Marianne Messina

Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression.

&NA; The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5‐hydroxytryptamine, 5‐HT) partial agonist active at the 5‐HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo‐controlled, parallel group studies involving 382 patients with DSM‐III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM‐D] and Hamilton anxiety [HAM‐A] scales ≥ 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p < 0.05) improvement in mean HAM‐D, HAM‐A, and Clinical Global Impression‐Global Improvement scale ratings for buspirone‐treated compared with placebo‐treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic‐type major depression and patients with more severe symptoms (judged by higher initial HAM‐D or HAM‐A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5‐HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5‐HT1A receptor function, have clinically important antidepressant properties.

Efficacy and Safety of Retreatment with Ipilimumab in Patients with Pretreated Advanced Melanoma Who Progressed after Initially Achieving Disease Control

Purpose: Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease control rate are assessed and considered with respect to the overall study population. Experimental Design: In the phase III study, 676 pretreated patients were randomly allocated to treatment with ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100 vaccine alone. Of these patients, 32 had a partial or complete objective response or stable disease after treatment and met the eligibility criteria for retreatment, although a total of 40 patients were retreated. Results: Best overall response rates (complete responses plus partial responses) for 31 retreatment-eligible patients in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease control rates were 65.2% and 75.0%. No new types of toxicities occurred during retreatment and most events were mild-to-moderate. Conclusion: Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen. Clin Cancer Res; 19(8); 2232–9. ©2013 AACR.

Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study.

This open‐label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100–340 mg/m2) + bortezomib (0·7–1·3 mg/m2) given on days 1, 4, 8 and 11 in each 21‐d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m2 and bortezomib at 1·3 mg/m2. Seventy‐two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy‐evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib‐naive patients and proved durable in all patient subgroups, including those with bortezomib‐refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM.

Serotonergic anxiolytics and treatment of depression.

The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor agonists buspirone and gepirone have effects on serotonergic systems, including presynaptic and postsynaptic receptors, that predict both anxiolytic and antidepressant activity. Chronic administration of both drugs produces a down-regulation of 5-HT2 receptors, a finding common to most antidepressant drugs irrespective of mechanism of action. In addition, gepirone induces a full-blown serotonin syndrome in rodents and is active in the behavioral despair test mediated by an action on serotonergic neurons. Buspirone is active in this paradigm when injected directly into the serotonergic dorsal raphe nucleus. The therapeutic effects of both buspirone and gepirone have been assessed in placebo-controlled studies of patients with major depression. Findings in these studies support antidepressant efficacy in addition to anxiolysis. In double-blind studies of patients with major depression treated for 8 weeks, each drug was found to be superior to placebo in improvement in Hamilton Depression and Anxiety total scores as well as individual depressive symptoms. These clinical findings are consistent with preclinical pharmacology suggesting that 5-HT1A partial agonists may possess intrinsic antidepressant activity.

Tanespimycin monotherapy in relapsed multiple myeloma: results of a phase 1 dose-escalation study

Tanespimycin, a heat shock protein 90 (HSP90) inhibitor, induces apoptosis in drug‐sensitive and ‐resistant MM cell lines and in tumour cells from patients with relapsed MM. In this phase 1 dose‐escalation study, the safety, plasma pharmacokinetics, and biological/antitumour activity of tanespimycin were evaluated in heavily pretreated patients with relapsed/refractory MM. Tanespimycin (150–525 mg/m2) was given on days 1, 4, 8, and 11 of each 3‐week cycle for up to 8 cycles. Non‐haematological AEs included diarrhoea (59%), back pain (35%), fatigue (38%), and nausea (35%); haematological AEs included anaemia (24%) and thrombocytopenia (21%). One patient (3%) achieved minimal response (MR), with a progression‐free survival (PFS) of 3 months, a 41% decrease from baseline in urine M protein, and a 33% decrease from baseline in serum M protein. Fifteen patients (52%) achieved SD with a median PFS of 2·1 months; 5/15 had reductions in serum M protein ranging from 7% to 38% and in urine M protein ranging from 6% to 91%. Mean HSP70 levels increased from day 1 h 0 to day 1 h 4 with further increases on day 11 h 0 and day 11 h 4, consistent with a therapeutic treatment effect. Tanespimycin monotherapy was well tolerated and demonstrated activity across all doses tested.

Gepirone in the treatment of major depression.

