Oral Panobinostat Research Articles

DIPG-93. OVERALL EXPERIENCE OF TWO PHASE I CLINICAL TRIALS WITH FOCUSED ULTRASOUND-MEDIATED BLOOD BRAIN BARRIER OPENING IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH PROGRESSIVE DIPG/DMG USING A NEURONAVIGATION-BASED DEVICE

Abstract OBJECTIVES DIPG/DMG is a fatal brain tumor developing in delicate areas of the brain with a median overall survival of 1 year. The dismal outcome is partly due to the blood-brain barrier (BBB) which poses a major challenge to delivering effective therapeutic agents. Over the past 4 years we opened two Phase I clinical trials using Delsona focused ultrasound (FUS) device developed at Columbia University to treat pediatric and AYA patients with relapsed DMG. In the first study, we delivered FUS with concomitant panobinostat and during the second study we gave oral etoposide. Here we present our experience of delivering neuronavigation based FUS for pediatric patients with progressive DMG. METHODS Pediatric and AYA patients with biopsy proven DIPG/DMG at disease progression were enrolled (FUS with oral panobinostat: NCT04804709 and FUS with oral etoposide: NCT05762419). Patients were allowed to have prior therapies, including radiation and reirradiation. FUS was delivered over the course of six or four cycles respectively. MRI was performed to validate BBB-opening and closure. RESULTS During the FUS-panobinostat study, we treated 3 patients. The study was closed prematurely when panobinostat was taken off the US market. In the FUS-etoposide study, we have already treated 2 patients (the study is currently open). For the two trials combined, we delivered over twenty-five FUS treatments. Four of the five patients treated had achieved BBB-opening. Two patients in the FUS and panobinostat study showed improvement in their neurological symptoms. The average time for FUS-delivery was approximately 47 minutes. All treatments were performed in the outpatient settings in the Department of Radiation Oncology. Side effects from FUS was limited to one grade 1 dermatological toxicity. CONCLUSION FUS-mediated BBB-opening delivered as an outpatient procedure is feasible, to date, in children with relapsed DIPG/DMG. Further studies are needed to assess for efficacy.

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.

Epigenetic Priming with Pre-Transplant Oral Panobinostat Followed By Post-Transplant Consolidation

