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Pasireotide treatment significantly reduces tumor volume in patients with Cushing's disease: results from a Phase 3 study.

ABSTRACT: PURPOSE:In the multinational, randomized, double-blind, Phase 3 B2305 study of patients with Cushing's disease (CD; ClinicalTrials.gov identifier NCT00434148), pasireotide substantially decreased urinary-free cortisol (UFC) levels, decreased mean corticotroph tumor volume, and improved clinical signs of disease. The current post hoc analysis further assesses the effects of pasireotide on corticotroph pituitary tumor volume. METHODS:Patients enrolled in the B2305 study had persistent or recurrent CD or newly diagnosed CD but were not surgical candidates. Enrollees were randomized to receive subcutaneous pasireotide, either 600-?g or 900-?g twice daily. Tumor volume was assessed independently at months 6 and 12 by 2 blinded radiologists and compared with baseline value and UFC response. RESULTS:Of 162 patients enrolled in the trial, 53 had measurable tumor volume data and were included in the post hoc analysis. Reductions in tumor volume were both dose and time dependent. Tumor volume reduction was more frequently observed at month 6 in the 900-?g group (75%) than in the 600-?g group (44%). Similarly, at month 12 (n?=?32), tumor volume reduction was observed more frequently in the 900-µg group (89%) than in the 600-µg group (50%). Control of UFC levels was not required for reduction of tumor volume. No relationship was noted between baseline tumor size and change in tumor size. CONCLUSIONS:Measurable decreases in pituitary tumor volume were observed in a large proportion of patients with CD and measurable tumor volume who were enrolled in the trial and treated with subcutaneous pasireotide; this decrease was not correlated with UFC control. CLINICALTRIALS. GOV IDENTIFIER:NCT00434148.

SUBMITTER: Lacroix A

PROVIDER: S-EPMC7181422 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Pasireotide treatment significantly reduces tumor volume in patients with Cushing's disease: results from a Phase 3 study.

Lacroix André A Gu Feng F Schopohl Jochen J Kandra Albert A Pedroncelli Alberto M AM Jin Lixian L Pivonello Rosario R

Pituitary 20200601 3

<h4>Purpose</h4>In the multinational, randomized, double-blind, Phase 3 B2305 study of patients with Cushing's disease (CD; ClinicalTrials.gov identifier NCT00434148), pasireotide substantially decreased urinary-free cortisol (UFC) levels, decreased mean corticotroph tumor volume, and improved clinical signs of disease. The current post hoc analysis further assesses the effects of pasireotide on corticotroph pituitary tumor volume.<h4>Methods</h4>Patients enrolled in the B2305 study had persiste ...[more]

PMID: 31875276

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Project description:PurposeCushing's disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia.MethodsClinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.ResultsThe frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3-67.0 %) than in patients with CD treated with pasireotide SC (68.4-73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791-799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875-884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320-326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914-924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues.ConclusionsDisease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation.

Project description:Introduction: The efficacy and safety of subcutaneous (sc) pasireotide have been evaluated in a Phase III trial. Here, we report safety and efficacy results from a multinational, expanded-access study of pasireotide sc in patients with Cushing's disease (CD) in a real-world setting (clinicaltrials.gov, identifier: NCT01582061). Methods: Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 μg twice daily (bid; EU countries) or 900 μg bid (non-EU countries; 600 μg bid in patients with impaired glucose metabolism). Pasireotide dose could be adjusted in 300 μg increments/decrements to a maximum of 900 μg bid or minimum of 300 μg bid for sustained urinary free cortisol (UFC) normalization/tolerability issues. Primary objective: document the safety of pasireotide sc in patients with CD. Key secondary objectives: assess the proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) and changes from baseline in clinical signs/symptoms and quality of life (QoL) to weeks 12, 24, and 48. Results: One hundred and four patients received pasireotide: female, n = 84 (80.8%); median duration of pasireotide exposure, 25.1 weeks; median (range) baseline mUFC, 321.2 nmol/24 h (142-10,920; 2.3 × ULN [1.0-79.2]). Forty (38.5%) patients completed the study. The most common reasons for premature discontinuation of pasireotide were unsatisfactory therapeutic effect (n = 26, 25.0%) and adverse events (AEs; n = 20, 19.2%). Drug-related grade 3/4 AEs or drug-related serious AEs (primary endpoint) were documented in 42 (40.4%) patients, most commonly diabetes mellitus (n = 12, 11.5%) and hyperglycemia (n = 8, 7.7%). All patients experienced ≥1 AE and most (n = 102; 98.1%) reported ≥1 drug-related AE; six (5.8%) patients discontinued treatment because of hyperglycemia-related AEs. At weeks 12, 24, and 48, respectively, 36/66 (54.5%), 22/46 (47.8%), and 9/21 (42.9%) evaluable patients had normalized mUFC levels. Clinical signs/symptoms and QoL were also improved. Conclusions: In an international, real-world, clinical-practice setting, pasireotide sc was generally well-tolerated (no new safety signals were identified), effectively reduced UFC (normalization in ~50% of evaluable patients) and improved clinical signs and QoL in patients with CD. While hyperglycemia-related AEs were common, consistent with previous studies, most were manageable, with <6% of patients discontinuing treatment because of these events.

