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Introduction The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Methods Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0–2. Patients took vorinostat 400 mg PO daily days 1–14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. Results Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1–6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Conclusions Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients.

Several cytotoxic chemotherapy regimens are active against metastatic breast cancer; however, benefits are modest and overall prognosis remains limited. For anthracycline and taxane-pretreated metastatic breast cancer, there remains a relative paucity of therapies with significant activity. This Phase II study evaluated the combination of capecitabine and oxaliplatin (XELOX) among patients with metastatic breast cancer being treated in the first- or second-line setting.Patients received oxaliplatin 85 mg/m(2) on days 1 and 15, and capecitabine 1,500 mg/m(2) twice daily on days 1-7 and 15-21 of a 28-day cycle. Patients were treated until progression or intolerable toxicity. The primary objective was to estimate the objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria with tumor assessments every 8 weeks.Ten patients were treated of which 3 had received prior neurotoxic therapy in the metastatic setting. There were no confirmed complete responses, 5 patients had partial response, 4 patients had stable disease for at least 24 weeks, and one patient was unevaluable. Median time to progression (TTP) was 10.4 months (95% lower confidence bound [LCB]: 5.75 months), median progression-free survival (PFS) was 14.2 months (95% LCB: 6.14 months), and median overall survival (OS) was 19 months (95% LCB: 12.8 months). Multiple patients experienced pain syndromes and unusual neuropathies. Other common toxicities included fatigue, diarrhea, and nausea.XELOX is a promising regimen for anthracycline-pretreated metastatic breast cancer although careful patient selection is indicated and alternate dosing schedules should be explored to minimize neurologic morbidity.

Phase I testing of the hu14.18-IL2 immunocytokine in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m2/day. In this phase II study, 14 patients with measurable metastatic melanoma were scheduled to receive hu14.18-IL2 at 6 mg/m2/day as 4-h intravenous infusions on Days 1, 2, and 3 of each 28 day cycle. Patients with stable disease (SD) or regression following cycle 2 could receive two additional treatment cycles. The primary objective was to evaluate antitumor activity and response duration. Secondary objectives evaluated adverse events and immunologic activation. All patients received two cycles of treatment. One patient had a partial response (PR) [1 PR of 14 patients = response rate of 7.1 %; confidence interval, 0.2–33.9 %], and 4 patients had SD and received cycles 3 and 4. The PR and SD responses lasted 3–4 months. All toxicities were reversible and those resulting in dose reduction included grade 3 hypotension (2 patients) and grade 2 renal insufficiency with oliguria (1 patient). Patients had a peripheral blood lymphocytosis on Day 8 and increased C-reactive protein. While one PR in 14 patients met protocol criteria to proceed to stage 2 and enter 16 additional patients, we suspended stage 2 due to limited availability of hu14.18-IL2 at that time and the brief duration of PR and SD. We conclude that subsequent testing of hu14.18-IL2 should involve melanoma patients with minimal residual disease based on compelling preclinical data and the confirmed immune activation with some antitumor activity in this study.

Multiple adjuvant regimens are used for HER2+ breast cancer, but experience in routine practice is not reported. We evaluated whether oncologists' perceptions of these regimens matches clinical experience. We surveyed Wisconsin medical oncologists throughout the state regarding factors impacting selection of TCH (docetaxel, carboplatin, and trastuzumab) or anthracycline-based therapy. We also reviewed 200 cases of HER2+ breast cancer treated at the University of Wisconsin and the Marshfield Clinic and collected data on patient and tumor characteristics, chemotherapy regimen, and toxicities. Two-thirds of surveyed oncologists prefer anthracycline-based therapy, particularly for node-positive cancers. However, TCH was preferred for early-stage (T1a-bN0) tumors. Half of oncologists use prophylactic G-CSF with TCH. In the 200 cases reviewed at our centers, acute toxicity occurred more frequently with TCH. There were fewer dose modifications or delays for AC-TH (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab) than TCH (31% vs. 47%, P = 0.07), possibly due to higher use of prophylactic G-CSF with AC-TH (77% vs. 34% with TCH, P

We investigated the anti-tumor effect of peritumoral resveratrol in combination with immunotherapy in vivo in neuroblastoma-bearing mice. Subcutaneous NXS2 tumors were induced in A/J mice. On day 10 some mice received 15mcg of intravenous immunocytokine for 5 days, mice received of 20mg of peritumoral resveratrol twice a week (starting on day 12) for a total of 5 injections, and a separate group received a combination of both regimens. Tumor progression and survival were assessed every 3–4 days. Blood and primary tumor tissue samples were collected on day 20 for Complete Blood Count and CD45 immunohistochemistry and histology, respectively. The primary tumor regressed in all mice receiving peritumoral resveratrol. Most of these mice receiving peritumoral resveratrol alone developed metastatic tumors and recurrence of the primary tumor after cessation of therapy. When resveratrol and immunocytokine regimens were combined, 61% of the mice receiving this combination therapy resolved their primary tumors and survived without developing metastatic tumors, compared to 15% and 13% receiving resveratrol or immunocytokine alone, respectively. None of the therapeutic regimes prevented lymphocyte infiltration or affected the Complete Blood Count. Greater necrosis was observed microscopically in tumors from mice receiving the combination therapy. These results demonstrate that the combination therapy of peritumoral resveratrol plus intravenous immunocytokine provides better anti-tumor effects in this model than either therapy alone.

