panobinostat and Diarrhea

Patients with relapsed or refractory multiple myeloma who have received several lines of therapy have no satisfactory treatment options. High-dose corticosteroid therapy or a combination of low-dose dexamethasone and pomaildomide may be proposed. Panobinostat is the first histone deacetylase (HDAC) inhibitor to be authorised in the European Union for use in this indication. A randomised, double-blind, placebo-controlled trial evaluated panobinostat in 768 patients with relapsed or refractory multiple myeloma who were also receiving bortezomib + dexamethasone. Panobinostat did not prolong survival. The median time to myeloma progression, relapse, or death was prolonged by about 3 months with the panobinostat-containing combination, and by a median of about 8 months in the subgroup of patients who had received at least two lines of chemotherapy including bortezomib and an "immunomodulatory" drug. There was no statistically significant increase in survival, however. In this trial, adverse events led one in six patients to discontinue panobinostat and resulted in numerous hospital admissions. The proportion of patients who died from causes unrelated to myeloma was 6.8% in the panobinostat group versus 3.2% In the placebo group. The toxicity of panobinostat affects most vital functions, resulting in a risk of infections as well as haematological, gastrointestinal, cardiac, renal, hepatic and thyroid disorders. These adverse effects are often severe and sometimes fatal. Panobinostat is subject to pharmacokinetic interactions via cytochrome P450 enzymes and P-glycoproteln, and also to pharmacodynamic Interactions. Panobinostat was teratogenic in animal studies. In practice, even when several previous lines of treatment have failed, panobinostatis more toxic than useful In patients with myeloma. It should therefore not be used.

Topics: Antineoplastic Agents; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Diarrhea; Drug Interactions; Gastrointestinal Diseases; Hemorrhage; Humans; Hypothyroidism; Infections; Mortality; Multiple Myeloma; Myocardial Ischemia; Neutropenia; Panobinostat; Progression-Free Survival; Renal Insufficiency; Survival Rate; Thrombocytopenia

Panobinostat, bortezomib, and dexamethasone combination therapy demonstrated progression-free survival (PFS) benefit over bortezomib and dexamethasone alone in the PANORAMA-1 study in relapsed/refractory multiple myeloma (MM). Here, we present data from a phase II study (NCT02290431) of this combination in Japanese patients with relapsed or relapsed-and-refractory MM.. Patients received 3-week cycles of 20-mg oral panobinostat (weeks 1 and 2), 1.3-mg/m2 subcutaneous bortezomib (days 1, 4, 8, and 11), and 20-mg oral dexamethasone (day of and the day following bortezomib administration) for a total of 8 cycles (24 weeks; treatment phase 1). Patients with treatment benefit had an option to enter the extension phase to receive 6-week (42-day) cycles of panobinostat (weeks 1, 2, 4, and 5) plus bortezomib (days 1, 8, 22, and 29) and dexamethasone (day of and the day following bortezomib treatment) for 24 weeks. The primary objective was complete response (CR) + near CR (nCR) rate after treatment phase 1 as per the modified European Society for Blood and Marrow Transplantation criteria.. Of the 31 patients, 4 (12.9%) completed the treatment and 27 (87.1%) discontinued; 17 (54.8%) entered the extension phase. In total, 24 patients (77.4%) entered the survival follow-up phase and followed until study closure when the last patient was treated for 1 year after treatment phase 1. The CR + nCR rate was 48.4% (90% CI: 33.6-63.2). The overall response rate (CR + nCR + partial response) was 80.6%. The median PFS, duration of response, time to response, and time to progression were 15.3, 22.7, 1.4, and 15.3 months, respectively. All patients experienced adverse events (AEs), with diarrhea (80.6%), decreased appetite (58.1%), and thrombocytopenia (54.8%) being the most frequent, regardless of relationship to the study treatment. Thrombocytopenia (48.4%), fatigue (25.8%), diarrhea (22.6%), neutrophil count decrease (22.6%), platelet count decrease (22.6%), and lymphocyte count decrease (22.6%) were the most frequent grade 3/4 AEs.. The study met the primary objective with 48.4% CR + nCR rate. The AEs associated with the combination treatment were safely managed using the existing AE management guidelines, including dose interruption/modification and/or supportive medical intervention. This treatment regimen is an effective option with a favorable benefit/risk profile for Japanese patients with relapsed/refractory MM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Diarrhea; Drug Administration Schedule; Half-Life; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Panobinostat; Progression-Free Survival; Recurrence; Remission Induction; Thrombocytopenia

Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received ≥ 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability.. In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1.3 mg/m. Thirty-nine patients with a median number of previous treatments of 4 (range, 1-12) were enrolled; most received subcutaneous bortezomib (87%). The overall response rate (partial response or better) was 56%. Grade 3/4 adverse events included thrombocytopenia (47%), fatigue (31%), dehydration (26%), and diarrhea (18%). Among the patients who received subcutaneous bortezomib, relatively low rates of peripheral neuropathy (all grade, 15%) and notable grade 3/4 adverse events (thrombocytopenia, 47%; diarrhea, 12%) were observed.. Overall, data from the PANEX trial support regulatory approval of panobinostat plus bortezomib and dexamethasone and suggest the potential tolerability benefits of subcutaneous bortezomib in this regimen.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dehydration; Dexamethasone; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Peripheral Nervous System Diseases; Thrombocytopenia; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Nausea; Neoplasm Recurrence, Local; Neutropenia; Panobinostat; Prospective Studies; Risk Factors; Transplantation, Autologous; Young Adult

Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial.. PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m. Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50).. The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this.. Novartis Pharmaceuticals.

Topics: Activities of Daily Living; Adult; Age Factors; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Asian People; Asthenia; Blood Cell Count; Bortezomib; Chromosome Aberrations; Creatinine; Dexamethasone; Diarrhea; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Resistance, Neoplasm; Fatigue; Female; Geography; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasm Staging; Panobinostat; Patient Dropouts; Peripheral Nervous System Diseases; Quality of Life; Renal Insufficiency; Sex Factors; Steroids; Survival Analysis; Thrombocytopenia; Time Factors; Treatment Outcome

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

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Diarrhea; Humans; Hydroxamic Acids; Indoles; Induction Chemotherapy; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Panobinostat; Preoperative Period; Stem Cell Transplantation; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome; Vomiting

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Boronic Acids; Bortezomib; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Male; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Panobinostat; Pyrazines; Recurrence; Remission Induction; Thalidomide; Thrombocytopenia; Treatment Outcome