panobinostat and Pain

Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen.. We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m. Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders.. Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma.. Novartis and Myeloma UK.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Constipation; Dexamethasone; Diarrhea; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Fatigue; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxamic Acids; Hyponatremia; Hypophosphatemia; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Nausea; Pain; Panobinostat; Peripheral Nervous System Diseases; Thalidomide; Therapeutic Index, Drug; Treatment Outcome; United Kingdom

Osteoarthritis (OA) is the most common articular degenerative disease characterized by chronic pain, joint inflammation, and movement limitations, which are significantly influenced by aberrant epigenetic modifications of numerous OA-susceptible genes. Recent studies revealed that both the abnormal activation and differential expression of histone deacetylases (HDACs) might contribute to OA pathogenesis. In this study, we investigated the chondroprotective effects of a marine-derived HDAC inhibitor, panobinostat, on anterior cruciate ligament transection (ACLT)-induced experimental OA rats. The intra-articular administration of 2 or 10 µg of panobinostat (each group,

Topics: Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Cartilage Diseases; Cartilage, Articular; Chondrocytes; Disease Models, Animal; Histone Deacetylase Inhibitors; Male; Osteoarthritis, Knee; Pain; Panobinostat; Rats; Rats, Wistar; Weight-Bearing