylacylfulvene (MGI-114, irofulven) in patients with advanced non-small cell cancer previously treated with chemotherapy.

PURPOSE: To test the efficacy and safety of the novel antitumor agent MGI-114 (NSC 683863) in patients with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. METHODS: A two-stage accrual design was used to ensure detection of a true response rate of at least 20% with a type I error of .04. Eligible patients received 11 mg/m2 daily for five consecutive days. Cycles were repeated every 28 days. RESULTS: Fifteen patients received a total of 34 cycles of MGI-114. All patients had a performance status of 0 or 1. Eleven patients had previously received carboplatin and paclitaxel +/- radiation. Two patients had received cisplatin and CPT-11, one patient had received weekly paclitaxel, and one patient had received carboplatin and docetaxel. None of the first 15 patients enrolled experienced objective tumor response, and the study was closed. Forty percent of patients developed > or = grade 2 thrombocytopenia. Grade 3 nausea and > or = grade 2 vomiting were observed in 40% and 47% of patients respectively. Thirty-three percent of patients experienced > or = grade 2 fatigue. CONCLUSIONS: MGI-114, at this dose and schedule, does not have significant activity as second line therapy for patients with advanced NSCLC.

Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group.

PURPOSE: To determine the efficacy of topotecan in combination with standard chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer (SCLC), the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial. PATIENTS AND METHODS: Eligible patients had measurable or assessable disease and an ECOG performance status of 0 to 2; stable brain metastases were allowed. All patients received four cycles of cisplatin and etoposide every 3 weeks (step 1; PE). Patients with stable or responding disease were then randomized to observation or four cycles of topotecan (1.5 mg/m(2)/d for 5 days, every 3 weeks; step 2). A total of 402 eligible patients were registered to step 1, and 223 eligible patients were registered to step 2 (observation, n = 111; topotecan, n = 112). RESULTS: Complete and partial response rates to induction PE were 3% and 32%, respectively. A 7% response rate was observed with topotecan (complete response, 2%; partial response, 5%). The median survival time for all 402 eligible patients was 9.6 months. Progression-free survival (PFS) from date of randomization on step 2 was significantly better with topotecan compared with observation (3.6 months v 2.3 months; P <.001). However, overall survival from date of randomization on step 2 was not significantly different between the observation and topotecan arms (8.9 months v 9.3 months; P =.43). Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2. Grade 4/5 infection was observed in 4.6% of PE patients and 1.8% of topotecan patients. Grade 3/4 anemia developed in 22% of patients who received topotecan. No difference in quality of life between topotecan and observation was observed at any assessment time or for any of the subscale scores. CONCLUSION: Four cycles of PE induction therapy followed by four cycles of topotecan improved PFS but failed to improve overall survival or quality of life in extensive-stage SCLC. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC patients with good performance status.

Weekly irinotecan and cisplatin in advanced non-small cell lung cancer: a multicenter phase II study.

The combination of weekly irinotecan (CPT-11) and monthly cisplatin has shown promising activity in advanced non-small cell lung cancer (NSCLC) in previous Phase I and II studies. However, same-day administration of these agents may better exploit their therapeutic synergy and minimize toxicities. This multicenter Phase II study was undertaken to evaluate the efficacy and safety of a combination of weekly CPT-11 and weekly cisplatin in patients with advanced NSCLC. Patients with chemotherapy-naive stage IIIB or IV NSCLC were treated with repeated cycles of therapy comprising weekly treatment with both cisplatin and CPT-11 for 4 weeks, followed by a 2-week rest. The starting doses of CPT-11 and cisplatin were 65 and 30 mg/m2, respectively. Treatment was continued until the occurrence of disease progression, unacceptable toxicity, or a maximum of six cycles. Fifty patients were enrolled. The median age was 59 years (range, 44-79 years). Eastern Cooperative Oncology Group performance status was 0 in 22 patients, 1 in 19 patients, and 2 in 9 patients. Seven and 43 patients had stages IIIB and IV disease, respectively. Five patients had brain metastasis. Patients received a median of three 6-week cycles (range, 1-6). The objective response rate was 36% (18 of 50; 95% confidence interval, 24-54%) and included 18 partial responses. Median time to tumor progression was 6.9 months (range, 0.6-15.2). The median survival was 11.6 months (range, 0.16-21.9 months), and the 1-year survival rate was 46%. Grade 3/4 nonhematological toxicities included vomiting (12%) and diarrhea (26%). Grade 3/4 hematological toxicities included anemia (14%), neutropenia (26%), and thrombocytopenia (14%). Relative dose intensities for CPT-11 and cisplatin were 89 and 62%, respectively. Weekly combined administration of CPT-11 and cisplatin achieved a promising overall response rate, median time to tumor progression, and median survival in patients with stage IIIB/IV NSCLC. The regimen was well tolerated, and the planned dose intensity was well maintained. Further evaluation of this combination in NSCLC is warranted.

