Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).

BACKGROUND: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. METHODS: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). RESULTS: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. CONCLUSIONS: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. CLINICALTRIALS.GOV IDENTIFIER: NCT00955305.

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.

BACKGROUND: Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer.

BACKGROUND: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated. PATIENTS AND METHODS: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m(2) Q3W)/carboplatin (AUC 6 mg min/ml Q3W). RESULTS: The trial was discontinued after preliminary analysis. Median progression-free survival (primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68-1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74-1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1-42.7) and 43.3% (30.6-56.8), respectively; risk ratio 0.676 (95% CI 0.41-1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. CONCLUSIONS: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated.

Baseline tumour measurements predict survival in advanced non-small cell lung cancer.

BACKGROUND: The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. METHODS: Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. RESULTS: A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. CONCLUSION: Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.

A direct comparison of biological response modulation and clinical side effects by interferon-beta ser, interferon-gamma, or the combination of interferons beta ser and gamma in humans.

To directly compare clinical side effects and biological response modification, IFN-beta ser, IFN-gamma, or the combination of IFN-beta ser plus IFN-gamma was administered to 21 cancer patients. Each IFN or the combination was given intravenously on days 1, 8, and 15 in varied order. Each IFN and the combination resulted in significant (P less than 0.05) modulation of IFN-induced proteins. IFN-beta ser was more effective than IFN-gamma in enhancing 2-5A synthetase activity (P = 0.001). IFN-gamma was more effective than IFN-beta ser in enhancing serum beta 2 microglobulin expression (P = 0.05) and indoleamine dioxygenase activity, as assessed by decreased serum tryptophan (P = 0.03). The combination enhanced tryptophan catabolism more effectively than IFN-beta ser in a dose-dependent manner (P less than 0.03). IFN-beta ser/IFN-gamma did not potentiate natural killer cells or antibody-dependent cellular toxicity (ADCC). IFN-beta ser/IFN-gamma enhanced monocyte guanylate cyclase activity, as assessed by serum neopterin, more effectively than IFN-gamma alone (P = 0.005). Both IFNs and the combination resulted in increases in HLA class II expression on monocytes. However, no significant difference in the level of induction of HLA DQ and HLA DR expression between IFN-beta ser/IFN-gamma and either IFN-beta ser or IFN-gamma was noted. Although frequency and servity of side effects of IFN-beta ser, IFN-gamma, or the combination were dose related, induction of induced proteins (with exception of influences on tryptophan catabolism) were not a function of dose administered over the 10-fold range. Continued treatment with the combination intravenously three times a week for 4 wk sustained but did not further potentiate, most of the changes in interferon-induced proteins. Thus, IFN-beta ser and IFN-gamma each resulted in effective and essentially equivalent patterns of induction of induced proteins. When combined, however, these IFNs did not result in potentiation of biological response modification in vivo.

Randomized phase II-III trial of combination beta and gamma interferons and etoposide and cisplatin in inoperable non-small cell cancer of the lung.

We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-beta and IFN-gamma, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II-III trial of etoposide and cisplatin, with or without IFN-beta and IFN-gamma, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-beta plus IFN-gamma followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplatin/m2 on day 1 and 120 mg of etoposide/m2 on days 4, 6, and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 micrograms of IFN-gamma and 30 x 10(6) U of IFN-beta three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of 18 (11%) patients in the combination arm had partial responses. All responses occurred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in the combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-beta and IFN-gamma does not enhance the efficacy of etoposide and cisplatin in this disease. Although the combined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects. This study also exemplifies a hybrid phase II-III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial.

Loss of the tumorigenic phenotype with in vitro, but not in vivo, passaging of a novel series of human bronchial epithelial cell lines: possible role of an alpha 5/beta 1-integrin-fibronectin interaction.

