A Pilot Study (SWOG S0429) of Weekly Cetuximab and Chest Radiotherapy for Poor-Risk Stage III Non-Small Cell Lung Cancer.

PURPOSE: Stage III non-small cell lung cancer (NSCLC) patients with poor performance status (PS) or co-morbidities are often not candidates for standard chemoradiotherapy (chemoRT) due to poor tolerance to treatments. A pilot study for poor-risk stage III NSCLC patients was conducted combining cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), with chest radiation (RT). METHODS: Stage III NSCLC patients with Zubrod PS 2, or Zubrod PS 0-1 with poor pulmonary function and co-morbidities prohibiting chemoRT were eligible. A loading dose of cetuximab (400 mg/m(2)) was delivered week 1, followed by weekly cetuximab (250 mg/m(2))/RT to 64.8 Gy in 1.8 Gy daily fractions, and maintenance weekly cetuximab (250 mg/m(2)) for 2 years or until disease progression. H-score for EGFR protein expression was conducted in available tumors. RESULTS: Twenty-four patients were enrolled. Twenty-two were assessed for outcome and toxicity. Median survival was 14 months and median progression-free survival was 8 months. The response rate was 47% and disease control rate was 74%. Toxicity assessment revealed 22.7% overall ≥Grade 3 non-hematologic toxicities. Grade 3 esophagitis was observed in one patient (5%). The skin reactions were mostly Grade 1 or 2 except two of 22 (9%) had Grade 3 acne and one of 22 (5%) had Grade 3 radiation skin burn. Grade 3-4 hypomagnesemia was seen in four (18%) patients. One patient (5%) had elevated cardiac troponin and pulmonary emboli. H-score did not reveal prognostic significance. An initially planned second cohort of the study did not commence due to slow accrual, which would have added weekly docetaxel to cetuximab/RT after completion of the first cohort of patients. CONCLUSION: Concurrent weekly cetuximab/chest RT followed by maintenance cetuximab for poor-risk stage III NSCLC was well tolerated. Further studies with larger sample sizes will be useful to establish the optimal therapeutic ratio of this regimen.

Southwestern oncology group phase II trial (S0526) of pemetrexed in bronchioloalveolar carcinoma subtypes of advanced adenocarcinoma.

BACKGROUND: Pemetrexed, a multitargeted antifolate drug, is an active agent in non-small-cell lung cancer (NSCLC), especially adenocarcinomas. Based on preclinical data supporting the relevance of alpha-folate receptors in adenocarcinoma of the bronchioloalveolar carcinoma (BAC) subtype, this trial was designed to assess pemetrexed in patients with this pathologic subtype of lung adenocarcinoma. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV adenocarcinoma with BAC features or pure BAC were eligible. Treatment consisted of pemetrexed, 500 mg/m(2), administered intravenously every 21 days. RESULTS: Of 27 patients enrolled, 24 were eligible and assessable for adverse events: Toxicity was primarily hematologic, consisting of leukopenia/neutropenia, thrombocytopenia, and anemia. The median follow-up among patients still alive (n = 8) was 35 months (range, 26-47 months). Among 17 patients with measurable disease, the response rate was 23% (all partial responses; 95% confidence interval [CI], 10%-56%). The median progression-free survival (PFS) and overall survival (OS) were 6 and 25 months, respectively. CONCLUSION: Pemetrexed is active and well tolerated and, in patients with adenocarcinoma BAC subtypes, likely related to its underlying mechanism of action as a multitargeted antifolate drug.

Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer: a California cancer consortium trial.

BACKGROUND: The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences. PATIENTS AND METHODS: Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m² intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m² I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints. RESULTS: Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively. CONCLUSION: Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.

Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023.

PURPOSE: Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non-small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease. PATIENTS AND METHODS: Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m(2) on days 1 and 8 plus etoposide 50 mg/m(2) on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m(2). Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease. RESULTS: Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. CONCLUSION: In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.

Erlotinib and vinorelbine in advanced malignant solid tumors: a phase I study.