&NA; Gepirone is a serotonin (5‐hydroxytryptamine, 5‐HT) type1A receptor agonist and a pharmacologic analogue of buspirone. Two double‐blind, placebocontrolled studies show the efficacy of gepirone in the treatment of major depression. Study 1 demonstrates gepirones superiority over placebo in an 8‐week acute treatment of patients with major depression, including the melancholic subtype. Gepirones antidepressant dose range is tentatively established at 5‐30 mg/day. Study 2 reveals the benefit of gepirone compared with placebo in 4‐week continuation therapy of patients with major depression who initially responded to 6 weeks of open therapy with gepirone. Analysis of Hamilton Rating Scale for Depression item scores show gepirone especially improves scores on items of core depression.

Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma

Tanespimycin (17‐allylamino‐17‐demethoxygeldanamycin, 17‐AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open‐label multicentre study, we compared 1·3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource‐based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.

Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment

BackgroundIn an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial’s 12 week treatment induction period.MethodsThe Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n = 403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo (ipilimumab alone, n = 137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20).ResultsIn the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated “no change” or “a little” impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p < 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain.ConclusionsIpilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.Trial registrationClinicaltrials.gov identification number NCT00094653

A Phase I Study of Ixabepilone in Combination With Epirubicin in Patients With Metastatic Breast Cancer

UNLABELLED In this phase I trial, 42 women with metastatic breast cancer were treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). The maximum-tolerated dose of ixabepilone in combination with epirubicin was 30 mg/m2 (the recommended dose for phase II evaluation), and the dose-limiting toxicity dose was 35 mg/m2 with grade 4 neutropenia. PURPOSE The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer. PATIENTS AND METHODS Patients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m(2)) and escalating doses of ixabepilone (25, 30, and 35 mg/m(2)). RESULTS Forty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m(2) (n = 6) in combination with 75 mg/m(2) epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m(2) was 30 mg/m(2), and the DLT dose was 35 mg/m(2) with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels. CONCLUSIONS The combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m(2), followed by ixabepilone 30 mg/m(2) every 3 weeks.

Abstract C125: Tanespimycin pharmacokinetics: Results of a randomized dose‐escalation crossover phase 1 study of two formulations

Introduction: Tanespimycin is an inhibitor of Hsp90, a chaperone for proteins involved in tumor growth and survival. In vitro, tanespimycin sensitizes tumors to anti‐cancer therapies. Tanespimycin has demonstrated clinical activity as monotherapy and in combination with bortezomib in multiple myeloma pts and with trastuzumab in pts with HER2+ breast cancer. Study Design: In this single‐center, open‐label dose‐escalation study, pts were randomized to receive 1 dose IV of Cremophor‐containing tanespimycin or tanespimycin suspension and then crossed over and received 1 dose of the other formulation. One cohort (3–6 pts) received 275 mg/m2 and 1 cohort (6–12 pts) received 340 mg/m2. After crossover, pts continued receiving tanespimycin suspension twice weekly on days 1, 4, 8, and 11 of each 21‐d cycle until disease progression. Blood samples were collected on days 1 and 8 at the following times: predose, during infusion, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h postdose. Plasma concentrations of tanespimycin and its metabolite 17‐AG were quantified by LC/MS/MS. Investigators graded adverse events (AEs) using the CTCAE v3.0 and tumor responses using RECIST. Results: A total of 17 pts were enrolled in the study: 5 pts in the 275 mg/m2 cohort; 12 pts in the 340 mg/m2 cohort. Fourteen pts continued treatment following crossover. The mean age was 59.5 y and 76.5% were women. The median time since diagnosis was 41.5 mos and most common primary diagnoses were breast cancer 29%, non‐small cell lung cancer 12%, and larynx cancer 6%. The plasma concentration:time curves show biexponential decay with a rapid distribution followed by a slower elimination phase. Profiles for the Cremophor‐containing and suspension formulations were similar with Cmax for the 275 mg/m2 dose of 8050 ng/mL and 5235 ng/mL, respectively, and Cmax for the 340 mg/m2 dose of 10,578 ng/mL and 9270 ng/mL, respectively. t1/2 ranged from 3–4 h for tanespimycin and 4–5 h for 17‐AG. Tmax for all doses was approximately 1 h for tanespimycin and 1.5–2.6 h for 17‐AG. The most common AEs (all grades) in the continuation phase were: vomiting (65%; Gr3/4 0%), diarrhea (53%; Gr3/4 18%), nausea (47%; Gr3/4 0%), fatigue (35%; Gr3/4 9%), and headache (24%; Gr3/4 0%). Of the 11 response evaluable pts, 7 pts had a best response of stable disease (duration ranged from 4.1+ to 35.6 wks). Conclusion: Tanespimycin suspension was well tolerated in pts with solid tumors. Plasma concentration:time curves were similar for the 2 formulations with biexponential decay showing a rapid distribution followed by a slower elimination. These results support ongoing studies with twice weekly doses of 340 mg/m2 tanespimycin suspension. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C125.