Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer.

LESSONS LEARNED: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND: The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS: Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION: The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.

Participant perceptions of a community-based lifestyle intervention: the CHIP.

ISSUE ADDRESSED: The Coronary Health Improvement Project (CHIP) is a community-based educational initiative designed to improve cardiovascular fitness and other health indicators associated with common, lifestyle-related health disorders in developed societies. Evaluations of the CHIP since the late 1990s, though yielding positive statistical results for change in participant physical health indicators, have not included qualitative assessments of the CHIP experience from the perspectives of CHIP participants. METHODS: Data were obtained using a mixed methods survey design via a questionnaire completed by 79 respondents (71% female) who had participated in Australian CHIP programs. Responses were analysed using descriptive statistics and thematic analysis. RESULTS: Participants commonly undertook the CHIP to fulfil their lifestyle and health aspirations and to target specific health conditions. Improved diet, enhanced exercise and weight loss were the most commonly reported benefits. Participation in the CHIP involves a process of conviction (involving risks and motivation), connection (involving support and reinforcement), challenge (involving control and struggle) and change (involving more and less). CONCLUSION: This study offers a model of a change process generated from the perspectives of participants of the CHIP in Australia. Not all participants found CHIP lifestyle recommendations straightforward to adopt, as some encountered resistance from within themselves or from family and friends.