Igor Espinoza-Delgado

Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma

Purpose: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically. Experimental Design: A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 and vorinostat at 100 to 500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory multiple myeloma patients. Vorinostat pharmacokinetics and dynamics were assessed. Results: Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range, 3-13), including autologous transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory. Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade >3 toxicities were myelo-suppression (n = 13), fatigue (n = 11), and diarrhea (n = 5). There were no drug-related deaths. Overall response rate was 42%, including three partial responses among nine bortezomib refractory patients. Vorinostat pharmacokinetics were nonlinear. Serum Cmax reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells before and on day 11 showed no correlation between protein levels of NF-κB, IκB, acetylated tubulin, and p21CIP1 and clinical response. Conclusions: The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation. (Clin Cancer Res 2009;15(16):5250–7)

Carboplatin and Paclitaxel in Combination With Either Vorinostat or Placebo for First-Line Therapy of Advanced Non–Small-Cell Lung Cancer

PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone-mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200 mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.

Phase II Study of Vorinostat for Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma

PURPOSE We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma. PATIENTS AND METHODS In this open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with ≤ 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability. RESULTS All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses [CR] and five partial responses [PR]). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue. CONCLUSION Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted.

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

Background: 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. Methods: 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/m2 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. Results: 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. Conclusions: 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.

Vorinostat (NSC# 701852) in Patients with Relapsed Non-small Cell Lung Cancer: A Wisconsin Oncology Network Phase II Study

Introduction: Vorinostat is a small molecule inhibitor of histone deacetylase, and has shown preclinical activity in non-small cell lung cancer (NSCLC). Methods: Patients with relapsed NSCLC were eligible. Patients received oral vorinostat, 400 mg daily. The primary objective was response rate, with the goal of at least one responder in the first 14 evaluable patients, according to the two-stage minimax design. Secondary objectives included time to progression (TTP), overall survival (OS), and safety. Results: Sixteen patients enrolled from January 2006 to April 2007. The median age was 59.5 years. Thirteen patients were female. Two patients were not evaluable for response due to progressive disease within Cycle 1. No objective antitumor responses were seen in the 14 evaluable patients. Eight patients experienced stable disease (median 3.7 months, range 1.4–19.4). Median TTP was 2.3 months (range 0.9–19.4 months), median OS was 7.1 months (range 1.4–30.0+ months), and estimated 1 year OS rate was 19% (SE 10%). One patient died on study from an acute ischemic stroke; this event was deemed possibly related to treatment. Grade 3/4 adverse events possibly related to vorinostat included neutropenia, lymphopenia, fatigue, pulmonary embolus/deep vein thrombosis, dehydration, elevated alkaline phosphatase, and hypokalemia. Conclusions: No objective antitumor activity was detected with single agent vorinostat in this setting; however, it yields TTP in relapsed NSCLC similar to that of other targeted agents. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.

Phase II Study of Belinostat in Patients With Recurrent or Refractory Advanced Thymic Epithelial Tumors

PURPOSE Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat. PATIENTS AND METHODS Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had failed were eligible for this study. Other eligibility criteria included adequate organ function and good performance status. Belinostat was administered intravenously at 1 g/m(2) on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance. The primary objective was response rate in patients with thymoma. RESULTS Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of two previous systemic regimens (range, one to 10 regimens). Treatment was well tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects. Two patients achieved partial response (both had thymoma; response rate, 8%; 95% CI, 2.2% to 25%), 25 had stable disease, and 13 had progressive disease; there were no responses among patients with thymic carcinoma. Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached v 12.4 months; P = .001). Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome. CONCLUSION Belinostat has modest antitumor activity in this group of heavily pretreated thymic malignancies. However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.

Clinical Toxicities of Histone Deacetylase Inhibitors

The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chemical compounds from unrelated chemical classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the observed toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addition, since preclinical models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities observed in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clinical experience is needed to determine the relative frequency of the observed side effects, and to identify and develop approaches to mitigate potential clinical sequelae.

Interleukin-2 and human monocyte activation.