BACKGROUND: Erlotinib is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Vinorelbine, a vinca alkaloid, interferes with microtubule assembly inhibiting mitosis during metaphase. Both drugs are commonly used as single agents in the treatment of advanced non small cell lung cancer (NSCLC). Given their efficacy in NSCLC and their non-overlapping toxicity profile, we conducted a phase I study of erlotinib and vinorelbine to establish the feasibility and safety of the combination and to determine the maximum tolerated dose (MTD). PATIENTS AND METHODS: Patients with advanced solid tumors were treated with vinorelbine intravenously on day 1 and 8 and erlotinib orally daily on a 21 day schedule. The dose levels of vinorelbine/erlotinib were 25 mg/m(2)/100 mg, 25/150 and 30/150. RESULTS: Sixteen patients were enrolled. Five patients were chemo-naïve; 11 had one prior therapy. The majority of patients had NSCLC (n = 7). Dose limiting toxicities included febrile neutropenia (4 patients) and grade 5 infection (1 patient). Non-hematologic grade 3/4 toxicities included diarrhea, hypokalemia, infection, dyspnea and mucositis. Of 12 patients assessable for radiologic response, there were no objective responses; eight had stable disease. CONCLUSIONS: (1) The MTD was vinorelbine 25 mg/m2 day 1 and 8 with erlotinib 100 mg/day every 21 days. (2) The combination was associated with high rate of febrile neutropenia (25%). (3) Due to subsequent data demonstrating a lack of efficacy of erlotinib in combination with platinum doublets in advanced NSCLC, this combination has not been explored further.

Phase II study of consolidation paclitaxel after concurrent chemoradiation in poor-risk stage III non-small-cell lung cancer: SWOG S9712.

PURPOSE: A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non-small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort. PATIENTS AND METHODS: Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21 days for three cycles. RESULTS: Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%. CONCLUSION: Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.

Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.

PURPOSE: Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC. METHODS: A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity. RESULTS: The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015). CONCLUSION: Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Sequential vinorelbine and docetaxel in advanced non-small cell lung cancer patients age 70 and older and/or with a performance status of 2: a phase II trial of the Southwest Oncology Group (S0027).

BACKGROUND: This phase II study (S0027) evaluated the efficacy and tolerability of planned sequential single-agent chemotherapy with vinorelbine followed by docetaxel in patients with advanced non-small cell lung cancer (NSCLC) age 70 and older and/or a performance status (PS) of 2. METHODS: Patients with stage IIIB (pleural effusion) or stage IV NSCLC, age 70 and older with a PS of 0-1 or 2, any age, received three cycles of vinorelbine 25 mg/m days 1 and 8 every 21 days followed by three cycles of docetaxel 35 mg/m days 1, 8, and 15 every 28 days. RESULTS: A total of 125 patients entered the study; 117 patients were assessable for response, survival, and toxicity. Seventy-five patients were in stratum1 (age 70 and older, PS 0-1) and 42 patients in stratum 2 (PS 2, any age). Objective response was 19% (95% confidence interval [CI]: 11%-30%) and 11% (95% CI: 3%-25%) in strata 1 and 2, respectively. Median survival was 9.1 months (95% CI: 7.1-12.7) and 5.5 months (95% CI: 3.1-6.5) in strata 1 and 2, respectively. Survival at 12 months was 41% and 13% in strata 1 and 2, respectively. Grade 3/4 neutropenia was seen in 32% and 31% of patients in strata 1 and 2, respectively. Three deaths probably related to treatment were noted: one in stratum 1 and two in stratum 2. CONCLUSION: Sequential vinorelbine and docetaxel is a well-tolerated and effective regimen in comparison with reports of other treatments tested in patients with advanced NSCLC age 70 and older and/or with a PS of 2.

Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial.

BACKGROUND: This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. METHODS: Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11). Dose escalation and MTD determination were based on the occurrence of dose-limiting toxicities in cycle 1 only. RESULTS: A total of 36 patients were enrolled, 26 of whom had NSCLC. All patients received at least one dose of study drug at one of five dose levels. The MTD of the combined regimen was determined to be 1.0/75 mg/m bortezomib/docetaxel. The combination was generally well tolerated. Toxicities were manageable, and no additive toxicities were observed. The most common adverse events were fatigue (67% of patients), nausea (50%), diarrhea (39%), and neutropenia (39%). Two patients with NSCLC achieved a partial response, and seven (19%) patients achieved stable disease (including six patients with NSCLC). CONCLUSION: The combination of bortezomib and docetaxel was feasible and well tolerated in patients with advanced NSCLC or other solid tumors. The recommended phase II dose is bortezomib 1.0 mg/m on days 1, 4, 8, and 11 plus docetaxel 75 mg/m on day 1, cycled every 21 days. Therapeutic doses of docetaxel and bortezomib are achievable for this combination.

Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m(2) in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine. RESULTS: Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003). CONCLUSION: The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.

Thrombotic thrombocytopenic purpura associated with quetiapine.

OBJECTIVE: To report a case of thrombotic thrombocytopenic purpura (TTP) caused by the antipsychotic quetiapine on 2 occasions in the same patient and review the hematologic adverse events associated with quetiapine. CASE SUMMARY: A 25-year-old African American male with a history of bipolar disorder was treated with quetiapine and developed thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure consistent with a diagnosis of TTP on 2 occasions 2 years apart. On each occasion, TTP was successfully treated with plasmapheresis. DISCUSSION: Many medications, including antibiotics, immunosuppressants, and antineoplastics, have been implicated as causative agents of TTP. Although, as of this writing, a review of the medical literature reveals no previous report of TTP associated with quetiapine, the Food and Drug Administration database of the Adverse Event Reporting System has compiled, as of this writing, 3 cases of TTP occurring in patients on quetiapine as their sole medication. In addition, this database has recorded other common hematologic adverse effects, including neutropenia and thrombocytopenia, that are possibly associated with quetiapine. In our patient, quetiapine-associated TTP presented within a few days after exposure to the drug, with early thrombocytopenia followed by delayed appearance (2-3 days) of microangiopathic hemolysis. CONCLUSIONS: An objective causality assessment suggests that quetiapine was the highly probable cause of TTP in this patient. Early recognition, discontinuation of the drug, and institution of plasmapheresis are paramount for prompt resolution of this life-threatening hematologic disorder.

Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial.

Tipifarnib (R115777) inhibits farnesylation of key proteins that modulate signaling pathways implicated in cell growth and proliferation, including members of the Ras and Rho families. It has broad-spectrum antiproliferative activity in vitro and in vivo. Clinical trials employing a continuous administration schedule have demonstrated dose-limiting neurotoxicity and myelosuppression. Preclinical studies have shown that intermittent oral administration can suppress tumor growth comparable to continuous administration. We conducted a National Cancer Institute-sponsored phase I trial to determine the feasibility of an intermittent dosing schedule of R115777 given orally twice daily on weeks 1 and 3 of a 28-day cycle in patients with malignant solid tumors. Starting dose was 300 mg twice daily (b.i.d.) with escalation by 300 mg b.i.d. increments over six dose levels to a maximum of 1800 mg b.i.d. Dose-limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity, grade 4 thrombocytopenia, grade 4 neutropenia (ANC) with fever (38.3 degrees C or above) or a documented infection. Twenty-one patients with advanced solid tumors, all of whom had prior systemic therapy, were accrued. Grade 3 fatigue was dose limiting for two of three patients at the 900 mg b.i.d. dose level. Although no responses were seen, four of six patients with stable disease remained on study for at least a year (16, 17, 13 and 12 months) before developing progressive disease. Three of these prolonged stable disease patients had non-small cell lung cancer. We conclude that intermittent dosing of R115777 is feasible and tolerable. The recommended phase II dose is 600 mg orally b.i.d. on alternate weeks.

Gemcitabine in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: a phase II California cancer consortium trial.

