Panobinostat In Patients Research Articles

ATRT-17. A phase II study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumours and atypical teratoid rhabdoid tumours.

BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.

ATRT-08. A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS

BACKGROUNDPanobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.METHODSFollowing cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.RESULTSSix patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.CONCLUSIONSTreatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.

Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma

Background Preclinical studies suggested synergistic anti-tumor activity when pairing mTOR inhibitors with histone deacetylase (HDAC) inhibitors. We completed a phase I, dose-finding trial for the mTOR inhibitor everolimus combined with the HDAC inhibitor panobinostat in advanced clear cell renal cell carcinoma (ccRCC) patients. We additionally investigated expression of microRNA 605 (miR-605) in serum samples obtained from trial participants. Patients and Methods Twenty-one patients completed our single institution, non-randomized, open-label, dose-escalation phase 1 trial. miR-605 levels were measured at cycle 1/day 1 (C1D1) and C2D1. Delta Ct method was utilized to evaluate miR-605 expression using U6B as an endogenous control. Results There were 3 dosing-limiting toxicities (DLTs): grade 4 thrombocytopenia (n = 1), grade 3 thrombocytopenia (n = 1), and grade 3 neutropenia (n = 1). Everolimus 5mg PO daily and panobinostat 10mg PO 3 times weekly (weeks 1 and 2) given in 21-daycycles was the recommended phase II dosing based on their maximum tolerated dose. The 6-month progression-free survival was 31% with a median of 4.1months (95% confidence internal; 2.0-7.1). There was higher baseline expression of miR-605 in patients with progressive disease (PD) vs those with stable disease (SD) (p = 0.0112). PD patients' miR-605 levels decreased after the 1st cycle (p = 0.0245), whereas SD patients' miR-605 levels increased (p = 0.0179). Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009.

Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial

Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the front-line treatment of multiple myeloma. Panobinostat is approved in combination with bortezomib and dexamethasone in patients with myeloma who 'have been given at least two previous regimens including bortezomib and an immunomodulatory agent. We aimed to determine the maximum tolerated dose of a new regimen combining VRd with panobinostat in patients with newly diagnosed multiple myeloma. In this phase 1 study, we enrolled patients from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) with newly diagnosed multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group 2014 diagnostic criteria. Participants were allocated either to the dose-escalation cohort or the dose-expansion cohort. In the dose-escalation cohort, in a 3 + 3 design, patients were treated in cycles of 21 days with bortezomib (1·3 mg/m2, subcutaneously) on days 1, 4, 8, 11; lenalidomide (25 mg, orally) on days 1-14; dexamethasone (20 mg, orally) on days 1, 2, 4, 5, 8, 9, 11, and 12; and escalating doses of panobinostat (10-20 mg, orally) on days 1, 3, 5, 8, 10, and 12. The dose level exceeded the maximum tolerated dose if at any given dose more than one of three patients, or two of six patients, had a dose-limiting toxic event. In the dose-expansion cohort, patients were given the maximum tolerated dose of the drug combination as determined from the dose-escalation cohort. Patients could proceed with upfront ASCT after two to four cycles of initial therapy or store their stem cells and proceed with a delayed ASCT approach. Patients with delayed ASCT could continue therapy for up to eight cycles, followed by maintenance with lenalidomide, dexamethasone, and panobinostat at their last tolerated dose for up to 2 years. The primary objective was to determine the maximum tolerated dose of VRd with panobinostat. Safety was assessed in all patients who completed at least one cycle of therapy. This trial is registered with ClinicalTrials.gov, number NCT01440582, and is no longer recruiting participants. Between Feb 18, 2013, and June 8, 2016, 55 patients were identified as eligible for enrolment. The dose-escalation cohort comprised 12 participants. The first three (25%) patients at dose level 1 (panobinostat 10 mg) did not encounter dose-limiting toxicity. Of six (50%) patients at dose level 2 (panobinostat 15 mg), two (33%) had dose-limiting toxic events during cycle 1; one (17%) had grade 4 thrombocytopenia with bleeding and the other had grade 3 diarrhoea, thus exceeding the maximum tolerated dose. Because the maximum tolerated dose had been exceeded, three more patients were accrued to dose level 1 and these patients did not experience dose-limiting toxic events. Dose level 1 (21 day cycles of bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg orally on days 1-14; dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12; and panobinostat 10 mg orally on days 1, 3, 5, 8, 10 and 12) was established as the maximum tolerated dose. The combination of VRd with panobinostat 10 mg is safe and effective in patients who are newly diagnosed with multiple myeloma and who are transplant eligible. Further studies in large randomised controlled settings are needed to confirm these results. Novartis and MD Anderson Cancer Center Support Grant.