Weekly irinotecan and concurrent radiation therapy for stage III unresectable NSCLC.

In preclinical studies, the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) has demonstrated activity as a radiosensitizer, probably due to its ability to inhibit potentially lethal radiation damage repair. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly irinotecan with concurrent thoracic radiation therapy for patients with unresectable stage III non-small-cell lung cancer. For this study, 13 patients received three dose escalations (from 30 to 40 to 50 mg/m2/wk). At the first dose level, one patient developed grade 5 esophagitis. Accrual was expanded to seven patients. None of the remaining six patients developed esophagitis. At the second dose level (40 mg/m2/wk), the worst toxicity, which developed in one patient, was grade 2 esophagitis. At the third dose level (50 mg/m2/wk), two of three patients developed grade 4 nausea and vomiting; grade 3 or 4 esophagitis also occurred in two patients. Of the 12 evaluable patients, seven achieved a partial response, for an overall response rate of 58%. In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m2 weekly for 6 weeks. To confirm the MTD of this combination, this study is still open to accrual at the second dose level (40 mg/m2) in combination with carboplatin.

A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study).

PURPOSE: We conducted a prospective phase II study to determine the response rate, toxicity, and survival rate of concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel/carboplatin/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer (NSCLC). The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. METHODS AND MATERIALS: Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). RESULTS: Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. CONCLUSIONS: Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study.

A phase I trial of outpatient weekly docetaxel and concurrent radiation therapy for stage III unresectable non small-cell lung cancer: a Vanderbilt Cancer Center Affiliate Network (VCCAN) Trial.

Docetaxel has demonstrated activity as a radiosensitizer in numerous preclinical studies, probably due to its role as a cell cycle synchronizer for the G2/M radiosensitive phase of the cell cycle. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of docetaxel with concurrent thoracic radiation therapy (TRT) to patients with unresectable stage III non small-cell lung cancer (NSCLC). Fifteen patients were entered into this study. Docetaxel was administered as a 1-hour intravenous (I.V.) infusion, repeated every week for 6 weeks with starting dose of 20 mg/m2. Doses were escalated in 10 mg/m2 increments in successive cohorts of three new patients, if tolerated. Unacceptable toxicity was defined as grade = 3 nonhematologic or hematologic toxicity according to Eastern Cooperative Oncology Group (ECOG) toxicity criteria. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). At the first dose level (20 mg/m2/week), one patient developed grade 4 hyperglycemia and accrual was expanded to five patients. At the second level (30 mg/m2/week), two out of six patients developed grade 3 esophagitis. At the third level (40 mg/m2/week), two out of four patients developed grade 3 esophagitis and one patient developed grade 3 pulmonary toxicity. The weekly docetaxel MTD with concurrent radiation therapy (RT) was found to be 30 mg/m2. The DLT was esophagitis and pulmonary toxicity. Other toxicities encountered included skin reaction, nausea and vomiting, as well as diarrhea. Additionally, there were no treatment-related mortalities or late-occurring toxicities. Esophagitis was the principal DLT of concurrent weekly docetaxel and thoracic radiation in the outpatient setting. The MTD of concurrent weekly docetaxel with TRT is 30 mg/m2 weekly for 6 weeks. This study is still open to accrual with weekly docetaxel and TRT in locally advanced NSCLC patients.

