Phase I study evaluating the safety and efficacy of oral panobinostat in combination with radiotherapy or chemoradiotherapy in patients with inoperable stage III non-small-cell lung cancer.

Panobinostat is a radiosensitizing agent and targets the epigenetics of malignancy. This phase I study evaluated the safety and efficacy of combining oral panobinostat with radiotherapy (RT) or chemoradiotherapy (CRT) in patients with inoperable stage III non-small-cell lung cancer. This study had a parallel dose-escalating design combining oral panobinostat twice a week (dose escalations 20, 30, 45 mg) with either palliative RT (group A) or radical CRT (group B) using a standard chemotherapy protocol of cisplatin and etoposide. In group A (RT), nine recruited patients received treatment with oral panobinostat (doses 20, 30, 45 mg) with RT. Two serious adverse events, rapid atrial fibrillation and tracheo-oesophageal fistula, were not attributable to study treatment. The most common grade 3/4 toxicities were thrombocytopenia and lymphopenia, which resolved promptly after cessation of panobinostat. The disease control rate was 66%, the progression-free survival was 3 months and the median overall survival was 9 months. In group B (CRT), panobinostat dose was not escalated beyond 20 mg because of infection-related complications. Serious adverse events included opportunistic infection associated with treatment-related lymphopenia and febrile neutropenia without a source. One patient had cerebral infarct that was not attributed to study treatment. All patients achieved a partial response to treatment. At 33 months of follow-up, all patients were still alive. Panobinostat can be combined with palliative-dose RT at doses up to 45 mg twice a week with tolerable toxicity. Dose-limiting toxicities prevented the dose escalation of the panobinostat with CRT.

Phase II study of celecoxib with docetaxel chemoradiotherapy followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer.

TITLE: Phase II study of celecoxib with docetaxel chemoradiotherapy (CRT) followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer. INTRODUCTION: Concurrent CRT has been associated with improvement in absolute 5-year survival by 10% and is the standard of care for inoperable stage III nonsmall cell lung cancer. Preclinical evidence suggests that cyclooxygenase-2 inhibition may increase the efficacy of CRT. METHODS: Patients were treated with CRT (weekly docetaxel at 30 mg/m2 over 6 weeks with concurrent external beam radiotherapy with 60 Gy in 30 fractions) followed by consolidation chemotherapy with docetaxel and cisplatin, each at 75 mg/m2 given 3 weekly for four cycles. Patients were to receive celecoxib 400 mg twice daily during treatment. Prophylactic cranial irradiation (30 Gy in 15 fractions) was offered if there was disease response. RESULTS: Twenty-four patients commenced CRT. Nineteen patients commenced consolidation therapy with 14 patients completing treatment. Twelve patients had treatment with celecoxib. In the total cohort, the median overall survival (mOS) was 21 months and progression-free survival (PFS) was 16 months. Overall response rate was 59% and disease control rate was 82%. Three patient deaths occurred. Significant grade 3/4 toxicity included radiation pneumonitis (17%), febrile neutropenia (17%), infection/sepsis with or with neutropenia (25%) and esophagitis (12.5%). Retrospective analysis of celecoxib versus no celecoxib treatment showed favorable mOS 26.5 versus 17.5 months and PFS 22 versus 16 months, but this did not reach statistical significance. CONCLUSIONS: The activity of this regimen has been demonstrated. Treatment-related toxicity was substantial. The role of celecoxib in addition to CRT could not be demonstrated in this study because of the small number of patients.

Feasibility and kinetics of CD34+ hematopoietic progenitor cell mobilization in response to a single administration of docetaxel chemotherapy and pegfilgrastim in a contemporary cohort of patients with metastatic breast cancer.

AIM: Autologous hematopoietic stem cell transplantation (auto-HSCT) remains an experimental therapy for metastatic breast cancer (MBC) and there is no established protocol for cluster of differentiation 34+ (CD34+ ) hematopoietic progenitor cell (HPC) mobilization with historic studies using growth factors with or without chemotherapy. This study describes the feasibility and kinetics of CD34+ HPC mobilization following a single administration of docetaxel and the pegylated form of recombinant human granulocyte colony-stimulating factor analogue filgrastim (pegfilgrastim). METHODS: The study design was serial measurement of peripheral blood CD34+ HPC in patients with MBC following a single administration of intravenous (IV) docetaxel 100 mg/m2 on day 1 and subcutaneous (SC) pegfilgrastim 6 mg on day 2. RESULTS: Eight patients with MBC were enrolled. The median age was 56 years (range 51-75 years). All patients had human epidermal growth factor receptor 2 (HER2) negative disease and either hormone refractory or negative disease. Three patients had bone only disease, four had visceral organ disease with or without bone involvement and one had locally unresectable disease only. All patients had prior therapy for early-advanced stage disease and prior therapy for MBC included seven patients receiving at least one line of hormone therapy and three having palliative chemotherapy. Six patients recorded a rise in the CD34+ count greater than 20 cells/µL. The median peak level was 40.2 cells/µL (standard deviation = 28.7) occurring on day 9 and with an average duration of 4 days. Overall, treatment was well tolerated with manageable side-effects. CONCLUSION: The single administration of docetaxel and pegfilgrastim was effective in mobilization of CD34+ HPC and peak levels followed a predictable course. This approach needs validation in prospective studies by preparation of auto-HSCT by leukapheresis and quantification of total CD34+ HPC yields.