Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

BACKGROUND: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS: In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS: Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION: GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER: NCT01564251.

Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women.

CONTEXT: Recent interventional studies indicate that post-menopausal hormone replacement therapy is associated with an increased risk of cardiovascular mortality and breast cancer. Isoflavones, a class of plant estrogens, have structural similarities to estradiol. Hence, isoflavones may exert beneficial estrogenic health effects in postmenopausal women with fewer adverse effects. OBJECTIVE: To evaluate the effect of high-dose isoflavones on self-reported quality of life (QOL), cognition, lipoproteins and androgen status in post-menopausal women. DESIGN AND SUBJECTS: Double-blind, randomized, placebo-controlled, 12-week trial of 93 healthy, ambulatory, post-menopausal women (mean age 56 yr). The study was conducted at a tertiary care center in the United States. INTERVENTION: Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). Both soy and the placebo were provided in the form of a powder to be mixed with beverages. MAIN OUTCOME MEASURES: QOL was judged by the Menopause-specific Quality of Life (MENQOL) questionnaire while cognitive function was assessed with standard instruments. Total, free, and bioavailable testosterone, gonadotropins, SHBG, and fasting lipids were measured. RESULTS: Eighty-four women (90%) completed the study (active=38, placebo=46). There was a significant improvement in all 4 QOL subscales (vasomotor, psychosexual, physical, and sexual) among the women taking isoflavones, while no changes were seen in the placebo group. No significant changes in cognition, serum androgens or plasma lipids were seen within any of the groups. However, at the end of the study, a group-by-time interaction was observed such that total testosterone and HDL levels were significantly lower in the isoflavones compared to placebo groups. CONCLUSION: High-dose isoflavones is associated with improved QOL among women who have become menopausal recently. Hence, the timing of isoflavone supplementation with regards to the onset of menopause appears to be important. The use of isoflavones, as an alternative to estrogen therapy, may be potentially useful and seemingly safe in this group of women who are looking for relief from menopausal symptoms.