Phase I study of the sequential combination of interleukin-12 and interferon alfa-2b in advanced cancer: evidence for modulation of interferon signaling pathways by interleukin-12.

PURPOSE: To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-alpha-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-alpha-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs. RESULTS: No IL-12-or IFN-alpha-related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-gamma by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-gamma achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021). CONCLUSION: The combination of rhIL-12 and IFN-alpha-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.

Phase II study of weekly docetaxel and capecitabine in patients with metastatic breast cancer.

PURPOSE: This phase II study evaluated the safety and efficacy of weekly docetaxel and capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Thirty-nine patients with metastatic breast cancer received 30 mg/m2 of docetaxel on days 1, 8, and 15 in combination with capecitabine 800 mg/m2 twice daily on days 1-21, repeated every 28 days. RESULTS: The median number of treatment cycles was 4 (range, 1-20 cycles). Grade 3 toxicities per patient were asthenia (n = 7; 18%), diarrhea (n = 7; 18%), nausea/vomiting (n = 5; 13%), stomatitis (n = 5; 13%), neutropenia (n = 5; 13%), and hand-foot syndrome (n = 4; 10%). There were only 2 grade 4 toxicities, febrile neutropenia and pulmonary embolism. The overall response rate was 44% (95% confidence interval (CI), 28%-60%), median duration of response was 9.1 months (95% CI, 6.2-12 months), and median time to progression was 5.5 months (95% CI, 3.7-7.3 months). CONCLUSION: Weekly docetaxel with capecitabine was active with acceptable toxicities. Additional trials to define the optimal schedule of docetaxel and capecitabine are justified.

Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies.

PURPOSE: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination. PATIENTS AND METHODS: Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m(2)/wk, whereas capecitabine was escalated in successive patients cohorts. RESULTS: Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m(2)/d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m(2) capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m(2) doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non-small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non-small-cell lung carcinoma, and bronchioloalveolar carcinoma. CONCLUSION: Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m(2)/d (625 mg/m(2) bid) with docetaxel 36 mg/m(2)/wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.

A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients.

PURPOSE: On the basis of preclinical studies, we hypothesized that interleukin (IL)12 would potentiate the antitumor actions of an antihuman epidermal growth factor receptor-2 (HER2) monoclonal antibody (trastuzumab). We conducted a Phase I trial to determine the safety and optimal biological dose of IL-12 when given in combination with trastuzumab. PATIENTS AND METHODS: Patients with metastatic HER2-positive malignancies received trastuzumab on day 1 of each weekly cycle. Beginning in week 3, patients also received intravenous injections of IL-12 on days 2 and 5. The IL-12 component was dose-escalated within cohorts of 3 patients (30, 100, 300, or 500 ng/kg). Correlative assays were conducted using serum samples and peripheral blood cells obtained during the course of therapy. RESULTS: Fifteen patients were treated, including 12 with HER2 2+ or 3+ breast cancer. The regimen was well tolerated with IL-12-induced grade 1 nausea and grade 2 fatigue predominating. Evaluation of dose-limiting toxicity and biological end points suggested that the 300 ng/kg dose was both the maximally tolerated dose and the optimal biological dose of IL-12 for use in combination with trastuzumab. Two patients with HER2 3+ breast cancer within the 500 ng/kg dose level experienced grade 1 asymptomatic decreases in left ventricular ejection fraction of 12% and 19% after 3 and 10 months of therapy, respectively. There was one complete response in a patient with HER2 3+ breast cancer metastatic to the axillary, mediastinal, and supraclavicular nodes, and 2 patients with stabilization of bone disease lasting 10 months and >12 months, respectively. Correlative assays showed sustained production of interferon (IFN)gamma by natural killer cells only in those patients experiencing a clinical response or stabilization of disease. Elevated serum levels of macrophage inflammatory protein-1alpha, tumor necrosis factor-alpha, and the antiangiogenic factors IFN-gamma inducible protein-10 and monokine induced by gamma were also observed in these patients. Patient genotyping suggested that a specific IFN-gamma gene polymorphism might have been associated with increased IFN-gamma production. The ability of patient peripheral blood cells to conduct antibody-dependent cellular cytotoxicity against tumor targets in vitro did not correlate with clinical response or dose of IL-12. CONCLUSIONS: The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment. Sustained production of IFN-gamma and other cytokines were observed in three patients: One who exhibited a complete response and two others who had stabilization of disease lasting over 6 months. Given the small sample size and heterogeneity of the patient population, the effects of IL-12 on the innate immune response to trastuzumab therapy should be further explored in the context of a larger clinical trial.

