A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies.

BACKGROUND: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). METHODS: Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. CONCLUSIONS: Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly.

A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group.

BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

Multidisciplinary team meeting and EUSOMA quality indicators in breast cancer care: A French regional multicenter study.

INTRODUCTION: We evaluate breast cancer (BC) pathway at a regional level including public, private and university institutions. We assessed the quality of multidisciplinary team meetings (MTM) and compliance with a panel of European high-quality indicators (EUSOMA QIs). METHODS: We conducted a retrospective multicenter (n = 20) study in the largest health care region in France. Between January and April 2015, we included all patients discussed at an MTM after a diagnosis of BC (n = 619). We analyzed quality of MTM by assessing the quorum, the reliability of data transcription and the exhaustivity of pre-therapeutic MTM. We then analyzed the compliance with a selected panel of 16 EUSOMA QIs. RESULTS: During MTM discussion, data were more than 95% consistent with medical records for 9/11 items. Pre-operative tumor histology (90.6%) and post-operative resection margins (84.3%) were the least concordant between medical records and MTM. Minimum standards as defined by EUSOMA were reached for 11/16 QIs, but not reached for pathology reports in non-invasive BC (78.2%), proportion of exclusive sentinel lymph node biopsies in patients with clinically negative axilla (85.2%), performing adjuvant chemotherapy (76.6%), and proportion of patients discussed in pre-therapeutic and post-operative MTM (63.5%). CONCLUSIONS: In this multicentric study evaluating the quality of BC care with a representative sample of institutions, compliance with EUSOMA indicators was satisfactory for all type of institutions. However, too few patients were discussed in pre-therapeutic MTM (especially in non-university hospitals 43.7% [39.4-48.1]) versus 88.7% for others [82.2-95.1]) and data transcription was likely responsible for up to 15% of discordance.