Belinostat In Patients Research Articles

Abstract 114: Mass balance study of 14C- belinostat in patients with recurrent or progressive malignancy

Abstract Background: Belinostat is a hydroxamic acid based pan-histone deacetylase (HDAC) inhibitor that inhibits Class I, II, and IV HDAC enzymes at micromolar concentrations; it (Beleodaq) was recently approved in the US for the treatment of relapsed/refractory PTCL. The excretion of belinostat and its metabolites has been studied using radiolabeled belinostat in dogs and rats (∼70% and 50% excreted fecally and 30% and 50% excreted renally, respectively). The renal excretion of parent belinostat was <1% in both species. Objective: To determine the excretion route of radiolabeled belinostat and its metabolites following single IV administration of 14C-labeled belinostat in patients with advanced cancers. Secondary objectives included an assessment of safety. Methods: Patients with progressive or recurrent malignancies who failed standard therapies were eligible for the study. Patients with severe constipation, urinary incontinence, primary hepatic or renal carcinomas were excluded. Six eligible patients received a single dose of 14 C-labeled belinostat (approximately 90 to 105 μCi, 1500 mg) as a 30-minute IV infusion. Blood, urine, and fecal samples were collected at pre-determined time points (up to 168 hours) for measurement of total radioactivity. Results: Six patients with a median age of 66 yrs (range: 55 to 75) were enrolled. Total recoveries of radiolabeled material ranged from 87.6% to 97.9% (mean 94.5% ± 4.0%). The majority of the excreted belinostat dose in urine was recovered within 48 hours (83.8%) with only 9.3% in the feces within 96 hours. Renal elimination was the principal route of excretion of radioactivity in all patients, representing a mean of 84.8% ± 9.8% of the administered dose. Fecal excretion accounted for only 9.7% ± 6.5% of the administered dose. Belinostat was shown to be extensively metabolized. The parent compound accounted for only ∼10% of the total drug exposure and was below the level of detection in plasma samples taken 4.5 hours post-dose. Belinostat glucuronide was the major circulating plasma metabolite accounting for ∼65% of the total drug exposure with urinary excretion as the major route of elimination. Belinostat glucuronide was the predominant urinary metabolite accounting for 36% of the total administered dose. Belinostat amide was the most abundant metabolite in feces, accounting for 6% of the total administered radioactivity. The most commonly treatment-related adverse events were Grade 1-2 nausea (50%), infusion site pain (50%) and fatigue (33%). Conclusion: In this study, mass balance was achieved with a mean recovery of 94% radiolabeled belinostat. Belinostat was shown to be extensively metabolized with parent compound accounting for only about 10% of the excreted radiolabeled material and radiolabeled material was primarily excreted by the renal route. Belinostat glucuronide is the primary circulating metabolite and the primary metabolite excreted in the urine. Citation Format: Emiliano Calvo, Valentian Boni, Lina Garcia Canamaque, Guru Reddy, Jette Tjornelund, Tao Song, Mi Rim Choi, Lee F. Allen. Mass balance study of 14C- belinostat in patients with recurrent or progressive malignancy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 114. doi:10.1158/1538-7445.AM2015-114

Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review.

Peripheral T-cell lymphoma (PTCL) is a disease with poor prognosis and limited treatment options. Recent advances in cancer biology suggest that PTCL may be characterized by gross epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors. HDAC inhibitors have demonstrated significant activity in T-cell neoplasms and recently, the BELIEF trial evaluated belinostat leading to its approval in the US. This review discusses the development of belinostat, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for patients with relapsed or refractory PTCL. Key clinical trials covered include phase I/II evaluation of belinostat in hematologic malignancies, cutaneous T-cell lymphoma (CTCL) and PTCL. In addition, the BELIEF trial in PTCL leading to FDA approval of belinostat is reviewed in detail.

A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: a California Cancer Consortium Study

We performed a phase II study of belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m2 daily on days 1–5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.

Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): Results from the BELIEF trial.

8507 Background: Therapies approved in US for R/R PTCL have overall response rates (ORR) of 25%-27%. The need for new therapies persists. BELIEF is a pivotal, single-arm study of belinostat in patients with R/R PTCL after failure of ≥1 prior systemic therapies. Methods: Entry criteria were measurable PTCL, platelets ≥ 50,000/µL, no prior HDACi therapy, and adequate organ function. PTCL was confirmed by central pathology review (CPRG). Belinostat 30 min IV infusion at 1000 mg/m2was administered on days 1–5 of a 3 week cycle until progression or unacceptable toxicity. Tumor response was assessed by Cheson 2007 criteria. The primary endpoint was ORR. Results: Patients with R/R PTCL (N=129, 53% male, median age 63 y) received belinostat a median of 2 cycles (range 1–33). The median number of prior therapies was 2 (1-8) including CHOP/CHOP-like (96%) and stem cell transplant (23%). The median administered dose intensity was 98%. One and two dose reductions of 25% occurred in 12% and 1% of patients, respectively, due to adverse events (AEs). For patients with CPRG confirmed PTCL (N=120), the ORR was 26% (n=31; 10% CR; 16% PR). The median time to response was 5.6 weeks (range 4.3-50.4). The median duration of response (DoR) was 8.3 months; longest DoR was 29.4 months. Seven patients remain on study in response. For the subgroup of patients with CPRG confirmed PTCL and baseline platelets ≥100,000/μL (N=100) ORR was 28% (CR 11%; PR 17%). The most frequent (≥ 5%) grade 3-4 treatment emergent AEs were thrombocytopenia (13%), neutropenia (13%), anemia (10%), dyspnea (6%), pneumonia (6%), and fatigue (5%). Patients with platelets <100K tolerated belinostat, with 98% dose intensity. Belinostat was well tolerated with a low incidence of myelosuppression. Discontinuations were due to PD (64%), death (11%), AEs (7%), patient request (8%), and other (4%). Conclusions: Belinostat demonstrated a 26%-28% ORR in BELIEF and was well tolerated with a favorable safety profile in patients with R/R PTCL including those with low platelets. The low incidence of myelosuppression observed warrants further investigation of belinostat combination therapy to develop new treatment paradigms for R/R PTCL. Clinical trial information: NCT00865969.

Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update

Abstract 3588Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC).To date, 25 patients with the following disease types have been treated: acute leukemia (n=19), MDS (n=4), and CML-BC (n=2). The male:female ratio was n=11 (44%):14 (56%); the median age was 62 (range 27–83) years; ECOG performance scores ranged from 0–2; and the median number of prior therapies was 2 (range 1–5). The schedule of administration was belinostat, 30 minutes intravenous (IV) infusion, on days 1–5 and 8–12; and bortezomib, IV bolus, preceding belinostat on days 1, 4, 8, 11; on a 21-day cycle. Dose levels were, in mg/m2(bortezomib/belinostat): 1.0/500 (n=6); 1.3/500 (n=6); 1.3/650 (n=4); 1.3/850 (n=3); 1.3/1000 (n=4); 1.3/1200 (n=2). The study is currently enrolling to dose level 6 (1.3/1200).No dose-limiting toxicities (DLTs) have been observed to date. Non-DLT ≥ grade 2 (CTCAE version 4) treatment-related adverse events have included: fatigue (grade 2, 36%), leukopenia (grade 4, 12%), nausea (grade 2, 12%), peripheral sensory neuropathy (grade 2, 12%), and thrombocytopenia (grade 3, 20%). No serious adverse events have occurred at an unexpected frequency or severity. Two deaths have occurred due to disease progression, and one death has occurred due to a cerebrovascular accident that was related to pre-existing comorbidities and not to study-therapy.Of the 25 patients treated, 22 have been evaluable for response, 2 are too early to evaluate, and 1 patient was not evaluable for response. There have been 2 partial responses (PRs) and 1 complete response (CR) in this heavily pretreated population. The CR was achieved at dose level 1 in a patient with biphenotypic acute leukemia refractory to 7+3 and Flag-IDA. The patient proceeded to allogeneic hematopoietic stem cell transplantation (SCT) after 4 cycles of treatment. In addition, 1 patient with CML-BC had stable disease (SD) by protocol criteria but a CR with incomplete blood count recovery (CRi) by standard criteria, and is undergoing evaluation for allogeneic hematopoietic SCT. The patient is currently in cycle 8 at dose level 4. One of the PRs was achieved in a patient with AML transformed from MDS (2 prior regimens); after 4 cycles of treatment at dose level 5, the patient proceeded to allogeneic hematopoietic SCT. The second PR was achieved in an AML patient after cycle 2; a bone marrow biopsy revealed chronic myelomonocytic leukemia, and the response was deemed sufficient to proceed to allogeneic hematopoietic SCT. Also of note, a patient with AML transformed from MDS is currently on treatment in cycle 5 at dose level 5 with SD. An additional 6 patients have had SD, and 11 patients have had progressive disease. Correlative studies examining pre- and post-treatment leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP are ongoing.Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC and shows evidence of activity. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, should determine its activity more definitively. Disclosures:No relevant conflicts of interest to declare.