Real-world outcomes with panobinostat in patients with penta- and quad-refractory multiple myeloma.

e19522 Background: Panobinostat (pano) is a pan histone de-acetylatase inhibitor (HDAC-i) approved by the FDA for use with bortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had ≥2 prior lines of therapy including both btz and an immunomodulatory agent (IMiD). The goal of this retrospective study is to evaluate the efficacy and safety of pano in combination with a variety of FDA approved agents as would be utilized in a real world management in relapsed/refractory (RR) MM. Methods: Between February 2015 and July 2016, 37 consecutive patients with RRMM treated with commercial pano were identified and the electronic medical record was reviewed. Results: Median age was 62 (range 27-78), with 57% percent male. Ten (27%) had high-risk FISH as defined by t(14;16), t(4;14), del p53, and gain 1q21. Median number of prior lines was 6 (range 2-9). All patients were RR to their last line of therapy, and 20 (54%) were btz-refractory, 27 (73%) were lenalidomide-refractory, 29 (78%) were pomalidomide-refractory, and 29 (78%) were carfilzomib-refractory. Thirty-three (89%) were penta-refractory; eight (21%) were penta-refractory, and 4 (11%) were refractory to prior HDAC-i therapy. Median number of cycles with pano was 2 (range 0.25 - 10). The overall response rate (≥ partial response) was 29.4% and the clinical benefit rate (≥ minor response) was 71.4%. Median progression-free survival was 2.4 months (95% CI: [1.63 – 4.43]). Median duration of response (≥SD) was 4.1 months. Median overall survival from initiation of pano was 7.5 months (95% CI: [5.17, NA]). One patient discontinued pano due to AEs. Grade 3 and 4 non-hematologic toxicities were diarrhea (N = 1), and respiratory failure (N = 1). Grade 3 and 4 hematologic adverse events (AEs) occurred in 13 (35%) patients, with 7 (19%) anemia, 11 neutropenia (30%), and 10 (37%) thrombocytopenia. Serious AEs included acute kidney injury, GI bleed, and febrile neutropenia each occurring in 1 patient. Conclusions: Use of pano outside of the FDA indication in combination with PI and IMiD-based regimens has activity and is well tolerated in quad and penta-refractory MM patients.

Real-World Outcomes with Panobinostat in Patients with Relapsed/Refractory Multiple Myeloma