Phase II study of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non-small-cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m(2)) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m(2)) after CPT-11 administration on day 1. RESULTS: Fifty-two patients were enrolled, including 33 men and 19 women. The median age was 61 years (range, 29 to 79 years). Southwest Oncology Group performance status was 0 in 12 patients, 1 in 32 patients, and 2 in eight patients. Eleven and 41 patients had stage IIIB and IV disease, respectively. Objective responses occurred in 28.8% of patients (15 of 52; 95% confidence interval, 16.5% to 41.2%). The median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%. Grade 3/4 adverse events consisted primarily of nausea (32. 7% ) or vomiting (13.5%), late-onset diarrhea (17.3%), and neutropenia (46.1%). The study design led to preferential modification of CPT-11 doses, resulting in CPT-11 dose attenuations to < or = 40 mg/m(2) in the majority of patients (31 of 52; 60%), whereas dose reductions of cisplatin were uncommon. CPT-11 pharmacokinetic parameters were comparable to those reported previously in single-agent studies. CONCLUSION: CPT-11/cisplatin is an active combination regimen with manageable toxicity in the therapy of stage IIIB/IV NSCLC. Future studies should be designed with schedules and dose modification provisions that avoid unnecessary CPT-11 dose reductions to exploit more directly the therapeutic synergy of these agents.

Concurrent paclitaxel, carboplatin, and radiation therapy for locally advanced non-small cell lung cancer.

Combination chemotherapy plus radiation therapy for non-small cell lung cancer has several theoretical advantages: the potential of chemotherapy to radiosensitize tumors, the possibility of improved local control due to combined treatment, and the opportunity for spatial cooperation, attacking disease both locally and systemically and thus potentially increasing response and, ultimately, survival. The combination of radiotherapy plus standard chemotherapy (etoposide plus cisplatin) has yielded limited success; therefore, new and novel chemotherapies have been sought. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the prototype of a novel class of drugs, the taxanes, has proven feasible both alone and with other agents in combined-modality regimens with radiation. Concurrent paclitaxel/carboplatin/radiotherapy appears to offer a relatively safe and more active regimen to control local and metastatic non-small cell lung cancer than the current standard. This report reviews the range of experience with paclitaxel-based combined-modality therapy.

A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma.

BACKGROUND: This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5-fluorouracil (5-FU)-based chemotherapy. METHODS: CPT-11 was given as a 90-minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicities between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age > or = 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS: CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicities. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.

Pharmacodynamic profile of prolonged etoposide administration in patients with small cell lung cancer and non-Hodgkin's lymphoma.

STUDY OBJECTIVE: To determine whether therapeutic drug monitoring can enhance administration of etoposide in patients with drug-responsive neoplasms. DESIGN: Prospective, open-label study. SETTING: University-affiliated hospital and cancer center. PATIENTS: Sixteen patients with small cell lung cancer or low-grade non-Hodgkin's lymphoma. INTERVENTIONS: Patients were treated with etoposide, 25 mg/m2/day over 24 hours by continuous infusion for 35 days. Peripheral blood samples were collected twice a week to measure etoposide levels. Plasma was separated, frozen and stored at -20 degrees C until assayed. MEASUREMENTS AND MAIN RESULTS: Steady-state plasma etoposide concentrations (ECpss) were determined and used to calculate total systemic clearance (Clsys). Despite differences in dosage and administration schedules, etoposide Clsys was similar to previous reports. In addition, a biexponential relationship between ECpss and absolute neutrophil count was demonstrated by nonlinear least squares estimation. Values generated from this equation indicated that ECpss above 1.5 microg/ml was strongly associated with grade III-IV leukocyte toxicity. Although less precise, there may also be a correlation between ECpss and antitumor activity. CONCLUSION: Based on these findings, we propose a pharmacodynamic construct that uses measurements of both pharmacokinetic (ECpss, Clsys) and pharmacodynamic (hematologic toxicity, tumor response) parameters for patients with etoposide-sensitive tumors. Therapeutic drug monitoring may be able to mitigate hematologic toxicity.

Docetaxel and cisplatin in patients with advanced non small-cell lung cancer (NSCLC): a multicenter phase II trial.