Project description:Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

Project description:Abstract Background: In a Phase II study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized mean urinary free cortisol (mUFC) in most patients with CD (Fleseriu M et al. Pituitary 2016;19:138-48). We report the efficacy and safety of osilodrostat in a large CD patient population in the first randomized withdrawal Phase III study in this rare, serious disorder (clinicaltrials.gov: NCT02180217). Methods: Phase III, multicenter, double-blind, randomized withdrawal study following a 24-week, open-label, single-arm treatment phase. Open-label osilodrostat was initiated at 2 mg bid in 137 adults with CD and mUFC (mean of three 24-h samples) >1.5xULN (ULN=50.0 µg/24h), with dose adjustments every 2 weeks (dose range 1-30 mg bid) up to week (W) 12 based on efficacy (if mUFC >ULN) and tolerability. At W26, 71 eligible patients (mUFC ≤ULN at W24 without a dose increase after W12) were randomized to continue osilodrostat (n=36) or matching placebo (n=35) for 8 weeks, followed by open-label osilodrostat until W48. Patients who remained on treatment at W26 but were not eligible for randomization continued open-label osilodrostat (n=47). Primary endpoint: patients in each randomized group with mUFC ≤ULN at the end of the randomized withdrawal phase (W34) without a dose increase after W26. For all mUFC assessments, patients who discontinued were classed as non-responders at subsequent time points. Results: At baseline, median (range) mUFC was 3.5xULN (0.3-69.6) in enrolled patients. At the end of the randomized withdrawal period (W34), significantly more patients maintained mUFC ≤ULN (without a dose increase after W26) in the osilodrostat group than in the placebo group (86% vs 29%; OR 13.7, P<0.001). Other endpoints: at W24, 53% of enrolled patients had mUFC ≤ULN without a dose increase after W12 (key secondary endpoint); at W48, 66% of enrolled patients had mUFC ≤ULN; 96% of enrolled patients had mUFC ≤ULN at least once during the study; median time to first mUFC ≤ULN was 41 days. Median (range) duration of osilodrostat exposure was 75 weeks (1-165). By W48, 24 (18%) patients had discontinued the study, 15 (11%) because of AEs. Overall, the most common AEs were nausea (42%), headache (34%) and fatigue (28%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 51% and 42% of patients, respectively. The most common AEs reported in the osilodrostat group during the randomized withdrawal period were nausea (11% vs 0% for placebo), anemia (8% vs 9%), arthralgia (8% vs 0%) and headache (8% vs 0%). Conclusion: Osilodrostat was significantly superior to placebo at maintaining mUFC ≤ULN after randomized withdrawal and normalized mUFC in two-thirds of enrolled patients at W48, with few patients discontinuing treatment because of AEs. This randomized withdrawal study demonstrates osilodrostat to be a highly effective treatment for CD, with good tolerability.

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Pasireotide treatment significantly reduces tumor volume in patients with Cushing's disease: results from a Phase 3 study.

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Pasireotide treatment significantly reduces tumor volume in patients with Cushing's disease: results from a Phase 3 study.

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