Summary
Background
Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ...ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors.
Methods
Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects.
Results
48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles.
Conclusions
MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.
Trial registration:
ClinicalTrials.gov
NCT00600496; registered 8 July 2009.
Fatigue in cancer Curt, Gregory A
BMJ,
2001-Jun-30, Letnik:
322, Številka:
7302
Journal Article
Recenzirano
Odprti dostop
Regular bed and waking times should be established, and the patient should perform restful activities before going to bed. 4 Although rest is commonly advised as a useful approach to fatigue, there ...is some observational evidence that moderate aerobic activity is actually more effective in reducing cancer related fatigue. 5 Exercise may also help improve sleep hygiene. Data from randomised, placebo controlled trials convincingly show the ability of α erythropoetin to maintain packed cell volume, reduce transfusion requirements, and improve overall quality of life. 8 Growth factor treatment with erythropoetin should be considered in patients whose fatigue may be secondary to moderate anaemia.
Cancer Fatigue: The Way Forward Curt, Gregory; Johnston, Patrick G.
The oncologist (Dayton, Ohio),
01/2003, Letnik:
8, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
Research in cancer‐related fatigue lags far behind research in cancer‐related pain and is astonishingly underdeveloped given the magnitude of the problem among cancer patients. This was recently ...recognized at the State‐of‐the‐Science Conference on Symptom Management in Cancer: Pain, Depression, and Fatigue, held at the U.S. National Institutes of Health in July 2002. The results of patient surveys on fatigue being conducted in Ireland by the All Ireland Fatigue Coalition (AIFC) closely mirror results from similar surveys conducted in the U.S., in some regards, with 53% of patients experiencing significant fatigue at least daily, and 80% at least monthly on both sides of the Atlantic. In other respects, such as duration of bouts of fatigue, how much and with whom patients discuss their fatigue symptoms, and economic impacts of fatigue, there are significant differences between survey findings in the U.S. and in Ireland. But in both places, the condition is underreported and undertreated and takes an enormous toll. Work by the AIFC to document the problem in Ireland, expand public awareness, and conduct research on which to base guidelines for diagnosis and treatment is an excellent beginning to tackling this long understudied condition that afflicts the overwhelming majority of cancer patients.
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