We examined the safety and efficacy of the docetaxel/cisplatin combination in patients with advanced, previously untreated NSCLC and evaluated changes in quality of life over time. Docetaxel was administered before cisplatin (both 75 mg/m2, 1-hour infusions) every 3 weeks to 47 patients with stage IIIB or stage IV NSCLC. Patients also received premedication of oral dexamethasone. The median age (range) of patients was 62 (45-78) years and 26 patients (55.3%) had adenocarcinoma. Of the 40 patients evaluable for response, one achieved a complete response and 14 had partial responses; the response rate was 37.5% (95% confidence intervals; 22.5, 52.5). In the intent-to-treat population the overall response rate was 31.9%. Time to response ranged from 3 to 20 weeks, and the median duration of response was 34.6 weeks. Median survival and median time to progression were 11.3 months and 18.9 weeks, respectively. One-year survival was 40%. Grade 3 or 4 neutropenia and febrile neutropenia were observed in 74.4% and 12.8% of patients, respectively. Severe asthenia was seen in 14.9% of patients. Other grade 3 or 4 toxicities included nausea (eight patients), vomiting (five), neurosensory effects (six), neuromotor effects (five), diarrhea (four), and infection (three). There was an improvement in emotional well-being; however, the overall quality of life score did not change with treatment. Docetaxel administered in combination with cisplatin is an active regimen in patients with NSCLC. This regimen of docetaxel (75 mg/m2) and cisplatin (75 mg/m2) repeated at 3-week intervals is being evaluated in an ongoing Eastern Cooperative Oncology Group (ECOG) randomized study in patients with advanced and metastatic NSCLC.

Biological and clinical correlates after chemotherapy and granulocyte colony-stimulating factor administration.

STUDY OBJECTIVE: To evaluate specific biological markers to improve understanding and use of granulocyte colony-stimulating factor (G-CSF) in patients receiving chemotherapy DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital and cancer center. PATIENTS: Twenty-five patients randomized to begin G-CSF either 24 hours after chemotherapy (standard arm), or on the day the absolute neutrophil count (ANC) was below 1000/mm3 after chemotherapy (delayed arm). INTERVENTIONS: To determine the effect of G-CSF on granulopoiesis, peripheral blood mononuclear cells were assayed by semisolid culture medium and flow cytometry for granulocyte progenitors and clonogenic CD34 antigen-positive cells. These biological markers were correlated with G-CSF administration schedules and the ANC. MEASUREMENTS AND MAIN RESULTS: The effect of timing of G-CSF administration on rate of neutrophil recovery, duration of neutropenia, length of G-CSF therapy, delays of chemotherapy cycles, and neutropenic fever events was evaluated. Regardless of G-CSF schedule or chemotherapy regimen, the appearance of mobilized hematopoietic progenitors begins at the neutrophil nadir and parallels granulocyte recovery. Our data also demonstrate that proper timing of G-CSF administration produces similar rates of neutrophil recovery and comparable clinical outcomes. CONCLUSION: Based on the correlation between biological markers and ANC, we propose that the postchemotherapy ANC is a surrogate marker of renewed granulopoietic activity. The relevance of this finding in relationship to the clinical application of G-CSF remains to be further defined.

Preliminary analysis of a phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small cell lung cancer.

We conducted a prospective phase II study to determine the response rate, toxicity profile, and survival rate among patients with locally advanced unresectable non-small cell lung cancer receiving concurrent weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), carboplatin, and hyperfractionated radiation therapy followed by two cycles of adjuvant paclitaxel and carboplatin. The weekly paclitaxel/carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. Thirty-two patients with unresectable stage IIIA and IIIB non-small cell lung cancer from Vanderbilt Cancer Center Affiliate Network institutions entered the study from June 1996 until February 1997. Weekly intravenous paclitaxel (50 mg/m2 over 1 hour) and weekly carboplatin (area under the concentration-time curve of 2) plus concurrent hyperfractionated chest radiotherapy (1.2 Gy twice daily [69.6 Gy total]) delivered for 6 weeks were followed by two cycles of paclitaxel (200 mg/m2) and carboplatin (area under the concentration-time curve of 6). Among 22 patients evaluable for response, one (4.5%) achieved a complete response and 16 (72.7%) achieved partial response, for an overall response rate of 77%. Among 23 patients evaluable for toxicity, esophagitis was the principal finding: grade 3 or 4 esophagitis occurred in eight patients (35%). Grade 3 and 4 pulmonary toxicities each occurred in 26% of patients. Thus, weekly paclitaxel/carboplatin plus concurrent hyperfractionated radiotherapy is a well-tolerated outpatient regimen with an encouraging response rate that is at least equivalent to more toxic chemoradiation regimens. These findings indicate that further clinical evaluation of weekly paclitaxel/carboplatin/hyperfractionated radiotherapy is warranted in phase III trials.

Paclitaxel by either 1-hour or 24-hour infusion in combination with carboplatin in advanced non-small cell lung cancer: preliminary results comparing sequential phase II trials.