Despite the rich armamentarium of novel agents that are available to treat multiple myeloma (MM), high dose melphalan (HDM) and stem cell transplant (SCT) remain an essential therapy that achieves long-term durable remissions. However, most patients relapse following HDM-SCT due to the persistence of minimal residual disease (MRD). Therefore, there remains an unmet clinical need to overcome chemoresistant MRD and potentially achieve a cure for MM patients. Here, we describe a phase Ib trial designed to epigenetically priming with pre-transplant oral panobinostat to increase MRD sensitivity to HDM-SCT.The contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides a strong rationale for the use of epigenetic modulators, such as the histone deacetylase (HDAC) inhibitor panobinstat as anti-myeloma therapy. Access to DNA is primarily governed by chromatin structure such that its configuration is under control of histone acetylators and deacetylators. Inhibition of histone deacetylases weakens the histone-DNA bonds and decondenses chromatin, i.e., epigenetic priming, which potentially enhances sensitivity to melphalan. Pre-clinical studies have demonstrated a strong synergistic effect between panobionostat (LBH589) and melphalan in in vitro as well as in vivo studies utilizing patient-derived xenograph models, i.e., SCID-hu model of human MM, LAG-1(Sanchez et al. Leukemia research. March 2011). Furthermore, HDAC inhibitors suppress multi-drug resistance protein-1 (MRP1) and it can count as another mechanism of synergy for this class of drugs and alkylating agents in hematologic disorders (Tsubaki M. et al. Leukemia research. Oct 2012). Taken together, these studies support HDAC inhibitors in combination with melphalan to augment anti-myeloma efficacy of HDM-SCT. Here, we propose the combination through a pre-SCT epigenetic priming phase with high dose panobinostat and a post-SCT lower dose panobinostat consolidation phase (Study Schema).Trial design: We propose a Simon 3+3 design to test panobinostat at three dose levels of 20, 30 and 40 mg every other day for four doses prior to high dose melphalan as study schema illustrates. There will not be any intra-patient dose escalation. The study will be extended to another 15 patients at the maximum tolerated dose for the pre-SCT phase. All patients regardless of the pre-SCT panobinostat dose level will received fixed dose of Panobinostat. Primary and Secondary objectives and endpoints are listed in Table 1.Rationale for high dose panobinostat in epigenomic phase: Previous reports of HDACi combined with standard-dose chemotherapy (e.g., Ifosfomide, Carboplatin, and Etoposide for lymphoma or 7+3 for acute myeloid leukemia) had shown prolonged myelosuppression as the main adverse effect, but no significant increase in the non-hematological toxicities. Therefore, we predict the use of peripheral blood progenitor cells in the offered study has potential to circumvent the increased myelotoxicity associated with pre-SCT high dose panobinostat, and it may render the opportunity to test higher doses such as 40 mg every other day before SCT as epigenetic priming strategy.Rational for low dose panobinostat dosing for the consolidation phase: The Panobinostat consolidation design will follow the positive landmark trial by the Australian group (Mithraprabhu S. et al. British J. Hemat. Apr 2021). In their study panobinostat was given at 20 mg three times weekly on alternate weeks for 6 months started 8-12 weeks post-transplant was administered. Forty eight percent of patients improved their depth of response after a median range of 4.3 months of panobinostat. In responders, T lymphocyte histone acetylation increased after both three cycles and six cycles of panobinostat when compare to baseline, with no differences in no-responders. [Display omitted] DisclosuresMalek: Janssen: Other: Advisory board ; Bluespark Inc.: Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Sanofi: Other: Advisory Board; Medpacto Inc.: Research Funding; Takeda: Honoraria. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. Stricker: Secura Bio: Current Employment. OffLabel Disclosure:Panobinostat has been used as single agent therapy before and after transplant in this trial.

Phase II, Multicenter, Single-Arm, Open-Label Study to Evaluate the Efficacy and Safety of Panobinostat in Combination with Bortezomib and Dexamethasone in Japanese Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies

Background: Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. Study design: The trial evaluated two schedules of oral panobinostat using 3 + 3 dose escalations in 28-day cycles. For children with leukemia, panobinostat was given once daily three days a week each week at 24, 30 and 34 mg/m2/day. For children with lymphoma, panobinostat was given once daily three days a week every other week at 16, 20 and 24 mg/m2/day. Cerebrospinal fluid (CSF) from Day 29 of the first cycle, when available, was evaluated for PK. The study was registered on clinicaltrials.gov (NCT01321346) Results: Twenty-two subjects enrolled with leukemia. Five enrolled at dose level 1, 6 at dose level 2, and 11 at dose level 3. There was one dose limiting toxicity (DLT) in the leukemia arm at dose level 3 (Grade 4 hypertriglyceridemia), but no maximum tolerated dose (MTD) was identified. No subjects required removal from protocol therapy for QTc prolongation. PK studies were available in 11 subjects with similar exposure in children as in adults. Four Day 29 CSF specimens were found to have panobinostat levels below the lower limit of quantification. Five subjects with lymphoma were enrolled and received study drug, and 4 were evaluable for DLT. A DLT was reported (Grade 3 enteritis) on the lymphoma arm. Conclusions: Panobinostat was tolerated in heavily pretreated pediatric subjects. Gastrointestinal effects were observed on this study. There were no cardiac findings. There were no responses.

Safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high-risk acute myeloid leukemia

The role of histone deacetylase inhibitors in the treatment of acute myeloid leukemia (AML) is not well characterized. The current study evaluated the safety and efficacy of panobinostat in combination with idarubicin and cytarabine in newly diagnosed patients aged ≤65 years with primary or secondary high-risk AML based on cytogenetic classification. Treatment included fixed dose idarubicin (12 mg/m2/d, IV; day 1–3) and cytarabine (100 mg/m2/d, continuous IV infusion; day 1–7) and escalating oral doses of panobinostat at 15 mg, 20 mg, and 25 mg, thrice weekly starting at week 2 of a 28-day cycle. Forty-six patients were enrolled (primary AML [n = 36], secondary AML [n = 10]). The median age was 55 years. The most common all-grade AEs were diarrhea (54.3%), nausea (39.1%), vomiting, and decreased appetite (each, 21.7%), stomatitis (19.6%), and fatigue (17.4%). The overall response rate was 60.9%, 43.5% achieved a complete remission (CR), and 17.4% achieved CR with incomplete count recovery. The event-free survival at 1-year was 78.3%. Panobinostat in combination with idarubicin and cytarabine demonstrated tolerable safety and efficacy in younger patients with high-risk AML. The recommended phase 2 dose of panobinostat in this combination was 20 mg. ClinicalTrials.gov registry no: NCT01242774, and European Trial Registry EudraCT no: 2009-016809-42.

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with \u2a7d30% blasts

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

A phase I trial of panobinostat with ipilimumab in advanced melanoma.

9547 Background: Immune checkpoint blockade is standard therapy for advanced melanoma (MEL), yet not all patients (pts) benefit. Panobinostat (PAN), a pan inhibitor of class I, II, and IV histone deacetylases (HDAC) is immunomodulatory, decreases tumor associated inhibitory cytokines and inhibition of effector T-cells. This dose finding study aimed to determine the safety and efficacy of escalating doses of PAN combined with ipilimumab (IPI) in advanced MEL. Methods: Eligible pts with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5mg thrice weekly (TIW) plus IPI at 3mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5mg was planned in 3-12 pt cohorts up to a maximum dose of 20mg TIW, without intra-pt dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy. Results: Seventeen pts (M/F: 13/4), median age 66 yrs (48, 80) were treated with a median of 4 cycles of IPI (1,4). Of 6 pts treated at PAN 5mg TIW, there was one DLT (G3 hydronephrosis). Eleven pts received PAN 10mg TIW; of 9 evaluable for DLT, there were 3 DLTs (G3 rash, G3 diarrhea, G4 thrombocytopenia) preventing further dose escalation. Other G3 toxicities included anemia, hypophysitis, diarrhea, fatigue (all n = 2); rash, colitis, nausea, dehydration, dizziness, hypotension, ↑ lipase, ↓ sodium, &amp; ↑ glucose (all n = 1). Three pts had previous anti-PD1 therapy. The response rate was 12% (2 PRs) with 35% stable disease. One pt remains on PAN &gt; 24m since start of therapy. Median progression free- and overall survival was 2.23m (95% CI,1.57, 5.8) and 20.97m (95% CI, 8.97, NR) respectively. Biomarker analysis from peripheral blood and limited tumor biopsies pre-and on treatment examining immunoregulatory markers, including EOMES promoter acetylation in T-cells from PAN are ongoing. Conclusions: At tolerated doses, PAN does not appear to increase response to standard IPI in advanced MEL. Biomarker analyses will inform if immunomodulation by PAM improves efficacy of IPI. Combinations with selective HDAC inhibitors may be more appropriate for future study. Supported by grant P50 CA168536, Moffitt Skin Cancer SPORE. Clinical trial information: NCT02032810.

