A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas.

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

Quality of life in phase II trials: a study of methodology and predictive value in patients with advanced breast cancer treated with paclitaxel plus granulocyte colony-stimulating factor.

BACKGROUND: Despite the clinical benefit that may be associated with reduction of tumor volume, chemotherapy may produce physical or psychological distress that could compromise a patient's quality of life. Although palliation may be as relevant as tumor response in patients with metastatic breast cancer, quality of life is not commonly evaluated in phase II clinical trials of new therapeutic agents. PURPOSE: We evaluated the utility of quality-of-life assessment in two phase II clinical trials of patients receiving paclitaxel (Taxol) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) as salvage therapy for metastatic breast cancer. METHODS: A battery of instruments (i.e., Memorial Symptom Assessment Scale [MSAS], Functional Living Index-Cancer [FLIC], Rand Mental Health Inventory [MHI], Brief Pain Inventory [BPI], and Memorial Pain Assessment Card [MPAC]) designed to capture information about social, psychological, and functional aspects of quality of life, as well as symptom prevalence and distress, was completed prior to treatment; serial assessments were obtained at regular intervals during the treatment period. Univariate and multivariate analyses were performed evaluating base-line quality-of-life parameters and standard prognostic factors in relation to outcome measures of survival, tumor response, and toxicity. For 30 consecutive patients with extensive prior chemotherapy for metastatic disease, longitudinal data were analyzed associating tumor response to changes in quality-of-life scores throughout the course of treatment with paclitaxel. RESULTS: Base-line scores of two validated quality-of-life instruments, the MSAS and the FLIC, independently predicted the overall survival (P < .01 for each). In this model, however, neither standard prognostic factors nor quality of life instruments predicted the likelihood of tumor response or the probability of encountering grade 3 or grade 4 nonhematologic toxicity. With serial assessments of quality of life, the majority of patients who achieved partial tumor response or stable disease reported improved or unchanged quality-of-life scores, while those patients with progressive disease experienced rapid deterioration in quality of life. CONCLUSIONS: Base-line quality-of-life assessment may provide prognostic information distinct from that obtained through standard prognostic indicators alone. The combination of two factors--extent of disease and a base-line quality-of-life assessment--predicted survival more accurately than either used separately. Evaluation of quality-of-life outcomes in relation to tumor response may illuminate previously unmeasured palliative effects of chemotherapy, such as pain relief, as well as the burdens it imposes. IMPLICATIONS: Information obtained from quality-of-life assessment in conjunction with phase II testing of new chemotherapeutic agents for metastatic breast cancer can guide quality-of-life evaluation planned in large, randomized future studies.