Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. PATIENTS AND METHODS: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. RESULTS: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. CONCLUSION: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

Micro-dose transdermal estradiol for relief of hot flushes in postmenopausal Asian women: a randomized controlled trial.

OBJECTIVES: To compare the effect of micro-dose transdermal estradiol and placebo on the incidence and severity of menopausal symptoms and well-being in postmenopausal Asian women with vasomotor symptoms. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. RESULTS: Of 165 subjects randomized to estradiol 0.014 mg/day or placebo for 12 weeks, 80 per group were included in the analysis. Groups were comparable at baseline, although time since menopause was slightly shorter in the estradiol group. There was a greater reduction in mean weekly hot flushes at week 12 in the estradiol group (55%) than the placebo group (40%; p < 0.01), which was evident by week 4. A similar pattern was seen for moderate and severe hot flushes (-58% vs. -39%, respectively). Reductions were statistically significant at weeks 4, 8, and 12. Vaginal pH fell significantly in the estradiol group by week 4 and then remained stable throughout the treatment period, but there were no significant changes in the placebo group. Vaginal maturation value increased more in the estradiol than the placebo group (p < 0.001). Few subjects had vaginal bleeding or spotting. Quality of life improved similarly in both groups. Urogenital symptoms improved considerably from baseline in both treatment groups, with no significant differences. Eight subjects experienced treatment-related adverse events (seven in the estradiol group). CONCLUSIONS: In Asian women, micro-dose estradiol was significantly superior to placebo in improving vasomotor symptoms. The bleeding profile was comparable with that of placebo. Micro-dose estradiol was safe and well tolerated in Asian women.