Background: Histone acetylation plays a key role in regulating gene expression and in control of cellular activities in multiple pathways involved in normal and cancer cell growth.Panobinostat (pano) is a pan histone de-acetylase inhibitor (HDAC-i) approved by the FDA on February 23, 2015 for use withbortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had at least 2 prior lines of therapy including bothbtz and an immunomodulatory agent (IMiD). The combination ofpano withIMiDs and proteasome inhibitors (PIs) has been found to demonstrate enhanced anti-myeloma activity in clinical trials (Berdeja JG et al, 2015,Haematologica;Mateos M et al, 2010, ASCO Abstract 8030, JCO 28:15s). The goal of this retrospective study is to evaluate the real world experience on efficacy and safety ofpano in combination with a variety of FDA approved agents including a PI, anIMiD or a monoclonal antibody-based regimen in patients with relapsed/refractory MM.Methods: Between February 23, 2015 and July 1, 2016, 34 consecutive patients with relapsed/refractory MM who were treated with commercialpano were identified from the JohnTheurer Cancer Center. Charts were analyzed for response and safety data. The study was approved by the institutional review board.Results: Median age was 63 (range 27-78), with 58% percent men. Thirty-one patients (91.2%) wereDurie-Salmon stage II or III. Ten (30%) had high-risk FISH as defined byt(14;16), t(4;14), del p53, and gain 1q21. Median number of prior lines was 5 (range 2-9). All patients were relapsed/refractory to their last line of therapy, and 18 (53%) werebtz-refractory, 25 (74%) werelenalidomide-refractory, 27 (79%) werepomalidomide-refractory, and 29 (85%) were carfilzomib-refractory. Twenty-five (74%) were refractory to the combination of carfilzomib with anIMiD. Five patients (14.7%) had priordaratumumab, and 4 (12%) had prior HDAC-i therapy. Median number of cycles withpano was 1 (range 1-5). The overall response rate (≥ partial response (PR)) was 23.5% and the clinical benefit rate (≥ minor response (MR)) was 67.6%. The median duration of response (≥ stable disease (SD)) was 3 months. The median progression-free survival (PFS) for all patients was 2.3 months (95% CI: [1.27 - 4.07]). See Figure 1. Median overall survival (OS) from initiation ofpano through 7/27/16 was 5.5 months (95% CI: [3.93, NA]). See Figure 2. Of the 4 patients who were refractory to a prior HDAC-i, 1 achieved PR (4 cycles), 1 achieved MR (5 cycles) and 2 had disease progression. Only 1 patient discontinuedpano due to toxicities. Grade 3 and 4 non-hematologic toxicities were diarrhea (N=1), and hypoxia/respiratory failure (N=1). Grade 3 and 4 hematologic toxicities occurred in 11 (32%) patients, with 5 (15%) anemia, 9 neutropenia (26%), and 8 (24%) thrombocytopenia. Serious adverse events included acute kidney injury, GI bleed, and febrile neutropenia in 3 patients, respectively.Conclusions: These observations demonstrate that real-world use ofpano outside of the FDA indication in combination with PI andIMiD-based regimens has activity and is well tolerated in heavily pretreated patients with relapsed/refractory MM, even those who have exhausted conventional treatments. Further assessment in a larger prospective study is warranted. [Display omitted] [Display omitted] DisclosuresBiran:Takeda: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. Vesole:Janssen: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Richter:Celgene: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Siegel:Celgene: Honoraria, Speakers Bureau; Merck: Honoraria; Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

A phase II study of panobinostat in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF)

Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16–56%). The median percent reduction in spleen volume was 34% (range, 1.6%–73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; −4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7–44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.

Efficacy and Safety of Panobinostat in Relapsed or/and Refractory Multiple Myeloma: Meta Analyses of Clinical Trials and Systematic Review.

During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer relapsing. Thus, novel therapeutic agents are needed. We aimed to assess the efficacy and safety of a novel agent panobinostat for patients with relapsed or/and refractory MM. A systematic literature review identified studies for clinical trials about panobinostat in patients with relapsed or/and refractory MM. We searched studies published between January 2000 and December 2015 in Pubmed, Ovid, EBSCO and the Cochrane library. Random-effect pooled estimates were calculated for overall response rate and rates of common adverse effects. The results showed 11 clinical trials including 700 patients with relapsed or/and refractory MM treated with panobinostat were identified. The ORR varied between 0.08 and 0.67. Pooled analyses showed the results that the ORR was 0.45 (95% CI: 0.31–0.59, I2 = 90.5%, P = 0.000) for panobinostat combined with any other kind of drugs. The most common Grade3/4 adverse effects were thrombocytopenia, neutropenia, lymphopenia, anemia, diarrhea, fatigue, nausea and so on. In conclusion, based on our analyses, the regimen of panobinostat combining with other agents seems to be well tolerated and efficacious in patients with relapsed or/and refractory MM.