We established an immortalized, nontumorigenic human bronchial epithelial cell line by transfection with the origin of replication-defective SV40 large T plasmid. This line spontaneously became tumorigenic at passage 184 (NL20T), although subsequent passages (passages 189, 200, and 205) failed to form tumors. The tumorigenic cell line NL20T was reinoculated back into athymic nude mice, and the two subsequently derived cell lines (NL20T-A and NL20T-B) have been passaged 85 times in vitro and remain tumorigenic. However, late-passage NL20T cells consistently lose their tumorigenicity when passaged in vitro on tissue culture plastic dishes (NL20T-n cells). Thus, two of the cell lines, NL20 and NL20T, reverted to the nontumorigenic phenotype reproducibly and spontaneously following serial passage on plastic tissue culture plates, whereas cells passaged in mice (NL20T-A and -B) did not. We used these nontumorigenic (NL20 and NL20T-n) and tumorigenic (early passage NL20T, NL20T-A, and NL20T-B) cells to study the role of the alpha 5/beta 1-integrin and attachment to fibronectin in tumorigenicity. The two nontumorigenic cell lines (NL20 and NL20T-n) attached slower to fibronectin-coated plates than the two tumorigenic cell lines in a cellular-extracellular matrix adhesion assay. Attachment was abrogated by exposure to a blocking antibody to the alpha 5/beta 1-integrin, the fibronectin receptor, in the two tumorigenic cell lines. Cell surface expression of the alpha 5/beta 1 cell surface protein by flow cytometry was highest in the tumorigenic NL20T and NL20T-A cells. NL20T-A cells were cultured with an antibody to alpha 5/beta 1 and inoculated s.c. into athymic nude mice; tumorigenicity of the NL20T-A cells was inhibited in a dose-dependent manner. Tumorigenicity was also inhibited partially with monoclonal antibodies to either alpha 5 or beta 1. A mixture of 10% tumorigenic NL20T-A cells and 90% nontumorigenic NL20 cells was cultured on plastic, type IV collagen, laminin, and fibronectin for 9 weeks. Only cells cultured on fibronectin formed tumors when inoculated s.c. into athymic nude mice. We conclude that these data are consistent with the hypothesis that neoplastic transformation in our original cell line arose from in vivo selection of a small mutant clone, which had arisen in culture and was selected subsequently in vivo but was lost with in vitro culture in NL20 cells, and that alpha 5/beta 1-integrin interaction with the extracellular matrix may play a role in tumorigenicity in our system.

Synergistic antitumor effects of tumor necrosis factor and gamma-interferon on human colon carcinoma cell lines.

We assessed the antiproliferative effects of tumor necrosis factor (TNF-alpha) and gamma-interferon (IFN-gamma) alone and in combination, on nine human colon carcinoma cell lines. All were resistant (less than 30% inhibition) to TNF-alpha alone. Four cell lines were resistant to IFN-gamma alone, two exhibited a minimal degree of sensitivity (30-50% inhibition), one was moderately sensitive, and two were inhibited 70% or greater. A synergistic antiproliferative effect occurred in eight of the nine cell lines treated with a combination of TNF-alpha and IFN-gamma. In seven of these eight, the combination of cytokines resulted in 30-40% more growth inhibition than predicted had an additive interaction occurred (P less than 0.005). In two cell lines with an induced resistance to mitomycin C, an increase in resistance to combined TNF-alpha and IFN-gamma treatment correlated with an increasing resistance to mitomycin C. The data were further analyzed to determine if combination treatment altered the sensitivity of the cells to one or both agents in addition to synergistically potentiating growth inhibitory effects. Combinations of TNF-alpha/IFN-gamma enhanced the dose response activity of TNF-alpha in three cell lines (P less than or equal to 0.09) and decreased the dose response activity of IFN-gamma in another three (P less than or equal to 0.02). Colony forming experiments on HCT 116 cells demonstrated a reduction in the number of 250-micron colonies in the IFN-gamma/TNF-alpha treatment groups when compared to controls, indicating that combined treatment had a cytotoxic effect. We conclude that combination TNF-alpha/IFN-gamma treatment has a synergistic cytotoxic effect on human colon carcinoma cells. IFN-gamma may enhance the effectiveness of TNF-alpha in some cell lines, but not conversely. These results may have therapeutic implications.

A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-alpha in humans.