Our group previously described the activity of carboplatin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (given as a 24-hour infusion) in 51 patients with advanced non-small cell lung cancer. To facilitate outpatient administration, the regimen was modified to infuse paclitaxel over 1 hour. Between February 1995 and August 1996, 63 patients with advanced non-small cell lung cancer were accrued by the Vanderbilt Cancer Center and its affiliate network. The first four patients received paclitaxel 175 mg/m2; all subsequent patients received paclitaxel 200 mg/m2. The carboplatin dose was determined using the Calvert formula, with a target area under the concentration-time curve of 6. Cycles were repeated every 4 weeks, to a maximum of six cycles. The median age of the patients was 62 years. There were 43 men and 20 women. Ten patients were stage IIIB and 53 were stage IV. Patients with Eastern Cooperative Oncology Group performance status < or =2 were enrolled. There were three complete remissions and 13 partial remissions, for an overall response rate of 25%. Median survival was 32 weeks. This compares with a response rate of 27% and a median survival of 38 weeks observed in our previous study, using 24-hour paclitaxel plus the same dose of carboplatin. Grade 3/4 leukopenia occurred in 47% versus 3% of treatment cycles in the 24-hour versus 1-hour patient groups, respectively. Febrile neutropenia was similar and occurred in 7% versus 4% of treatment cycles. Grade 1 to 3 neurotoxicity occurred in 7% versus 41% of patients in the 24-hour versus 1-hour schedule groups, respectively. Likewise, the incidence of grade 1 to 3 arthralgia/myalgia was greater among patients receiving 1-hour infusion of paclitaxel (3.5% v 28%). Although not randomized, these data suggest that survival may be comparable whether paclitaxel is given by short or prolonged infusion in advanced non-small cell lung cancer. Toxicity profiles differ, however, with greater myelosuppression following 24-hour paclitaxel, but a higher incidence of neurotoxicity and arthralgia/myalgia with the 1-hour infusion.

Phase I study of the antineovascularization drug CM101.

CM101 is a bacterial polysaccharide that induces neovascular inflammation in malignant tumors. Fifteen patients with refractory malignancies received CM101 i.v. by a 15-min infusion every other day, three times in 1 week, at doses ranging from 1 unit (7.5 microgram)/kg to 5 units/kg. Serum was analyzed for anti-CM101 IgG and IgM weekly. Plasma levels of inflammatory cytokines, including tumor necrosis factor alpha, interleukin 8, interleukin 10, MIP-1alpha, and soluble E-selectin, were analyzed from -15 min to 12 h during each treatment. Dose-limiting toxicities, including grade IV dyspnea and arrhythmia, were encountered at the 5-unit/kg level. Toxicities occurred primarily within the first 12 h after therapy and included mild-to-moderate fever and chills, nausea, cough, headache, facial flushing, dyspnea, myalgias, and acute tumor-related pain. No patient developed detectable antibodies to CM101. All patients experienced marked time- and dose-dependent elevations in all cytokines studied. Three patients experienced tumor shrinkage. The results show that CM101 can be safely administered at doses that produce evidence for severe, and possibly tumor-specific, inflammation. Further study is necessary to better characterize the mechanism of action and determine the optimal dose and schedule of this new agent.

Soluble E-selectin in cancer patients as a marker of the therapeutic efficacy of CM101, a tumor-inhibiting anti-neovascularization agent, evaluated in phase I clinical trail.