We consider a class of random effects models for clustered multivariate binary data based on the threshold crossing technique of a latent random vector. Components of this latent vector are assumed to have a Laird–Ware structure. However, in place of their Gaussian assumptions, any specified class of multivariate distribution is allowed for the random effects, and the error vector is allowed to have any strictly positive pdf. A well known member of this class of models is the multivariate probit model with random effects. We investigate sufficient and necessary conditions for the existence of maximum likelihood estimates for the location and the association parameters. Implications of our results are illustrated through some hypothetical examples.

Randomized consent designs have been advocated in some setting. It has been argued that the use of the randomized consent designs is justified as it eliminates the so-called Hawthorne effect in the control group. Besides the ethical issue in not informing the patients, there are other potentially serious issues regarding the confounding and resultant bias in treatment comparison. This is particularly so in behavioral intervention trials. There is not only the placebo effect, but also the so-called Hawthorn effect that could muddy the comparisons. Based on a randomized consent design with control and intervention which results in three distinct groups, this presentation will show using very simple statistical contrasts why unbiased comparison is impossible due to confounding and self-selection.

Purpose: We conducted a phase I trial of interleukin 2 (IL-2) in combination with chimeric 14.18 (ch14.18) and murine R24 antibodies to determine the maximal tolerated dose (MTD), immunological effects, and toxicity of this treatment combination. Experimental Design: Twenty-seven patients with either melanoma (23 patients) or sarcoma (4 patients) were enrolled to receive a combination therapy with ch14.18 and R24 antibodies together with continuous infusion of Roche IL-2 (1.5×106 U/m2/day, 26 patients) or Chiron IL-2 (4.5×106 U/m2/day, 1 patient) given 4 days/week for 3 weeks. The antibodies ch14.18 (2–7.5 mg/m2/day) and R24 (1–10 mg/m2/day) were scheduled to be administered for 5 days during the second week of IL-2 therapy. Results: When given in combination in this study, the MTD for ch14.18 was 5 mg/m2/day and the MTD for R24 was 5 mg/m2/day. Dose-limiting toxicities were severe allergic reactions to both ch14.18 and R24 as well as pain related to ch14.18. This ch14.18 MTD was lower than the 7.5 mg/m2/day MTD previously determined for ch14.18 given alone with the same dose and schedule of IL-2. Immunological effects included the induction of lymphokine-activated killer (LAK) activity and antibody-dependent cell-mediated cytoxicity (ADCC). Anti-idiotype response to ch14.18 was seen in six patients, including two melanoma patients who had a partial response to treatment. In addition to two partial responses, four patients had a stable disease and one patient remained without any evidence of disease. Conclusions: Immunotherapy with IL-2 in combination with ch14.18 and R24 antibodies augments LAK function and ADCC measured in vitro in all patients. While there exist theoretical advantages of combining these two antibodies, the MTD of ch14.18 and of R24 were lower than the MTD of each antibody in prior studies evaluating single antibody therapy with IL-2. As such, the combination of these two antibodies together with IL-2 therapy appeared to influence the MTD and toxicity of each of the administered antibodies.

We evaluated recurrent NXS2 neuroblastoma tumors that developed following NK- or T-cell-mediated immunotherapy in tumor-bearing mice. Recurrent tumors developed following an NK-dependent antitumor response using a suboptimal dose of hu14.18-IL2, a humanized IL-2 immunocytokine targeted to the GD(2)-ganglioside. This treatment initially induced complete resolution of measurable tumor in the majority of mice, followed, however, by delayed tumor recurrence in some mice. These recurrent NXS2 tumors revealed markedly enhanced (fivefold) MHC class I antigen expression when compared with NXS2 tumors growing in PBS-treated control mice. A similar level of enhanced MHC class I antigen-expression could be induced on NXS2 cells in vitro by culturing with interferon gamma, and was associated with reduced susceptibility to both NK-cell-mediated tumor cell lysis and antibody-dependent cellular cytotoxicity in vitro. In contrast, Flt3-ligand treatment of NXS2-bearing mice induced a protective T-cell-dependent antitumor memory response. Recurrent NXS2 tumors that developed following Flt3-L therapy revealed a decreased expression of MHC class I antigens. While NXS2 tumors are susceptible to in vivo destruction following either hu14.18-IL2 or Flt3-ligand immunotherapies, these results suggest that some tumor cells may be selected to survive and progress by expressing either higher or lower levels of MHC class I antigen in order to resist either NK- or T-cell-mediated antitumor responses, respectively.

Lan and DeMets (1) introduced a flexible procedure for the analysis of sequential trials based on the discretization of the Brownian motion. In this paper, we consider an extension of this strategy that preserves both the desired significance level and the power of any group sequential trial. We propose a procedure that allows for any number and timing of interim analyses. This entails the derivation of boundaries at the monitoring stage by means of two spending functions, one for the type I and one for the type II error probabilities, as well as the adjustment of the target maximum information as the trial progresses. The general solution to the problem is provided together with a discussion of implementation strategies. The procedure is intended for group sequential designs that allow early stopping in favor of both the null and the alternative hypotheses, and an example is presented for this case. However, its application is also easily extended for designs where there is no early stopping in favor of the null.