Panobinostat: first global approval.

Novartis has developed oral and intravenous formulations of panobinostat (Farydak(®)), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical development worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma.

A Phase I/II Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin’s Lymphoma (HL)

Introduction: Phase 2 single agent trials with lenalidomide and panobinostat in patients with relapsed or refractory HL have demonstrated overall response rates (ORR) of 19% (Fehniger et al., Blood 118:5119-5125, 2011) and 27% (Younes et al., JCO 30:2197-2203, 2012), respectively. We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with combined lenalidomide and panobinostat in patients with relapsed HL.Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy were eligible. Measurable disease > 1 cm, ejection fraction ≥ 45%, ECOG PS 0-2, QTc ≤ 450 msec, ANC ≥ 1200/mm3, platelets ≥ 100,000/mm3, AST/ALT ≤ 2.5 x the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN, and creatinine clearance 60 ≥ ml/min were also required. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly were combined with lenalidomide 25 mg days 1-21 utilizing a 3+3 standard dose escalation design. DLT was defined during cycle 1 as grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, or other grade 3-4 non-hematologic toxicity. Twenty-eight days defined a cycle and patients could remain on therapy until disease progression. Response was assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 25:579-586, 2007).Results: From Feb 2012 through June 2014, 22 patients (16 males) with cHL (n=21) and LP HL (n=1) and a median age of 45 (range 22-72) have been enrolled. Patients had received a median of 4 prior therapies (range 2-13), 9 patients were refractory to their most recent therapy, and 91% had stage III-IV disease at study entry. Ten patients had a prior autologous SCT, 1 patient had received prior allogeneic EBV-directed cytotoxic T-cells, 1 patient had a prior syngeneic transplant, and 1 patient had both prior autologous and allogeneic transplants. Eleven patients were enrolled in the phase 1 study at dose level (DL) 1 (25 mg lenalidomide + 15 mg panobinostat, n=6) and at DL 2 (25 mg lenalidomide + 20 mg panobinostat, n=5). Although there were no DLTs observed in cycle 1, 2 patients treated at DL 2 experienced grade 4 neutropenia and thrombocytopenia for > 14 days in cycle 2 and 3 of 5 patients were dose reduced to DL 1 in cycles 2 or 3. Therefore, DL 1 was expanded to 6 patients to ensure patient safety at this dose level and the phase 2 study was conducted at DL 1. Eleven patients have been treated in the phase 2 study. In all 22 patients, the median number of cycles completed on study was 4 (range 1-22). Grade 3-4 toxicities in all patients included neutropenia (59%), thrombocytopenia (41%), lymphopenia (27%), febrile neutropenia (27%), hypophosphatemia (9%), hypocalcemia (5%), QTc prolongation (5%), fatigue (5%), nausea/vomiting (5%), erythema nodosum (5%), transaminitis (5%), and unexplained altered mental status after administration of study medications (5%). Dose reductions were required in 10 patients (45%, 5 in the phase 2 study and 3 patients with multiple dose reductions) for febrile neutropenia, grade 3-4 neutropenia/thrombocytopenia, erythema nodosum, and transaminitis. Twenty-one patients have discontinued protocol therapy for PD (n=15), adverse events (n=5, including grade 4 neutropenia/thrombocytopenia or unexplained altered mental status after drug dosing), and to undergo elective CABG (n=1). ORR is 14% (2 CR and 1 PR) in 21 evaluable patients with complete responses in 1 patient with cHL and 1 patient with LP HL of 6 and 25 months duration, respectively.Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL. Due to myelosuppression at higher doses, the recommended phase 2 dose of the combination is 25 mg lenalidomide days 1-21 with 15 mg panobinostat days 1, 3, and 5 weekly on a 28-day cycle. Accrual continues to the two-stage phase 2 trial, but based on preliminary data in the first 22 patients, the efficacy of combined lenalidomide and panobinostat appears similar to that previously reported with these drugs as single agents. DisclosuresChristian:Celgene: Research Funding. Fehniger:Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Bartlett:Celgene: Research Funding; Novartis: Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of Hodgkin’s lymphoma.