Efficacy of belinostat in advanced hepatocellular carcinoma (HCC): Phase I and II multicentered study of the Mayo Phase 2 Consortium (P2C) and the Cancer Therapeutics Research Group (CTRG).

259 Background: Belinostat is a novel histone deactylase inhibitor which demonstrates preclinical activity in HCC. We report the results of a phase I/II study on belinostat in patients (pts) with unresectable HCC. Methods: Major eligibility criteria included histologically confirmed HCC not amenable to curative treatment; PS ≤ 2; adequate organ function; prior systemic therapy was allowed. In the phase I portion, belinostat was given i.v. on D1-5 every 3 weeks with dose levels of 600, 900, 1200 and 1400 mg/m2/day. In the phase II portion, belinostat was tested at the MTD. Primary endpoint was PFS and secondary endpoints were RR according to RECIST and OS. CT assessment was done every 8 weeks. Results: Phase I portion: a total of 18 pts were accrued; no DLTs were observed at 1400mg/m2/day for 5 days, and this dose was selected for phase II development. Phase II portion: 42 pts were accrued; Median age = 57.5 years; 41 had Child’s A function, and 24 pt had ECOG 0. Sixteen (38%) had previous systemic therapy, and 21 (50%) had previous transarterial therapy. Median follow-up was 20.0 months. The PR and SD rate was 2.4% (1/42) and 45.2% (19/42). Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade 3 or higher toxicities (>5% rate) were abdominal pain (9.5%), (9.5%) hyperbilirubinemia (9.5%), raised ALT (9.5%); anemia (7.1%) and vomiting (7.1%). Conclusions: Belinostat demonstrates disease stabilization in a predominantly pretreated population of pts with unresectable HCC with an acceptable safety profile. Further randomized studies are warranted.Supported in part by N01-CM-62205.

Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis

Abstract 2598Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors, particularly in B-cell malignancies (e.g., myeloma and lymphoma). However, investigation of this strategy in acute leukemias has been limited. Very recent preclinical findings have shown marked synergism between the HDAC inhibitor belinostat and the proteasome inhibitor bortezomib administered at very low (sub-micromolar) concentrations, in various cultured and primary acute myelogenous leukemia and acute lymphocytic leukemia specimens (Dai Y et al. Br J Haematol. 2011). These interactions were associated with multiple perturbations in survival signaling proteins, including inactivation of NF-kappa B, down-regulation of Bcl-xL and XIAP, and up-regulation of the pro-apoptotic protein Bim. These findings prompted initiation of a phase I trial with the primary objective of determining the recommended phase II doses (RPTDs) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC).To date, 13 patients have been enrolled. Patients with the following disease types have been treated: acute leukemia (n=9), MDS (n=3), and CML-BC (n=1). Patient characteristics include male/female ratio n = 6 (46%)/7 (54%), with a median age of 59 years [range 27–75]. ECOG performance score 0–2. The median number of prior therapies was 2 [range 2–5]. The schedule of administration was belinostat 30 minutes intravenous (IV) infusion on days 1–5 and 8–12; and bortezomib IV bolus preceding belinostat on days 1, 4, 8, 11; on a 21 day cycle. Dose level enrollment was: Level 1 = bortezomib 1.0 mg/m2, belinostat 500 mg/m2 (n=6); Level 2 = bortezomib 1.3 mg/m2, belinostat 500 mg/m2 (n=6); and Level 3 = bortezomib 1.3 mg/m2, belinostat 650 mg/m2 (n=1). The study is currently enrolling to dose level 3.No dose-limiting toxicities (DLTs) have been observed to date. Non-DLTs (CTCAE v4) include: leukopenia (grade 4, 23%), thrombocytopenia (grade 3, 15%), and peripheral sensory neuropathy (grade 2, 23%). No serious adverse events have occurred at unexpected frequency or severity. Two deaths have occurred due to disease progression.Of the 13 patients treated, 12 have been evaluable for response. There has been 1 complete response in this heavily pretreated population. This response was achieved in a patient with biphenotypic acute leukemia, refractory to 7+3 and Flag-Ida. The patient proceeded to allogeneic hematopoietic stem cell transplantation. Four patients had stable disease, and 7 patients had progressive disease. Correlative studies examining leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP pre- and post-treatment are ongoing.Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC. The maximum tolerated dose (MTD) has not been reached. Pending identification of the RPTDs, phase II evaluation of this therapeutic strategy, if warranted, should define its activity more definitively. Disclosures:No relevant conflicts of interest to declare.

Interim Results of a Phase 1 Trial of An Oral Histone Deacetylase Inhibitor Belinostat In Patients with Lymphoid Malignancies.

AbstractAbstract 1787 Background:Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I study of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with allowance for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma. Objectives:safety and efficacy assessments of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; D 1500, E 1750; F 2000), treated d 1–14, q3w in pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions. Results:21 pts, sex (9 F, 12 M) - median age 48 (range 21 – 81), prior regimens, median 5 (range 1 – 13), 12 had BM transplants, including 3 pt with allogeneic have been enrolled. Diagnoses included Mantle Cell lymphoma (MCL; 5 pts), HD (7 pts), other NHL (9 pts).Median number of Belinostat cycles 3 (range 1–29) 1 pt remains on trial. In 21pts evaluable for tox the most frequent adverse events (regardless of attribution or grade) were: Diarrhea and fatigue (each in 18pts), vomiting (14 pts), cough and constipation (each in 12 pts), anxiety and decreased appetite (each in 11pts). Non-hem gr 3/4 events: 6 pts had gr 3 diarrhea – no dose dependency, – (1 grade 3 diarrhea at 1500-mg dose resulting in hospitalization - DLT) Gr 3 Abdominal pain; cholelithiasis; DVT; hyperthyroidism (each seen in 1 pt;), only gr 4 event was respiratory distress (1 pt in cohort C). Gr 4 Thrombocytopenia (2 pts - Cohort C and E) gr 3 Thrombocytopenia (4 pts - Cohorts, D, E, F) Gr 4 anemia (1 pt - cohort B) Gr 3 anemia (2 pts - Cohort C and D) Leucopenia grade 3 or 4 was not seen-. In 16 pts evaluable for efficacy, stable disease have been noted in 12 pts, including 4- pts with MCL, 4 pts with NHL and 4 with HD. 1 pt with HD had CR after C2 and was treated with additional 2 cycles. Conclusions:Oral Bel can be administered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. Protocol defined DLTs have been encountered in the dose range 750 – 2000mg in pts with lymphoma. Cohort D at 1500 mg was expanded due to 1 DLT (diarrhea). Cohort E at 1750 mg was tolerated without DLT and cohort F 2000 mg is currently being investigated. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds. Disclosures:Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Neylon:Allos Therapeutics, Inc.: Honoraria. Knoblauch:TopoTarget: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

Phase I pharmacokinetics and metabolic pathway of belinostat in patients with hepatocellular carcinoma.