Improved Safety with the Use of Subcutaneous Bortezomib in Combination with Panobinostat and Dexamethasone: Preliminary Data from a Panobinostat Global Expanded Treatment Protocol

Introduction:Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its epigenetic effects as well as its effect on the aggresome. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN+BTZ+Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to approval in Europe of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory agent. The purpose of this expanded treatment protocol (ETP) is to further evaluate safety and to provide panobinostat prior to commercial availability to patients with relapsed/refractory MM who have received ≥ 2 prior lines of therapy but for whom satisfactory treatment alternatives are not available.Methods:Panobinostat-ETP is a multicenter, open-label, ETP study of PAN+BTZ+Dex in adult patients with MM relapsed and/or refractory to ≥ 2 prior lines of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN 20 mg (days 1, 3, 5, 8, 10, and 12) plus intravenous or subcutaneous BTZ 1.3 mg/m2 (days 1, 4, 8, and 11) for eight 21-day cycles. Patients with ≥ stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex 20 mg was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed prior to TP2 as a dose reduction strategy.Results:A total of 49 patients with a median age of 67 years (range, 45-85 years) were enrolled in the study. Patients were heavily pretreated; 73.5% received ≥ 3 prior lines of therapy. Most patients (n = 43 [87.8%]) received subcutaneous BTZ, while 3 (6.1%) received intravenous BTZ, and another 3 (6.1%) received both. The median duration of treatment with PAN+BTZ+Dex was 67 days (range, 12-305 days). The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (51.0%), anemia (12.2%), and neutropenia (10.2%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were diarrhea (14.3%), fatigue (8.2%), infection (6.1%), and nausea (6.1%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (51.0%), constipation (16.3%), and nausea (16.3%). Interestingly, in the patients receiving subcutaneous BTZ, the rates of grade 3/4 diarrhea (11.6%), thrombocytopenia (48.8%), anemia (14.0%), and neutropenia (11.6%) were lower than those seen with intravenous BTZ administration in the phase 3 PANORAMA 1 trial (25%, 57%, 16.8%, and 24.1%, respectively). Two patients died while on treatment; one due to disease progression and the other due to infection. Common serious AEs included diarrhea (12.2%) and thrombocytopenia, atrial fibrillation, infection, pneumonia, and syncope (all 6.1%); serious AEs of atrial fibrillation and syncope were higher than in PANORAMA 1 (1.0% and 1.3%, respectively). AEs led to PAN, BTZ, and Dex dose adjustment in 36.7%, 42.9%, and 16.3% of patients, respectively; the most common AE leading to dose adjustment or temporary interruption was thrombocytopenia (all-grade, 30.6%; grade 3/4, 28.6%). Efficacy data will be reported after sufficient follow-up.Conclusions:Overall, the safety results from panobinostat-ETP, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1, with only a slight increase in atrial fibrillation, potentially because of the older population. In the subgroup of patients receiving subcutaneous BTZ, rates of diarrhea and hematologic toxicities, AEs of interest with PAN+BTZ+Dex therapy, appear to be reduced compared with PANORAMA 1 data with intravenous BTZ administration; however, because of the small size of this study, these results should be interpreted with caution. Further clinical experience with the use of subcutaneous BTZ in this combination will help to determine the potential impact of the route of BTZ administration on tolerability. DisclosuresGuenther:Takeda: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol Myers-Suibb: Honoraria. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lechner:Novartis: Honoraria. Gisslinger:Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria. Greil:Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen: Consultancy, Honoraria; Bristol Myer-Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Munder:Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria. Kiani:Novartis: Consultancy, Honoraria, Speakers Bureau. Campello-Iddison:Novartis: Employment, Equity Ownership. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.

Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma.

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3-4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.