A phase II trial was designed to evaluate the efficacy and toxicity of gemcitabine in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-containing regimens and prospectively categorized for platinum response status. Treatment consisted of gemcitabine 1000 mg/m2 given intravenously on days 1 and 8 of a 21-day cycle. The status of p53 in pretreatment tumor tissue was assessed by immunohistochemistry (IHC). Sixty-one patients who progressed or recurred following platinum-based therapy were enrolled, 26 platinum-sensitive and 35 platinum-refractory. A median of 4 treatment courses (range, 2-7 courses) was delivered. Of the 55 patients assessable for response, there was 1 confirmed complete response and 3 with a confirmed partial response for an overall response proportion of 7%. Twenty-one patients had stable disease while 28 progressed and 2 patients had an unconfirmed partial response. Three of the responders (2 confirmed, 1 unconfirmed) were platinum-refractory. Median progression-free survival (PFS) and overall survival for all patients were 4.1 months and 8.6 months, respectively. Median PFS and overall survival for the platinum-sensitive and platinum-refractory cohorts were 5.4 months versus 3.1 months, and 11.9 months versus 7.1 months, respectively. Toxicity was principally hematologic with grade 3/4 neutropenia in 21% and grade 4 platelets in 8%. There were no treatment-related deaths. Twenty-four of 33 patients (73%) had p53-positive tumors. Although no significant association between platinum sensitivity and p53 status was seen, patients with platinum-sensitive disease and negative p53 by IHC had a trend toward longer survival compared to those with platinum-refractory disease and/or p53 positivity (P = 0.06). We concluded that salvage gemcitabine in this dose and schedule is safe and tolerable in previously platinum-treated patients with NSCLC.

Bronchioloalveolar carcinoma: a model for investigating the biology of epidermal growth factor receptor inhibition.

Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.

Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial.

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-naïve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.

Phase I trial of gemcitabine and paclitaxel in advanced solid tumors.

PURPOSE: Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. PATIENTS AND METHODS: Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m2 while paclitaxel was administered at an initial dose of 60 mg/m2, then escalated by 15 mg/m2 increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m2. Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. RESULTS: All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m2/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. CONCLUSION: This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m2 and paclitaxel 150 mg/m2 on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.

Antisense oligonucleotides in the treatment of non-small-cell lung cancer.

Antisense oligonucleotides (ASONs) are one of the new classes of molecularly targeted agents that have transitioned from the laboratory into clinical trials. Rational drug design has resulted in agents directed against a number of important cellular targets, including the mRNA of bcl-2, protein kinase (PK) C-alpha, PKA-I, H-ras, c-raf, R1 and R2 subunit of ribonucleotide reductase, and transforming growth factor beta2. These drugs are well tolerated with favorable toxicity profiles, and preliminary studies have demonstrated that they can be feasibly combined with chemotherapy. Plasma half-life is short, generally necessitating continuous prolonged intravenous infusion. Shorter administration schedules are being investigated. Efficacy has been demonstrated in early-phase studies in non-small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, ovarian cancer, melanoma, and prostate cancer. Molecular correlative studies with peripheral blood mononuclear cells and tumor tissue have demonstrated suppression of target proteins, suggesting that these drugs are indeed reaching the target. Here we discuss the current status of development of ASONs, focusing on LY900003 (formerly ISIS 3521), an agent directed against PKC-alpha currently under study in NSCLC. Phase III studies will determine the ultimate role these agents will play in the treatment of cancer. Future areas of study include combination with radiation and other molecularly targeted agents, alternative dosing schedules, liposomal administration, and the development of new antisense agents directed against additional molecular targets.

Non-small-cell lung cancer progression after first-line chemotherapy.

Platinum-based chemotherapy is the cornerstone of care for patients with metastatic non-small-cell lung cancer (NSCLC). It provides symptom relief, improved quality of life, and prolongation of life, compared with supportive care alone. However, all patients with stage IV disease inevitably develop resistance to chemotherapy and progressive disease. Many of these patients continue to have acceptable performance status and would therefore be eligible for second-line or even third-line treatments. Unfortunately, despite an increasing number of chemotherapeutic agents (which are effective in chemo-naive NSCLC), very few have been shown to have reproducible activity in the second-line setting. Nevertheless, recent randomized clinical trials have demonstrated that single-agent docetaxel improves survival and quality of life when delivered as second-line therapy, resulting in FDA-approval for this indication. Phase II studies evaluating other new agents, delivered singly or in combination, also have reported that gemcitabine, weekly paclitaxel, and the epidermal growth factor receptor (EGFR) inhibitors are active in a subset of patients who progress after first-line platinum-based therapy. Clinical trials are imperative in identifying additional new agents and approaches that may improve outcomes in this disease. In view of the recently established role of docetaxel, ongoing randomized studies are using a common design of single-agent docetaxel versus docetaxel plus a novel investigational agent.

Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.

Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.