A polysaccharide toxin, GBS toxin, is produced by group B Streptococcus (GBS) isolates from neonates who died of "early-onset disease". GBS toxin, named CM101 in the clinic, was hypothesized, on the basis of our previous in vivo studies, to induce inflammation in pulmonary neovasculature in neonates by cross-linking of embryonic receptors still expressed after birth and in tumor neovasculature in adults. Immunohisto chemical in vitro analysis of human biopsies showed that tumor neovasculature is indeed a binding site for CM101. In vivo studies in mice have demonstrated that CM101 induced inflammatory responses in neoplastic tumor neovasculature causing inhibition of tumor growth and tumor cell necrosis. These experimental observations warranted a phase I clinical trial for CM101 as an anti-neovascularization agent in human cancer therapy. Cancer patients received one cycle of therapy consisting of three treatments during 1 week. CM101 was administered over 15 min by i.v. infusion. Dosages of 7.5 micrograms/kg (1 U/kg), n = 3; 15 micrograms/kg (2 U/kg), n = 6; 24.75 micrograms/kg (3.3 U/kg), n = 3; and 37.5 micrograms/kg (5 U/kg), n = 3 were used. Enzyme-linked immunosorbent sandwich assays (ELISA) of the patients sera showed a marked elevation of soluble E-selectin with a peak concentration observed at 8-12 h after each CM101 infusion. The average baseline value for soluble E-selectin prior to the first treatment was 97.3 +/- 23.4 ng/ml (mean +/- SEM, n = 15) and the average peak level at 8 h was 441.6 +/- 62.4 (mean +/- SEM, n = 15; P < 0.001). Subsequent treatments gave average maximum soluble E-selectin levels again at 8 h of 466.9 +/- 87.6 and 412.0 +/- 67.8 ng/ml, for treatments 2 and 3 respectively. Baseline values for treatments 2 and 3 were 192.3 +/- 26.4 and 226.4 +/- 26.1 ng/ml respectively (p < 0.01 versus treatment 1). Out of 15 patients, 5 showed tumor reduction or stabilization and were given additional cycles of therapy. CM101 induced an increase in soluble E-selectin levels, which remained elevated over baseline at the start of the following treatment cycles. The baseline remained elevated for several weeks after the final treatment, i.e., P < 0.01 for levels before treatment 1 compared to those at week 4 after treatment. Elevated soluble E-selectin is considered proof of endothelial engagement in an inflammatory process. Our data support the contention that the inflammatory response observed in these cancer patients is targeting the tumor neovasculature and that measurement of soluble E-selectin levels in patients treated with CM101 can provide important information on the magnitude of CM101-mediated neovascular endothelial activation and tumor cell damage in cancer of endothelial origin, or cancer with a major neo-angiogenic component.

Epidermal growth factor regulates topoisomerase II activity and drug sensitivity in human KB cells.

Because of its unique DNA-cleaving and strand-passing activities, topoisomerase II is involved in many aspects of DNA metabolism, including replication, transcription, recombination, and repair. The cytotoxic potential of topoisomerase II-targeted drugs, such as etoposide, is related to their ability to stabilize covalently linked enzyme-DNA complexes, which are intermediates in the enzyme's catalytic cycle. Epidermal growth factor receptor is expressed on the cell surface of the majority of squamous cell carcinomas, and epidermal growth factor binding is known to stimulate a number of cellular transduction pathways, including tyrosine kinase, protein kinase C, and phospholipase C. Because topoisomerase II is a proliferation-dependent protein and has been shown to be a high-affinity substrate for many of these cellular transduction pathways, the effects of epidermal growth factor on cellular regulation and sensitivity to etoposide were studied with the human oral cavity squamous cell line, KB. Topoisomerase II catalytic activity was rapidly and transiently inhibited after the addition of epidermal growth factor to the cellular growth media. Western blot on nuclear extracts did not demonstrate alterations in topoisomerase II polypeptide levels to account for changes in catalytic activity. Epidermal growth factor treatment also led to the formation of stabilized, covalently linked enzyme-DNA complexes. Furthermore, epidermal growth factor-induced, topoisomerase II-mediated DNA strand breaks were additive to those induced by etoposide. This study indicates that epidermal growth factor specifically regulates the catalytic and DNA-cleaving activities of topoisomerase II in KB cells. This may direct clinical strategies for circumventing the intrinsic cellular resistance to chemotherapy commonly observed in squamous cell carcinomas of the head and neck.

Paclitaxel plus carboplatin for advanced lung cancer: preliminary results of a Vanderbilt University phase II trial--LUN-46.

Based on their good activity and minimal toxicity in non-small cell lung cancer and other cancers, we initiated a phase II trial of carboplatin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with previously untreated stage IIIB and IV non-small cell lung cancer. Among 51 patients treated, the overall response rate was 27.5% (14 partial responses). Seventeen patients had stable disease, while 16 patients experienced disease progression after two cycles of treatment. Apart from myelosuppression, toxicity has been modest, with fewer than 5% of patients experiencing grade 3 or greater nonhematologic toxicity. Objective response and survival rates were modestly improved among patients given the higher of two paclitaxel doses (175 mg/m2 v 135 mg/m2). These data suggest that paclitaxel plus carboplatin warrants further study in metastatic non-small cell lung cancer.