A randomized phase II study of paclitaxel and bevacizumab with and without gemcitabine as first-line treatment for metastatic breast cancer.

BACKGROUND: The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB). PATIENTS AND METHODS: In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m(2) (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m(2) (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life. RESULTS: Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia (P = .001) and dyspnea (P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) (P = .021), FACT-B Social/Family Well-being (P = .041), and Breast Cancer-Additional Concerns (P = .008) scores than patients treated with PB+G. CONCLUSION: The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.

Older women with breast carcinoma are less likely to receive adjuvant chemotherapy: evidence of possible age bias?

BACKGROUND: Older women with breast carcinoma are less likely than younger women to receive adjuvant chemotherapy. The authors hypothesized that after controlling for confounders (i.e., variables related to both age and chemotherapy use) and effect modifiers (i.e., variables that have a significant interaction with age), age would become a less significant factor for predicting adjuvant chemotherapy use. METHODS: Data on 480 women with localized breast carcinoma were entered into the National Comprehensive Cancer Network database at The Ohio State University Medical Center. Women were divided into 3 groups: women age < 50 years (n = 143 [30%]), women ages 50-65 years (n = 216 [45%]), and women age > 65 years (n = 121 [25%]). Chi-square and Wilcoxon rank sum tests were used for univariate analyses of the variables of interest, and logistic regression was used for multivariate analyses. RESULTS: After adjustment for confounders (stage, tumor size, progesterone receptor status, and lymph node involvement) and effect modifiers (namely, estrogen receptor [ER] status), the odds of not receiving chemotherapy for women ages 50-65 years and women age > 65 years with ER-positive breast carcinoma were approximately 6 (odds ratio [OR], 6.4; 95% confidence interval [CI], 3.1-13.3; P < 0.001) and 62 (OR, 62.4; 95% CI, 21.8-178.7; P < 0.001) times greater, respectively, than the odds for women age < 50 years. Women ages 50-65 years with ER-negative breast carcinoma were not significantly different from women age < 50 years with respect to chemotherapy use (OR, 1.9; 95% CI, 0.5-7.3; P = 0.374). However, the odds of not receiving chemotherapy for women age > 65 years with ER-negative breast carcinoma were 7 times (OR, 6.7; 95% CI, 1.5-30.6; P = 0.013) greater than the odds for women age < 50 years. CONCLUSIONS: The results of the current study indicate that based on older age alone, women are less likely to receive adjuvant chemotherapy. In addition, the results suggest that age bias may contribute to undertreatment and lack of accrual of older women into clinical trials.

Comparison endoscopic ultrasound with computed tomograpy for the detection of mediastinal lymphadenopathy

To compare the rate of detección of mediastinal lymphadenopathy by endoscopic ultrasound (EUS) and computed tomography (CT) scan. Data collected from 40 consecutive mediastinal EUS examinations. EUS examination revealed lymphadenopathy in 33 patients. Only 7(21 per cent) had mediastinal adenopathy detected by CT scan while 26(79 per cent) had mediastinal lympha nodes by EUS that were not detected by CT scan. Non-detection of mediastinal lymph nodes by CT was significantly associated with small lymph nodes (p=0.035), location in the paraesophageal area (p<0,001), and co-existing esophageal cancer (p=0.009). Ten patients among these 56 cases after EUS underwent linear EUS-guided fine needle aspiration (EUS-FNA) of mediastinal lymph nodes. CT scan did not detect lymph nodes in 4 out of these 10 patients (40 per cent), two of which were found to have malignant lymph nodes. Conclusion: The detection rate of mediatinal lymphadenopathy is significantly better by EUS compared to CT scan. It may be reasonable to perform EUS in cases of thoracic malignancies even if CT scan does not show mediatinal lymph nodes. If lymph nodes are seen on EUS, they can be subjected to EUS-FNA and the information obtained could alter management decisions