Pharmacodynamic Studies in Early Phase Drug Development

Camidge, D. Ross; Jimeno, Antonio

doi:10.1007/978-1-4419-7358-0_9

Cited by 2 publications

(1 citation statement)

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“…Such studies also offer the potential for providing unique insights into the molecular signaling pathways involved in aspects of normal human endocrine physiology. If this is entirely an ALK ‐specific effect, then the potential for using T changes as a pharmacodynamic marker during the early phase development of other ALK inhibitors should be considered 31. In contrast, if it reflects a combination of both ALK and MET or other off‐target kinase inhibition, then hormone side effects offer the potential to differentiate crizotinib from other more specific ALK inhibitors currently in development 32…”

Section: Discussionmentioning

confidence: 99%

Rapid‐onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer

Weickhardt

Rothman

Salian-Mehta

et al. 2012

Cancer

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BACKGROUND:The objective of this study was to document the differences in testosterone (T) levels between crizotinib-treated and noncrizotinib-treated patients with metastatic nonsmall cell lung cancer (NSCLC). METHODS: Testosterone levels were measured in 19 men with metastatic NSCLC who received crizotinib and in 19 men with metastatic NSCLC who did not receive crizotinib. Clinical characteristics of the patients were compared, and additional hormone assays were performed as appropriate. Two patients who began crizotinib and 4 patients who had dose interruptions or who stopped crizotinib therapy had serial hormone measurements, permitting the documentation of dynamic hormone changes on and off crizotinib treatment. RESULTS: Total T levels were low (<241 ng/dL) in 19 of 19 (100%) crizotinib-treated men and in 6 of 19 men (32%) with metastatic NSCLC who did not receive crizotinib (mean T levels, 131 ng/dL and 311 ng/dL, respectively; P ¼ .0002). Only 1 in 5 patients who had anaplastic lymphoma kinase (ALK) gene rearrangements and had not yet received crizotinib had low T. The initiation of crizotinib in 2 patients who had previously normal T levels was associated with a rapid decreases in T and in luteinizing hormone and follicle stimulating hormone levels within 14 to 21 days. Discontinuation of crizotinib led to increases back to normal T levels. CONCLUSIONS: Crizotinib therapy caused rapid suppression of T levels in men. The current results indicated that the site of action must include a central (hypothalamic or pituitary) effect, but additional direct testicular effects could not be excluded. Further work is required to assess the correlation between low T levels and crizotinib side effects as well as the exact molecular mechanism and site of drug toxicity. Cancer 2012;118:5302-9. V C 2012American Cancer Society.KEYWORDS: crizotinib, nonsmall cell lung cancer, testosterone, anaplastic lymphoma kinase gene rearrangements, hypogonadism. INTRODUCTIONApproximately 4% of patients with nonsmall cell lung cancer (NSCLC) have rearrangements in the anaplastic lymphoma kinase (ALK) gene, leading to an oncogene-addicted state from aberrant ALK activation. 1-9 Crizotinib, an oral ALK and MET-directed tyrosine kinase inhibitor, has produced a high response rate and prolonged median progression-free survival in patients with ALK-positive NSCLC. 10 Side effects of crizotinib include grade 1/2 nausea (54%), diarrhea (48%), visual disturbance (41%), constipation (24%), dizziness (15%), and fatigue (10%). 10 Crizotinib (Xalkori; Pfizer, New York, NY) recently received US Food and Drug Administration approval for the treatment of patients with advanced, ALK-rearranged NSCLC, a group that potentially represents >10,000 patients per year in the United States alone. 11 The potential for crizotinib-related hypogonadism came to our attention through an index case. A man aged 35 years with metastatic NSCLC and an ALK rearrangement who received crizotinib (250 mg twice daily in 28-day cycles) for 14 cycles reported worsening fatigue...

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Section: Discussionmentioning

confidence: 99%