2585 Background: Metabolic inactivation of several hydroxamic acid-derived histone deacetylase inhibitors (HDACi) involves glucuronidation. Vorinostat, a pan-HDACi, undergoes glucuronidation by UGT...

Phase II Study of Belinostat (PXD101), a Histone Deacetylase Inhibitor, for Second Line Therapy of Advanced Malignant Pleural Mesothelioma

Belinostat (PXD 101) is a novel inhibitor of class I and II histone deacetylases. This class of compounds has demonstrated anticancer activity in malignant mesothelioma. We conducted a phase II study of belinostat in patients with relapsed malignant pleural mesothelioma. Patients with advanced mesothelioma, progression with one prior chemotherapy regimen and Eastern Cooperative Oncology Group performance status 0-2 were eligible. Belinostat was administered at 1000 mg/m intravenously over 30 minutes on days 1-5 of every 3 week cycle. The primary end point was response rate. The Simon two-stage design was used. Disease assessments were performed every two cycles. Thirteen patients were enrolled. Baseline characteristics were: median age of 73 years; Eastern Cooperative Oncology Group performance status 0 (n = 4), 1 (8) and 2 (1). A median of two cycles of therapy were administered. Disease stabilization was seen in two patients. No objective responses were noted and the study did not meet criteria to proceed to the second stage of accrual. Median survival was 5 months with a median progression-free survival of 1 month. Salient toxicities included nausea, emesis, fatigue, and constipation. One patient died as a consequence of cardiac arrhythmia which was deemed 'possibly' related to therapy. Belinostat is not active as monotherapy against recurrent malignant pleural mesothelioma. Evaluation of combination strategies or alternate dosing schedules may be necessary for further development of this novel agent in mesothelioma.

404 POSTER A phase I study of oral administration of the histone deacetylase (HDAC) inhibitor belinostat in patients (pts) with advanced solid tumors

404 POSTER A phase I study of oral administration of the histone deacetylase (HDAC) inhibitor belinostat in patients (pts) with advanced solid tumors

A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia

To determine the safety, dose-limiting toxicity and maximum tolerated dose (MTD) of the novel hydroxamate histone deacetylase inhibitor belinostat (PXD101) in patients with advanced hematological neoplasms. Sequential dose-escalating cohorts of three to six patients with hematological malignancies received belinostat administered as a 30-min i.v. infusion on days 1-5 of a 21-d cycle. Experience from a parallel dose-finding study in patients with solid tumors influenced the selection of the final dose. Sixteen patients received belinostat at one of three dose levels: 600 mg/m(2)/d (three patients), 900 mg/m(2)/d (three patients) and 1000 mg/m(2)/d (10 patients), the dose determined to be the MTD in a phase I solid tumor study [Steele et al. (2008) Clin Cancer Res, 14, 804-10]. The most common treatment-related adverse events (all grades) were nausea (50%), vomiting (31%), fatigue (31%) and flushing (31%). No grade 3 or 4 hematological toxicity compared with baseline occurred except one case of grade 3 lymphopenia. There were two related grade 4 adverse events of renal failure observed. Both events occurred in patients with multiple myeloma and had similar characteristics, i.e. an acute episode of decrease in renal function (pre-existing nephropathy in one patient), with a metabolic profile and decrease in tumor burden consistent with tumor lysis syndrome. No other related grade 4 events were noted. The only related grade 3 events noticed in more than one patient were fatigue and neurological symptoms (one patient had status epilepticus in association with uremia and one patient had paresthesia), all other related grade 3 events occurred in single patients. No cardiac events were noted. No complete or partial remissions were noted in these heavily pre-treated (median of four prior regimens) patients. However, five patients, including two patients with diffuse large-cell lymphoma [including one patient with transformed chronic myelocytic leukaemia (CLL)], two patients with CLL and one patient with multiple myeloma, achieved disease stabilization in of two to nine treatment cycles. Intravenous belinostat at 600, 900 and 1000 mg/m(2)/d is well tolerated by patients with hematological malignancies. The study was carried out in parallel to a similar dose-finding study in patients with solid tumors, in which the MTD was determined to be 1000 mg/m(2)/d days 1-5 in a 21-d cycle. This dose can also be recommended for phase II studies in patients with hematological neoplasms.