Interleukin 2 (IL-2) and interferon-alpha (IFN-alpha) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase 1B trial of IL-2 plus or minus IFN-alpha in 38 cancer patients. The objectives of this trial were to determine which doses of IFN-alpha and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN-alpha and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 x 10(6) units/m2/day or 3.0 x 10(6) units/m2/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN-alpha (0.5 x 10(6) or 5 x 10(6) units/m2/day) was administered s.c. on days 1-4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/IFN-alpha for course 2, or IL-2/IFN-alpha in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2. A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-alpha. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-alpha. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN-alpha group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum beta 2-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-alpha. No dose response effect for IFN-alpha was observed for any of the parameters assessed. Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN-alpha and IL-2.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly.

Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.

Modulation of interferon receptor expression during combination beta ser-interferon and gamma-interferon treatment of human colon carcinoma cells.

Combination treatment of SKCO1 human colon carcinoma cells with beta ser-interferon (IFN-beta ser) and gamma-interferon (IFN-gamma) results in a synergistic antiproliferative effect. The role of IFN-beta ser and IFN-gamma receptor modulation was investigated as a possible mechanism for this response. IFN-gamma (0.05-50 ng/ml) pretreatment of SKCO1 cells for 24 h decreased specific binding of 125I-IFN-beta ser by 35-60%. Scatchard analysis of binding data obtained following 24-h treatment with 5 ng/ml IFN-gamma showed that this reduction in binding was due to a decreased receptor affinity (control cells, Kd = 46 +/- 1.6 pM; IFN-gamma-treated cells, Kd = 106 +/- 6 pM, n = 2) rather than a significant change in receptor number (receptor number/control cell = 1214 +/- 471, receptor number/IFN-gamma treated cell = 1118 +/- 153, n = 2). In contrast, pretreatment of SKCO1 cells with IFN-beta ser (5 ng/ml) resulted in slight (10-35%) increases in 125I-IFN-gamma-specific binding. Scatchard analysis of binding data obtained following 24-h treatment with 5 ng/ml IFN-beta ser showed a decrease in binding affinity (control cells, Kd = 28 +/- 7 pM; IFN-beta ser-treated cells, Kd = 38 +/- 7 pM, n = 2) and a 32% increase in IFN-gamma receptor sites (receptor number/control cell = 4257 +/- 464, receptor number/IFN-beta ser-treated cell = 5570 +/- 730; n = 2). 125I-IFN-gamma internalization studies performed at 37 degrees C confirmed the cell surface binding assays; IFN-beta ser-treated cells internalized 30-50% more labeled IFN-gamma than untreated cells. However, it is unlikely that differences in binding and internalization of this magnitude play a primary role in the synergistic antiproliferative effect of IFN-gamma with IFN-beta ser in SKCO1 cells. Biochemical modulation at sites distal to the ligand receptor interaction should be investigated.

Biological and clinical effects of the combination of beta- and gamma-interferons administered as a 5-day continuous infusion.

A phase I trial involving continuous infusion of both beta- and gamma-interferon (IFN-beta and IFN-gamma) was conducted in 20 patients in order to determine whether combinations of high doses of IFN-beta and IFN-gamma were tolerable when administered under conditions which mimic conditions of in vitro antiproliferative studies. Patients received a 5-day continuous infusion of IFN-beta/IFN-gamma, followed by a 9-day rest period. Two cycles were administered. Doses of IFN-beta/IFN-gamma were escalated between 4 dose levels, with 5 patients per dose level. Dose-dependent side effects, consisting primarily of constitutional symptoms typical of those experienced with IFN, were observed. The maximally tolerated dose of continuous IFN-beta/IFN-gamma infusion was 3 x 10(6) units of IFN-beta and 200 micrograms of IFN-gamma. Dose-limiting side effects consisted of severe headache, fatigue, fever, and hepatic toxicity. No clinical responses were observed. Serum IFN was measurable only at the highest 3 dose levels. Only 5 patients (4 at the highest dose level) had total serum levels which exceeded 50 laboratory units/ml (55, 63, 800, 800, and 550 laboratory units/ml, respectively). In order to confirm the biological effectiveness of this schedule, we measured IFN-inducible proteins prior to therapy, 24 h after the initiation of the infusion, and at the completion of the 5-day infusion. 2'-5'-Oligoadenylate synthetase, serum beta 2-microglobulin, neopterin, and p78 levels all increased significantly, and serum tryptophan decreased significantly within 24 h after the initiation of treatment (P less than 0.0001). A dose-response effect was observed for serum beta 2-microglobulin, neopterin, and p78 (P less than 0.02). We retrospectively compared the results of this trial with those of another IFN-beta/IFN-gamma trial in which IFN-beta and IFN-gamma were administered by i.v. bolus. Within the limitations of a retrospective comparison, continuous infusion was less well tolerated than our previous schedule of bolus administration 3 times/week. However, the continuous infusion schedule appeared to be more effective in enhancing 2'-5'-oligoadenylate synthetase levels in mononuclear cells. We conclude that tolerable doses of IFN-beta and IFN-gamma do not result in serum IFN levels which produce significant synergistic antiproliferative responses in vitro. This study and other findings suggest that, unless higher doses can be achieved, combinations of IFN-beta and IFN-gamma are unlikely to have significant therapeutic activity.