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis

Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here.Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose.Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a >50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies.Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. [Display omitted] DisclosuresKiladjian:Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

572 Oral panobinostat in patients with advanced tumors and impaired renal function: Relationship between pharmacokinetics and key safety parameters

KDM1A, a FAD dependent histone demethylase with high homology to amino-oxidases, is responsible of the demethylation of mono and dimethyl lysine 4 on histone H3. KDM1A is part of various transcriptional corepressor complexes and interacts with the co-repressor complex CoREST and histone deacetylases (HDAC) 1 and 2. KDM1A is an essential gene with important roles in different biological relevant processes, including hematopoietic maturation. Its activity has also been demonstrated on non histone substrates such as p53, DNMT1 and MYPT1. High expression and correlation with poor prognosis has been reported for KDM1A in several cancer types, such as neuroblastoma, prostate cancer and non small cell lung cancer. Moreover the high expression of KDM1A and its inverse correlation in hematological malignancies, mostly in acute myeloid leukemia, was observed. Furthermore the enzyme has been demonstrated to sustain the in vivo leukemiogenic potential of MLLAF9 expressing leukemia stem cells. In the light of these findings, KDM1A has been increasingly recognized as an attractive therapeutic target in oncology. We have developed a novel series of potent and irreversible KDM1A inhibitors based on tranylcypromine. The compounds were obtained by a versatile and scalable synthetic process which allows a stereoselective synthesis of the trans enantiomers of the cyclopropane ring. Biochemical and biological characterization of these inhibitors, including their transcriptional effect on KDM1A targets and efficacy in reducing colony forming ability in leukemia cells, will be reported, together with ADME and pharmacokinetic properties of selected compounds. Finally, the best inhibitors of the series induced after oral administration a significant survival increase and provided evidences of target modulation in an in vivo murine promyelocytic leukemia model.

Use of Panobinostat in Patients with Classical Hodgkin Lymphoma

SUMMARY Panobinostat is a deacetylase inhibitor that exerts antitumor activity by modifying the acetylation status of histones and other critical cellular proteins. Panobinostat as a single agent produced an overall response rate of 27% in patients with relapsed or recurrent Hodgkin lymphoma after stem cell transplantation. Clinical trials of panobinostat combined with chemotherapy or with other targeting agents such as mTOR inhibitors or lenalidomide have shown promising interim results. The most common toxicity with panobinostat as a single agent or in combination is thrombocytopenia. Patient enrollment in ongoing or future clinical trials of panobinostat is encouraged so that the role of this agent in patients with recurrent classical Hodgkin lymphoma can be further studied.

Post-Transplant Maintenance With The Deacetylase Inhibitor Panobinostat In Patients With High-Risk AML Or MDS: Results Of The Phase I Part Of The Panobest Trial