A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors

To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors. Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels. Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m(2)/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m(2); one patient at 1,200 mg/m(2)), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m(2)), grade 3 atrial fibrillation (one patient at 1,200 mg/m(2); one patient at 1,000 mg/m(2)), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m(2)). The maximum tolerated dose was 1,000 mg/m(2)/d. I.v. belinostat displayed linear pharmacokinetics with respect to C(max) and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for > or =4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m(2)/d), 50% achieved stable disease. I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.

Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma: Results of a Phase II Study.

Background: Belinostat (PXD101) is a hydroxamate pan-histone deacetylase inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. Phase I studies have shown that belinostat is well-tolerated.Methods: This Phase II trial evaluated the activity of belinostat in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Belinostat (1000 mg/m2) was administered as a 30-min IV infusion on Days 1–5 of a 3-wk cycle. The primary endpoint was objective response (OR) rate analyzed separately for PTCL and CTCL using the Cheson criteria and Severity Weighted Assessment Tool (SWAT), respectively. For each arm, a Simon 2-stage design was used based on target OR rate of 25%, with expansion to 34 pts if ≥ 2/13 OR were observed.Results: In the PTCL arm, 12 pts (9 with stage III/IV disease) were enrolled; (7 PTCL-unspecified (PTCL-U), 2 anaplastic large cell lymphoma (ALCL), 2 angioimmunoblastic T-cell lymphoma and 1 NK-T-cell lymphoma), treated for a median of 2 cycles (range 1–8). Of 11 evaluable pts, 2 achieved a CR and 5 pts had SD. The two CR (11+ and 15+ wks) were both in pts with PTCL-U. A third pt with PTCL-U had SD lasting 14 wks and discontinued treatment due to an adverse event (AE). Both pts with ALCL had durable SD (20+ and 14 wks). In the CTCL arm, 16 pts were enrolled (9 Mycosis Fungoides (MF), 5 Sezary Syndrome (SS), 2 primary cutaneous ALCL) and treated for a median of 2 cycles (range 1–6). Four ORs were observed (25%): 1 CR (ALCL) and 3 PR (MF/SS). The median duration of the OR was 10 wks (range 7 to 39+ wks). Four additional pts had a 25 – 50% decrease in SWAT. Improvement in pruritus score by ≥ 3 on a visual analog scale was reported in 5/6 patients with significant pruritus at baseline. Overall in both study arms the drug was well-tolerated and most AE were grade 1/2 (nausea, fatigue, constipation, diarrhea, and vomiting). Grade 3 AE attributed to the study drug was reported in 7 pts and included peripheral edema, apraxia, adynamic ileus, pruritus, rash, and infections. Only 1 treatment related Grade 4 AE was noted (thrombocytopenia). One patient with progressive PTCL died 6 days after last belinostat dose with ventricular fibrillation and drug causality could not be excluded.Conclusions: Belinostat (PXD101) is generally well tolerated and demonstrates encouraging clinical activity in recurrent or refractory PTCL and CTCL. The objective response rate in both arms has met the pre-defined criteria for study expansion to stage II of enrollment.