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Because the exclusive source of sex steroids (at least estrogens) after menopause is recognized to be dehydroepiandrosterone (DHEA), this study examines the interindividual variability of serum DHEA and its metabolites as well as the contribution of the ovary to global sex steroid physiology in postmenopausal women.

Because the secretion of dehydroepiandrosterone (DHEA), the exclusive source of sex steroids in postmenopausal women, is already decreased by 60% and continues to decline at the time of menopause, the objective of this study was to examine the effect of intravaginal DHEA on the symptoms and signs of vaginal atrophy.

The objective of this study was to provide evidence that the transformation of DHEA into both androgens and/or estrogens locally in cells of the three layers of the vagina (epithelium, lamina propria, and muscularis) would have effects of greater impact, including effects on sexual function, than only effects on superficial epithelial cells as achieved with estrogens.

Because a previous 1-week study has shown no or minimal changes in the serum levels of dehydroepiandrosterone (DHEA) and its metabolites after up to daily 1.8% (23.4 mg) intravaginal DHEA, the objective of the present study was to investigate the serum steroid levels during a 12-week daily intravaginal administration of 0%, 0.25%, 0.5%, and 1.0% DHEA (Prasterone) 1.3 mL ovules.

Romidepsin is a potent class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for treatment of patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy and patients with peripheral T-cell lymphoma (PTCL) who have received at least 1 prior therapy. Approval for use in patients with PTCL was based in part on results from the phase 2, single-arm, open-label registration study GPI-06-0002, which demonstrated clinical benefit and tolerability of romidepsin in patients with recurrent or refractory PTCL. The aim of this subanalysis was to evaluate the efficacy and safety of romidepsin on GPI-06-0002 in the three major subtypes of PTCL: PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase-1–negative anaplastic large cell lymphoma (ALK-1–negative ALCL).Patients with histologically confirmed PTCL who failed or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for patients achieving stable disease (SD) or better. The primary efficacy endpoint was rate of confirmed/unconfirmed complete response (CR/CRu); secondary endpoints were objective response rate (ORR: CR/CRu + partial response [PR]) and duration of response (DOR). Because of the aggressive nature of PTCL, prolonged disease stabilization can provide patient benefit, thus ORR + SD ≥ 90 days was used as an overall measure of disease control. Efficacy assessments were made by an Independent Review Committee (IRC) and consisted of an initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters.Of the 131 enrolled patients, 130 patients had histologically confirmed PTCL by central review, with a median of 2 (range 1–8) prior systemic therapies for PTCL. The majority of patients (117/130) had PTCL-NOS (n = 69), AITL (n = 27), or ALK-1–negative ALCL (n = 21). Responses assessed by the IRC and the most common grade ≥ 3 adverse events (AEs) for the 3 major subtypes are noted in the table. ORR was similar across subtypes, including 30% in patients with AITL, with 19% CR/CRu. With a median duration of follow-up of 10.9 months, the median DOR for all responders was 17 months for patients with PTCL-NOS and 12 months for patients with ALK-1–negative ALCL. Median DOR was not yet evaluable for patients with AITL, who had the longest DOR ongoing at 34 months. Overall, 66% of patients experienced at least 1 grade ≥ 3 AE; 78% in patients with AITL, 67% in patients with PTCL-NOS, and 48% in patients with ALK-1–negative AITL. Eighteen of 117 patients (15%) experienced grade ≥ 3 infection; however infections led to discontinuation in only 4 of 117 patients (3%), 1 with PTCL-NOS and 3 with ALK-1–negative ALCL. Infection rates were higher in patients whose disease had bone marrow involvement or who had received prior monoclonal antibody therapy.Similar CR/CRu rates were observed across the 3 major PTCL subtypes (PTCL-NOS, AITL, and ALK-1–negative ALCL). Romidepsin induced durable responses in patients with the major subtypes of PTCL, with nearly half (46%) of these patients experiencing disease control. These data support the use of single-agent romidepsin to treat relapsed or refractory PTCL-NOS, AITL, and ALK-1–negative ALCL as well as the development of romidepsin-based combination regimens and front-line therapies in these histologiesCoiffier: Celgene: Consultancy; Gloucester: Consultancy. Pro:Celgene: Consultancy, Honoraria. Prince:Celgene: Honoraria, Research Funding. Foss:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy. Sokol:Celgene: Consultancy, Speakers Bureau; Gloucester: Research Funding. Caballero:Celgene: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau; Pfizer: Speakers Bureau. Morschhauser:Bayer: Honoraria; Roche: Consultancy, Honoraria. Pinter-Brown:Celgene: Consultancy; Allos: Consultancy; Merck: Consultancy; Spectrum: Honoraria; Genetech: Speakers Bureau. Padmanabhan:Celgene: Consultancy, Honoraria. Shustov:Celgene: Research Funding, Speakers Bureau. Nichols:Celgene: Employment, Equity Ownership. Carroll:Celgene: Employment, Equity Ownership. Balser:Celgene: Contracted Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Merck: Honoraria; Millennium: Consultancy; Genzyme: Research Funding.

Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL.Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety.131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles).Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment.Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases.As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo.Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.