Metchnikoff first described mononuclear phagocytic cells at the end of the last century and proposed their critical involvement in the host immune defense. Since then, an impressive body of literature has documented the involvement of monocytes in the immune response as immunomodulating cells [1, 2], antigen‐presenting cells [3], and effector cells [1, 4–7]. Human monocytes can be induced to express new or augmented biological functions in a process generally referred to as activation. The expression of the activated phenotype in monocytes is transient and, in contrast to that of other immune cells such as lymphocytes or natural killer (NK) cells, it is not associated with proliferation. Monocyte proliferation, occurring primarily in the bone marrow [8–10], maintains an adequate supply of circulating monocytes ready to extravasate to the tissues in response to physiological or pathological stimuli. The recognition that proliferation is not part of the genetic program of monocyte activation poses interesting questions about the function and biology of growth factor receptors on these cells. Monocytes express receptors for a variety of growth factors that are either monocyte lineage specific, such as the macrophage colony‐stimulating factor (CSF‐1) receptor [11, 12]; shared with other cell lineages, such as the granulocyte‐macrophage CSF (GM‐CSF) receptor [13]; or typical of other lineages, such as the interleukin‐2 receptor (IL‐2R) [14–16]. However, monocytes respond to stimulation by growth factors not with proliferation but with functional changes. Two remarkable examples are CSF‐1 and IL‐2. CSF‐1 induces proliferation of monocyte precursors in the bone marrow [17], but it promotes survival [18], migration [19], cytokine secretion [20], and cytotoxic responses [21] in circulating monocytes. IL‐2, originally described as a T cell growth factor [22], is a powerful activator of human monocytes. Fresh human monocytes respond to IL‐2 with microbicidal [23] and tumoricidal activities [1, 4–7], cytokine [24–28] and growth factor [29–31] production, and expression of growth factor receptors [21, 32]. We will discuss the effects of IL‐2 on human monocytes, the differential expression and modulation of the IL‐2R subunits, and their relationship with the responsiveness of monocytes to IL‐2. Finally, we will briefly discuss the regulation of IL‐2–induced monocyte activation by inhibitory signals. IL‐2 can also activate murine macrophages. However, we will limit our discussion to the human monocyte system. 33–35], tumor necrosis factor α (TNF‐α) [25, 28], interleukin‐6 (IL‐6) [26], and interleukin‐8 (IL‐8) [27]. TNF‐α and IL‐β are inflammatory mediators cytotoxic or cytostatic for tumor cells, whose involvement in the acute‐phase response and in monocyte antitumor activity has been reviewed [36–38]. Monocytes are the predominant source of IL‐6 and IL‐8 in peripheral blood [26, 39], although other cell types contribute to the IL‐6 and IL‐8 levels [26, 40–42]. IL‐8 induces chemotaxis in basophils, neutrophils, and T lymphocytes [43–47] and is member of the family of chemoattractant cytokines now called chemokines (for a review see ref. 48). IL‐6 is a pleiotropic cytokine whose biological activities include regulation of the acute‐phase response [37, 49], stimulation of multipotent colony formation of hematopoietic stem cells [50], induction of immunoglobulin production [51], and induction of T cell growth and cytotoxic T lymphocyte differentiation [52, 53]. IL‐8 and IL‐6 induction by IL‐2 occurs at the transcriptional level. The promoter of both genes contains a consensus sequence for the nuclear transactivator complex NF‐χB [54, 55]. The observation that IL‐2 increases the expression of NF‐χB complexes in the nucleus of monocytes suggests that NF‐χB may be involved in the transcriptional activation of IL‐8 and IL‐6 genes by IL‐2 (T. Musso et al., unpublished observation). Secretion of IL‐6 and IL‐8 is a specific response to IL‐2 and not a general response to activating stimuli, because interferon‐γ (IFN‐γ), which is also a potent monocyte activator, inhibits rather than induces IL‐6 or IL‐8 production [26, 27]. IL‐2 stimulates IL‐6 and IL‐8 production both directly and indirectly by inducing IL‐1β and TNF‐α secretion, which, in turn, stimulates the expression of IL‐8 and IL‐6 [26, 56]. The indirect response to IL‐2 represents an amplifying loop that is delayed with respect to direct stimulation and that may be important in allowing prolonged production of IL‐6 or IL‐8 during an inflammatory response.

Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation

Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non‐malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo‐immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine‐based non‐myeloablative conditioning regimen in patients with transfusion‐dependent non‐malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty‐six patients with transfusion dependent/anti‐thymocyte globulin (ATG)‐refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)‐compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft‐versus‐host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion‐independence. Twenty‐four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II–IV, 54% grades III–IV) and chronic GVHD (56%) was observed, only one patient died from transplant‐related causes (cumulative incidence 7%). These data show that HCT following fludarabine‐based non‐myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.

Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas

Purpose: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. Patients and Methods: Patients with advanced solid tumors or non-Hodgkins lymphomas were eligible. Sequential and concurrent schedules were studied. Results: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m2/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. Conclusion: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkins lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types. Clin Cancer Res; 17(6); 1582–90. ©2011 AACR.