An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients with Previously Treated Myeloma

Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its effects on epigenetics and protein metabolism. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN-BTZ-Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to US Food and Drug Administration approval of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens including BTZ and an immunomodulatory agent. The "PANobinostat EXpansion treatment protocol" (PANEX) study was developed to provide access to PAN and gather additional safety data on the PAN-BTZ-Dex combination until PAN became commercially available.Methods: PANEX is a multicenter, open-label, expanded treatment protocol study of PAN-BTZ-Dex in adult patients with MM relapsed and/or refractory to ≥ 1 prior line of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN (20 mg; days 1, 3, 5, 8, 10, and 12) plus intravenous (IV) or subcutaneous (SC) BTZ (1.3 mg/m2; days 1, 4, 8, and 11) for eight 21-day cycles. Patients with at least stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex (20 mg) was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed before TP2 as a dose reduction strategy. Response assessments were completed per modified European Group for Blood and Marrow Transplantation criteria.Results: A total of 39 patients, with a median age of 70 years (range, 44-88 years), were enrolled in the study. Patients were heavily pretreated, with a median of 3 prior lines of therapy (range, 1-12; 21% ≥ 7 prior therapies), with nearly half of the patients (48.7%) having progressed on their most recent therapy. Most patients received SC BTZ (87.2% [n = 34] vs 12.8% [n = 5] IV BTZ), with a median treatment duration of 9.4 weeks (range, 2-34). A total of 21 patients achieved a partial response, leading to an overall response rate of 53.8%; an additional 17.9% achieved a minimal response, for a clinical benefit rate (≥ minimal response) of 71.8%, with 25.6% having stable disease. Notably, no patients in the current trial had a best response of progressive disease. The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (53.8%), anemia (17.9%), and neutropenia (17.9%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were dehydration (28.2%), fatigue (28.2%), diarrhea (17.9%), asthenia (10.3%), and pneumonia (10.3%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (48.7%), nausea (25.6%), and vomiting (12.8%), and nearly all cases of dehydration were associated with these gastrointestinal events. Interestingly, in the patients receiving SC BTZ (n = 34), the rate of grade 3/4 diarrhea was 11.8%, approximately half the rate seen with IV BTZ administration in the phase 3 PANORAMA 1 trial (25%). Common serious AEs included dehydration (15.4%), diarrhea (12.8%), and pneumonia (10.3%). AEs led to PAN, BTZ, and Dex dose reductions in 59.0%, 59.0%, and 46.2% of patients, respectively.Conclusions: Overall, the results from PANEX, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1. In the subgroup of patients receiving SC BTZ, the rate of diarrhea, an AE of interest with PAN-BTZ-Dex therapy, appeared to be reduced when compared with PANORAMA 1 data with IV BTZ administration. Further clinical experience with the use of SC BTZ in this combination will help to determine the potential impact of route of BTZ administration on tolerability. DisclosuresElkins:Pharmacyclics/Janssen: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Letzer:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Levy:Takeda: Consultancy. Seneviratne:Novartis: Honoraria, Speakers Bureau. Rine:Novartis: Employment. White:Novartis: Employment. Kuriakose:Novartis: Employment, Equity Ownership.

Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial

Patients with relapsed or refractory peripheral T-cell lymphoma have a poor prognosis after conventional chemotherapy. Approved novel agents have only modest single-agent activity in most subtypes of peripheral T-cell lymphoma. Panobinostat is a potent oral pan-deacetylase inhibitor. Findings of many preclinical studies have shown synergistic antilymphoma activity when panobinostat is combined with the proteasome inhibitor bortezomib. We aimed to study the effect of panobinostat and bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma. In this open-label, multicentre phase 2 trial, we recruited patients aged 21 years or older with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy from five tertiary hospitals in Singapore, Malaysia, and South Korea. Patients received 20 mg oral panobinostat three times a week and 1·3 mg/m(2) intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The primary endpoint was the proportion of patients who achieved an objective response in accordance with the International Working Group revised response criteria; analyses were by intention to treat. The study is completed and is registered with ClinicalTrials.gov, number NCT00901147. Between Nov 9, 2009, and Nov 26, 2013, we enrolled 25 patients with various histological subtypes of peripheral T-cell lymphoma. Of 23 patients assessable for responses, ten (43%, 95% CI 23-63) patients had an objective response, of which five were complete responses. Serious adverse events were reported in ten (40%) of 25 patients. Common treatment-related grade 3-4 adverse events included thrombocytopenia (17 [68%]), neutropenia (ten [40%]), diarrhoea (five [20%]), and asthenia or fatigue (two [8%]). We recorded peripheral neuropathy of any grade in ten (40%) patients. Combined proteasome and histone deacetylase inhibition is safe and feasible and shows encouraging activity for patients with peripheral T-cell lymphoma. Our findings validate those of preclinical studies showing synergism in the combination and represent a rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma. Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Singhealth Foundation.