Inhibitors of class I/II histone deacetylases (HDACi) possess anti-leukemic activity and have been reported to modulate the function of immune effector cells. Thus, they could provide specific clinical benefit in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. Panobinostat (PAN) is a potent, orally available pan-HDACi reported to either suppress or stimulate regulatory T cells (T reg), depending on the administered dose (Shen L & Pili R, OncoImmunology 1;7:948, 2012). The feasibility and efficacy of PAN treatment following HSCT for patients (pts) with high risk acute myeloid leukemia (AML) has not been established. We report clinical and translational results of the dose-escalation phase of the PANOBEST study with PAN as post-HSCT maintenance.Primary objectives were, based on dose-limiting toxicity (DLT), determining the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PAN in patients with high risk AML or myelodysplastic syndromes (MDS) in complete remission (CR) after reduced-intensity conditioning HSCT. Secondary objectives were the evaluation of safety, tolerability and immunoregulatory properties of PAN, and overall (OS) and disease-free survival (DFS) of treated patients.PAN was started at 10 mg p.o. three times a week (TIW) and escalated to 20 and 30 mg TIW using a 3+3 design. Treatment was initiated 60-150 days after HSCT and continued for up to one year. Eligibility criteria included: recovery of peripheral blood counts, adequate organ function and no severe graft versus host disease (GvHD). All pts gave written informed consent. DLT was defined as prolonged grade 4 hematologic or grade 3/4 non-hematologic toxicity within 28 days of the first PAN dose. Immunophenoytyping of lymphocyte subsets was performed pre-treatment and on days 3, 8, 30, 90, 180 and 360.12 pts (11 AML, 1 MDS), median age of 52 years (21-62) were enrolled. PAN was started within a median of 73 days (60-126) after HSCT, which was performed with active disease (n=11) or in CR2 (n=1). The RP2D was determined to be 20 mg TIW based on one DLT (fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 mg. Grade 2-4 adverse events (AEs) were reported in 10 out of the 12 pts (83%). Grade 3/4 AEs included hematologic toxicity (50% of pts), laboratory alterations (33%), gastrointestinal symptoms (25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was reversible and required at least one PAN dose reduction in 3 pts. Acute GvHD grade 2 (1 pt) and 3 (2 pts) was responsive to steroids in 2 pts or salvage therapy in 1 pt. Four pts developed mild (n=3) or moderate (n=1) chronic GvHD. To date, 5 pts have completed one year of PAN and 2 pts remain on treatment (days 238, 290). Five pts discontinued treatment prematurely after 10-217 days due to grade 3 toxicities (n=4) or AML relapse (n=1). With a median follow up of 579 days (129-911), 11/12 pts are alive and 10/12 in continuous CR after HSCT. Seven pts received prophylactic donor lymphocyte infusions (DLIs, 1-5 doses of 0.1-20x106 CD3+ cells/kg). Immunophenotyping revealed no impact of PAN on absolute T reg numbers (9 pts), but a significantly reduced proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 after 3 doses of PAN (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). While Treg/Th proportion continuously decreased in pts with ongoing CR, it again increased after PAN discontinuation or remained stable under PAN treatment in both relapsing patients. Outcome of the study population was compared with a historical cohort of 29 consecutive pts with active AML transplanted in Frankfurt in 2000-2009. Both cohorts were similar in age, gender, disease stage or BM blasts at time of HSCT, donor type and use of DLIs. In a landmark analysis including all pts who were in CR and without severe GvHD on day 73 after HSCT, probabilities for DFS and OS at 18 months after HSCT were 83±11% vs. 55±9% (p=0.145, log-rank test) and 92±8% vs.66±9% (p=0.085) in the PANOBEST vs. historical cohort (Fig 1). [Display omitted] PAN is well tolerated after HSCT at a RP2D of 20 mg TIW. Comparison with a historical control cohort of pts transplanted with active AML shows a low relapse rate, which appears to be associated with a PAN-induced modulation of the T reg/Th proportion. Disclosures:Bug:Novartis: Honoraria, Travel grants, support for the clinical study Other. Ottmann:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group

Background:Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS.Methods:We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate.Results:Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21–79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10–35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months.Conclusion:Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer

Panobinostat, a pan-deacetylase inhibitor, increases acetylation of proteins associated with growth and survival of malignant cells. This phase 2 study evaluated the efficacy of intravenous (IV) panobinostat in patients with castration-resistant prostate cancer (CRPC) who had previously received chemotherapy. The primary end point was 24-week progression-free survival. Secondary end points included safety, tolerability, and the proportion of patients with a prostate-specific antigen (PSA) decline. IV panobinostat (20mg/m(2)) was administered to patients on days 1 and 8 of a 21-day cycle. Tumor response was assessed by imaging every 12weeks (4 cycles) according to modified response evaluation criteria in solid tumors (Scher et al. in Clin Cancer Res 11:5223-5232, 23), and PSA response was defined as a 50% decrease from baseline maintained for ≥4weeks. Safety monitoring was routinely performed and included electrocardiogram monitoring. Of 35 enrolled patients, four (11.4%) were alive without progression of disease at 24weeks. PSA was evaluated in 34 (97.1%) patients: five (14.3%) patients demonstrated a decrease in PSA but none ≥50%; one patient (2.9%) had carcinoembryonic antigen as a marker of his prostate cancer, which declined by 43%. Toxicities regardless of relationship to panobinostat included fatigue (62.9%), thrombocytopenia (45.7%), nausea (51.4%), and decreased appetite (37.1%). Despite promising preclinical data and scientific rationale, treatment with IV panobinostat did not show a sufficient level of clinical activity to pursue further investigation as a single agent in CRPC.

Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia

AbstractThe present study aimed to determine the safety and activity of the histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia (WM). Eligibility criteria included patients with relapsed/refractory WM with any number of prior therapies. Patients received panobinostat at 30 mg 3 times a week; 12 of 36 (33%) patients were enrolled at 25 mg dose. A total of 36 patients received therapy. The median age was 62 years (range, 47-80) and the median number of prior therapies was 3 (range, 1-8). All of the patients had received prior rituximab. Minimal response (MR) or better was achieved in 47% of patients (90% confidence interval [CI], 33-62), with 22% partial remissions and 25% MR. In addition, 18 (50%) patients achieved stable disease and none showed progression while on therapy. The median time to first response was 1.8 months (range, 1.7-3.2). The median progression-free survival was 6.6 months(90% CI, 5.5-14.8). Grade 3 and 4 toxicities included thrombocytopenia (67%), neutropenia (36%), anemia (28%), leukopenia (22%), and fatigue (11%). We conclude that panobinostat is an active therapeutic agent in patients with relapsed/refractory WM. This study (www.clinicaltrials.gov identifier: NCT00936611) establishes a role for histone deacetylase inhibitors as an active class of therapeutic agents in WM.

Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.

A phase I dose-escalation study of intravenous panobinostat in patients with lymphoma and solid tumors

Panobinostat, a pan-deacetylase inhibitor, is a promising anti-cancer agent that increases acetylation of proteins associated with growth and survival pathways of malignant cells. The primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) of intravenous (i.v.) panobinostat administered on different dosing schedules in patients with advanced solid tumors or lymphoma. Secondary objective was to characterize safety and tolerability, pharmacokinetic profiles, and activities of the i.v. formulation. i.v. panobinostat was administered at escalating doses on a daily (days 1-3 and 8-10 of a 21-day cycle; days 1-3 and 15-17 of a 28-day cycle) or weekly (days 1, 8, and 15 of a 28-day cycle; days 1 and 8 of a 21-day cycle) schedule, and safety and tolerability were monitored. Serial blood samples were collected following dosing for pharmacokinetic and pharmacodynamic analyses. The MTD for the daily administration schedule was 7.2 g/m(2), whereas the MTD for the weekly schedule was 20.0 mg/m(2). In addition to fatigue and cardiac arrhythmias, including prolonged QTcF, DLTs associated with the study drug were principally due to myelosuppressive effects. Maximum concentrations and bioavailability of i.v. panobinostat increased dose-proportionally across all doses evaluated. Based on the results of this study and others, the i.v. formulation of panobinostat was well tolerated in many patients, but concerns remain regarding its potential suitability outside the study setting due to potential electrocardiogram abnormalities. Therefore, further development will focus on the panobinostat oral formulation.

Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.