Synergistic antiproliferative effects of human recombinant alpha 54- or beta ser-interferon with gamma-interferon on human cell lines of various histogenesis.

The antiproliferative effects of human interferon (IFN), IFN-gamma, IFN-alpha 54, and IFN-beta ser, alone and in combination, were assessed on 10 human cell lines. All IFNs were produced by recombinant technology and purified to homogeneity. In all cell lines except one, the addition of IFN-gamma to either IFN-alpha 54 or IFN-beta ser resulted in a synergistic antiproliferative effect, regardless of individual IFN sensitivities or tissue of origin. The only exception was a normal diploid fibroblast cell in which an additive antiproliferative effect occurred with combination IFN treatment. A malignant fibrosarcoma cell line of similar mesenchymal origin demonstrated a synergistic antiproliferative effect. One cell line was sensitive to both type I and type II IFN alone. Three cell lines were relatively resistant to IFN-gamma but not to IFN-beta ser, one was relatively resistant to IFN-beta ser but not to IFN-gamma, and the remainder were resistant to both IFN-gamma and IFN-beta ser or IFN-alpha 54. The addition of IFN-alpha 54 to IFN-beta ser in the SKCO 1 cell line resulted in an antagonistic interaction. Timing experiments with RT112 cells indicate that IFN-gamma and IFN-beta ser need not be in the media at the same time for the synergistic effect to occur. Combinations of type I and type II IFN thus resulted in synergistic antiproliferative effect for transformed human cells of various histogenesis, including some with a relative resistance to one or both IFN types.

Dose-ranging study of recombinant human granulocyte-macrophage colony-stimulating factor in small-cell lung carcinoma.

PURPOSE: This randomized, multicenter, dose-finding study was undertaken to determine the dose of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) that can safely reduce neutropenia after cyclophosphamide, doxorubicin, and etoposide (CAVP-16) chemotherapy in patients with small-cell lung cancer (SCLC). Secondary clinical end points included incidence of infection, intravenous (IV) antimicrobial use, and chemotherapy delivered. PATIENTS AND METHODS: A total of 290 newly diagnosed SCLC patients were to receive six cycles of standard CAVP-16 chemotherapy on days 1 to 3 of every 21 days alone or with rhGM-CSF at 5, 10, or 20 micrograms/kg, administered subcutaneously (SC) on days 4 to 13 of each cycle. RESULTS: In cycle 1, median absolute neutrophil count (ANC) nadirs were twofold to threefold higher in patients who received rhGM-CSF, although all values were less than 500/microliters, and recovery from neutropenia was faster at all rhGM-CSF dosages versus observation (P < or = .01). In cycle 2, 56% of all patients given rhGM-CSF received full chemotherapy dosages (87.5% to 112.5% of projected dose) versus 36% of observation patients. During days 5 to 21 of cycle 1, fewer patients who received 10 micrograms/kg of rhGM-CSF required antibiotics compared with observation patients (11% v 29%, P < or = .01). Adverse events that occurred more frequently in rhGM-CSF-treated patients included injection-site reaction, edema, asthenia, paresthesia, diarrhea, myalgia, musculoskeletal pain, Pruritus, and rash (P < or = .10). Fever occurred more frequently in the 10- and 20-micrograms/kg rhGM-CSF groups than in the observation groups. The incidence in the 5-microgram/kg group was comparable to that in observation patients. Patients who received rhGM-CSF had a higher incidence of thrombocytopenia. CONCLUSION: rhGM-CSF at 5 to 10 micrograms/kg reduces chemotherapy-associated neutropenia and should be the dose range used in future studies.

Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer.

PURPOSE: We conducted a phase I trial of a 3-hour infusion of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) to identify the maximum-tolerated dose of Taxol as a 3-hour infusion with and without granulocyte colony-stimulating factor (G-CSF) support. MATERIALS AND METHODS: Thirty-five patients with advanced, untreatable malignancies were treated with a 3-hour infusion of Taxol once every 3 weeks. Groups of three patients were entered at escalating dose levels of Taxol in a traditional phase I design in each of two parallel arms: arm A, without G-CSF, and arm B, with G-CSF. Patients assigned to the G-CSF arm received G-CSF 5 micrograms/kg/d subcutaneously starting on day 2 for 9 to 14 days. All patients were pretreated with dexamethasone, diphenhydramine, and ranitidine, and were monitored continuously for cardiac arrhythmias during the first treatment. RESULTS: Dose-limiting myelosuppression with Taxol without G-CSF was observed at the 250-mg/m2 dose level. The dose-limiting toxicity for Taxol with G-CSF was peripheral neuropathy at the 300-mg/m2 dose level. One of 35 patients (2.8%) had a grade 3 anaphylactic reaction at 250 mg/m2. No clinically significant cardiac arrhythmias were documented. Twenty-seven of 111 courses (24%) were associated with grade 3 arthralgias or myalgias requiring narcotics for pain control. Taxol plasma concentrations declined in a triexponential fashion, with a final elimination half-life of 10 to 12 hours. The peak Taxol plasma concentrations and total area under the curve (AUC) increased with increasing doses of Taxol, although this increase appeared to be somewhat nonlinear. CONCLUSION: The maximum dose of Taxol recommended for phase II and III studies, when administered as a 3-hour infusion alone and with G-CSF support, is 210 mg/m2 and 250 mg/m2, respectively. No increased incidence of hypersensitivity reactions or other side effects were observed, with the possible exception of arthralgias and myalgias. If ongoing trials demonstrate that a 3-hour infusion is as efficacious as a 24-hour infusion, we conclude that with proper monitoring and premedication, high-dose Taxol can be safely administered in the outpatient setting.

Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival.

PURPOSE: Based on preclinical and clinical studies that suggested amifostine may potentiate the effects of cytotoxic drugs, we conducted a phase II trial of amifostine, cisplatin, and vinblastine (ACV) in patients with metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with metastatic NSCLC received amifostine (740 or 910 mg/m2) before 120 mg/m2 of cisplatin on day 1, plus weekly 5 mg/m2 of vinblastine without amifostine. Cycles were repeated every 4 weeks. Patients were required to have good performance status, no prior chemotherapy or biologic therapy, adequate organ function, and measurable disease. RESULTS: Sixteen of 25 assessable patients had an objective response documented by computed tomographic (CT) scan (64%; 95% confidence interval, 45% to 85%). With a median duration of follow-up of 19.2 months, the estimated median survival is 17 months and 1-year survival is 64% (+/- 10%). Toxicities included grades 3 and 4 neutropenia (8% and 92%, respectively) and nausea and vomiting (32% and 4%, respectively). Reversible grade 3 nephrotoxicity occurred in 12% of patients, although only one of 13 patients (7%) who received > or = four cycles of therapy had > or = 40% reduction in creatinine clearance. Grade 3 neuropathy was observed in seven patients at cumulative cisplatin doses that ranged from 324 to 660 mg/m2; grade 3 ototoxicity occurred in three patients at cumulative cisplatin doses that ranged from 390 to 450 mg/m2. Four patients (16%) required early stopping of an amifostine infusion due to hypotension. CONCLUSION: ACV appears to be a highly active regimen in metastatic NSCLC. Acute toxicities were generally reversible and the data suggest that amifostine may protect against long-term renal insufficiency from cumulative doses of cisplatin. Although the sample size of this trial is small, the results are significantly encouraging to warrant confirmation in randomized multiinstitutional trials.

Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial.

PURPOSE: To determine the response rate and survival of chemotherapy-naive patients with extensive-stage small-cell lung cancer (SCLC) treated with topotecan, and to determine the relationship of topotecan pharmacokinetics with response and toxicity. PATIENTS AND METHODS: Forty-eight patients with previously untreated, extensive-stage SCLC received 2.0 mg/m2 of topotecan daily for 5 days. The first 13 patients were treated without colony-stimulating factor (CSF) support; the next 35 patients received 5 micrograms/kg of granulocyte-colony-stimulating factor (G-CSF) for 10 to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of four cycles. Patients who had a partial response to topotecan after four cycles, stable disease after two cycles, or progressive disease at any time received salvage chemotherapy with cisplatin and etoposide. Topotecan pharmacokinetics were measured using a four-point sampling scheme. RESULTS: Of 48 patients, none had a complete response and 19 had a partial response, for an objective response rate of 39% (95% confidence interval [CI], 25.2% to 53.0%). The median response duration was 4.8 months (95% CI, 3.0 to 7.3). After a median follow-up duration of 18.2 months, the overall median survival time was 10.0 months (95% CI, 8.2 to 12.7); the 1-year survival rate was 39% (95% CI, 25.2% to 53.0%). Eight of 34 patients (24%) who received salvage chemotherapy responded. Four of 17 patients who did not respond to first-line therapy with topotecan responded to cisplatin and etoposide. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared with 29% who received G-CSF. However, the incidence of neutropenic fevers was similar between the two groups (8% and 11%, respectively), and one patient in each group died of neutropenic fevers. There were no differences in objective tumor response, duration of response, time to treatment failure, or survival between the 13 patients who entered the study before G-CSF administration was mandated and the 35 patients who entered after and received G-CSF. There was poor correlation between the WBC count and absolute neutrophil counts (ANCs) and both the area under the curve (AUC) and maximum concentration++ (Cmx) of total topotecan in plasma. There was no correlation between the tumor response and either AUC or Cmx of total topotecan. CONCLUSION: The activity of topotecan in extensive-stage SCLC noted in this study warrants further investigation of this agent in phase III clinical trials.

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.

Effect of amifostine on toxicities associated with sequential chemotherapy and radiation therapy for unresectable non-small-cell lung cancer: results of a phase II trial.

PURPOSE: To determine the effect of amifostine on the safety and efficacy of induction chemotherapy with high-dose cisplatin and vinblastine followed by large-field thoracic irradiation to 60 Gy in patients with stage IIIA or IIIB non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-six patients with unresectable stage IIIA or IIIB NSCLC were entered onto the study between May 1991 and November 1994. Patients received amifostine (740 or 910 mg/m2) followed by cisplatin (120 mg/m2) on days 1 and 29. Vinblastine (5 mg/m2) was given weekly for 5 weeks with no amifostine pretreatment. Following chemotherapy, patients received amifostine (340 mg/m2 4 days a week for 5 weeks, or 200 mg/m2 5 days a week for 6 weeks) 15 minutes before definitive thoracic radiation therapy to a total dose of 60 Gy in 6 weeks. RESULTS: Twenty-five patients were assessable for response and survival. The objective response rate was 60%. One-, 2-, and 3-year survival rates were 55%, 23%, and 23%. There was no grade 3 or greater renal toxicity during chemotherapy or grade 3 or greater esophagitis during radiation therapy. Neutropenia (secondary to vinblastine use) was the only grade 4 toxicity. There were no treatment-related deaths. CONCLUSION: Amifostine can be administered safely with high-dose cisplatin, vinblastine, and radiation therapy for NSCLC. The response rate and survival data provide no evidence that amifostine impairs response to treatment. Amifostine appears to reduce cisplatin-related nephrotoxicity and radiation-induced esophagitis.