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.

Activation of latent human immunodeficiency virus by the histone deacetylase inhibitor panobinostat: a pilot study to assess effects on the central nervous system.

In a substudy of a clinical trial, we assessed whether activation of latent human immunodeficiency virus (HIV) by the histone deacetylase inhibitor panobinostat had detrimental effects on the central nervous system (CNS). Adults infected with HIV received oral panobinostat 20 mg 3 times per week every other week for 8 weeks. In cerebrospinal fluid (CSF), we assayed panobinostat concentration, HIV RNA, and the level of neuroinflammatory or degenerative biomarkers in 11 individuals before and during study therapy. Neither panobinostat nor HIV RNA was detected in CSF. In addition, there was no change from baseline in CSF biomarkers. Thus, panobinostat administration was not associated with CNS adverse effects as assessed by CSF biomarkers.

A Phase II, Single-Center, Open-Label Study of Oral Panobinostat in Combination with Lenalidomide and Weekly Dexamethasone in Patients with Multiple Myeloma

Background: Treatment options for patients with multiple myeloma (MM) refractory (ref) to immunomodulatory drugs and proteasome inhibitors are urgently needed. A promising strategy is the use of epigenetic agents such as the pan histone deacetylase inhibitor (HDACi) panobinostat (pan) to modulate the acetylation of histones and proteins involved in oncogenesis. Pre-clinical studies with pan demonstrate synergy against MM cells when combined with dexamethasone (dex), lenalidomide (len), and bortezomib (btz) (Ocio EM et al. Haematologica 2010). Interim data from the phase 3 PANORMA 1 study of 768 patients randomized to receive IV btz and dex with either pan or placebo revealed a 3.9 month increase in PFS with pan along with an increase in CR rates. However, this was accompanied by 25% grade 3/ 4 diarrhea versus 8% in the placebo arm.The safety and preliminary efficacy of the pan-len-dex triplet regimen was assessed in a phase 1b study of relapsed (rel) or rel/ref MM patients (Mateos et al, ASCO 2010) but was complicated by high dose dex toxicities. The maximum tolerated dose of pan and dex in that study are the doses selected for this phase 2 study. However we investigated a modified schedule (table 1) of this triplet regimen. Here, pan is given thrice weekly only every other week (instead of weekly) and dex is given weekly (instead of three 4 day pulses).Patients and Methods: Inclusion criteria were patients with rel or rel/ref MM, measurable disease, adequate performance status, organ function, and hematologic parameters. Patients previously treated with a HDACI or currently receiving medications with a risk of prolonging the QTc interval were excluded.The primary objective was to evaluate the best overall response rate (ORR). Secondary objectives were to evaluate safety, response duration, and overall and progression-free survival. Each drug was administered at the doses and schedule shown in Table 1.Results: Overall, 13 evaluable patients with progressive disease (PD) at screening have been enrolled, including 9 len-refractory (2 also pomalidomide refractory) and 4 len sensitive with a median of 4 and 3 lines of prior therapy respectively (range 1–10). High-risk molecular findings were present in 9 patients, including 6 with gain of 1q21 by FISH and 3 with del p53. Three of the patients with gain of 1q21 also had t (4;14).Of the 13 patients, there have been 3 very good partial responses (VGPR), 2 partial responses (PR), 3 minimal responses (MR), 4 stable diseases (SD), and 1 PD, for an ORR of 38% and clinical benefit rate (CBR i.e. MR or greater) of 61 %. With a median follow up of 4.5 months the median progression free survival and duration of response have not been reached. Of the 9 patients who were len refractory, there were 2 VGPR, 2 MRs, 4 SD, and 1 PD for a 22% ORR and 44% CBR. Notably, 3 len refractory patients remain on treatment for 11, 16, and 16 months including 2 with gain of 1q21 that have attained VGPRs.Grade 3/4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia, thrombocytopenia, lymphopenia, and anemia noted in 7, 4, 1, and 1 patients respectively. Grade 3/4 nonhematologic AEs included infections in 4 (with 1 one occurring while neutropenic), and 1 patient with each of the following: pulmonary embolus, neck pain, QTc prolongation, and weight loss 1. Dose modifications for neutropenia were required in 4 patients for len and in 2 patients for pan. 1 additional patient required pan dose reduction for asymptomatic T wave inversions. Nausea was noted in 2 patients and diarrhea in 3 with 2 additional patients experiencing both – however these were transient, Grade 1/2, and did not require dose modifications. Importantly, no patients discontinued therapy for toxicity.Conclusions: In rel/ref MM patients, pan in combination with len and dex demonstrates durable responses, even in len-refractory patients with high-risk molecular findings, indicating the essential role of pan in attaining a response. These results suggest that pan modulates expression of genes to restore sensitivity to len, In notable contrast to the PANORMA 1 results, this completely oral regimen is well tolerated with no Grade 3/4 GI toxicities and primarily expected hematologic toxicities. Updated results, including correlative studies, will be presented at the annual meeting.Table 1:Study Drug DosesPanobinostatLenalidomideDexamethasone20 mg po Day 1, 3, 5, 15, 17,1925 mg po Day 1-2140 mg po Day 1, 8, 15 DisclosuresChari:Array Biopharma: Membership on an entity’s Board of Directors or advisory committees; Millenium : Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

Efficacy and Safety Based on Duration of Treatment of Panobinostat Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma in the Phase 3 Panorama 1 Study

Efficacy and Safety Based on Duration of Treatment of Panobinostat Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma in the Phase 3 Panorama 1 Study

AT-36PANOBINOSTAT IN COMBINATION WITH BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA AND ANAPLASTIC GLIOMA

Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as the exploratory study. Patients received oral panobinostat 30 mg 3 x per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was PFS6 in the GBM cohort and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). At planned interim analysis, 13 of the first 21 patients accrued to the GBM cohort had progressed within 6 months of initiating study treatment. The GBM cohort did not meet criteria for continued accrual and was closed early. In the GBM cohort, PFS6 rate was 30.4%, median PFS 5 months, median OS 9 months. Accrual in the AG cohort continued to completion and a total of 15 patients were enrolled. In the AG cohort, PFS6 rate was 46.7%, median PFS 7 months, median OS 17 months. The most common grade 3 or 4 toxicities in the GBM arm were hypophosphatemia (12.5%), thrombocytopenia (12.5%), lymphopenia (8.3%), neutropenia (8.3%), and ALT elevation (8.3%). In the AG arm, the most common toxicities were thrombocytopenia (20.0%) and hypophosphatemia (13.3%). Although reasonably well-tolerated, this phase II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the GBM cohort of the study was closed. In the recurrent AG cohort, the PFS6 rate was similar to historical controls. Updated data will be presented.

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.

Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial

Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased significantly at all timepoints when patients were taking panobinostat (p < 0·0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3·5-fold (range 2·1-14·4). Panobinostat induced plasma viraemia with an odds ratio of 10·5 (95% CI 2·2-50·3; p = 0·0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. Panobinostat effectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to significantly affect the latent HIV reservoir. The Danish Council for Strategic Research and Aarhus University.

Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome

Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m2 subcutaneously (days 1–5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.