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Papers by Mark Kirschbaum

Journal of Clinical Oncology, 2012

Purpose Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refr... more Purpose Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population. Patients and Methods Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed. Results The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 pa...

Clinical Cancer Research, 2019

Purpose: Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize t... more Purpose: Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize that ipilimumab would augment the efficacy of rituximab (R) in patients with relapsed/refractory (R/R) CD20+non-Hodgkin's lymphoma (NHL). This phase I study aimed to identify a recommended phase 2 dose, document toxicities, and preliminarily assess efficacy and potential predictive biomarkers. Patients and Methods: Thirty-three patients with R/R CD20+B-cell lymphoma received R at 375 mg/m2weekly for 4 weeks and I at 3 mg/kg on day 1 and every 3 weeks for four doses. Responding patients went on to maintenance with each agent given every 12 weeks. To facilitate correlative analysis, the expansion phase randomized patients to simultaneous R+I versus R with I delayed 2 weeks. Results: Toxicity was manageable; no dose-limiting toxicity was observed at the doses studied. When considering the entire cohort, efficacy was modest, with an objective response rate (ORR) of 24% and median progress...

Leukemia & lymphoma, Oct 19, 2016

We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide red... more We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1-4 and 15-18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 12, 2015

RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor ... more RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a Phase I study of RG7112 in patients with hematologic malignancies was conducted. Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, such as TP53-mutation status and MDM2 expression, and preliminary clinical activity. Patients were divided into 2 cohorts: Stratum A (relapsed/refractory AML (except APL), ALL, and CML) and Stratum B (relapsed/refractory CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 DLTs were reported. PK analysis indicated that twice-daily dosing enhanced daily exposure. Anti-leukemia activity was observed in t...

Anticancer research

DNA methylation can influence histone modification and gene expression. The growth-arrest DNA dam... more DNA methylation can influence histone modification and gene expression. The growth-arrest DNA damage inducible gene 45beta (Gadd45beta) has been reported as a potential diagnostic marker for aggressive hepatocellular carcinoma. In this study, the synergistic effect of the histone deacetylase inhibitor depsipeptide and the DNA methyltransferase inhibitor 5-azacytidine on the Gadd45beta gene expression in human liver cells was examined. The effects of depsipeptide and 5-azacytidine in CL-48, HepG2 and Hep3B cells were examined by PCR, cell viability test, Western blot and chromatin immunoprecipitation assay. Two microM depsipeptide reactivated Gadd45beta gene expression considerably within 4 h in HepG2 cells, but not in CL-48 or Hep3B cells. Up to 10 microM 5-azacytidine had no reactivation effect on Gadd45beta. A sequential treatment of depsipeptide+5-azacytidine (but not 5-azacytidine+depsipeptide) exhibited a synergistic effect on Gadd45beta gene reactivation in the HepG2 cells. Th...

Cell Death & Disease, 2013

We explored the activity of SIRT1 activators (SRT501 and SRT2183) alone and in combination with p... more We explored the activity of SIRT1 activators (SRT501 and SRT2183) alone and in combination with panobinostat in a panel of malignant lymphoid cell lines in terms of biological and gene expression responses. SRT501 and SRT2183 induced growth arrest and apoptosis, concomitant with deacetylation of STAT3 and NF-jB, and reduction of c-Myc protein levels. PCR arrays revealed that SRT2183 leads to increased mRNA levels of pro-apoptosis and DNA-damage-response genes, accompanied by accumulation of phospho-H2A.X levels. Next, ChIP assays revealed that SRT2183 reduces the DNA-binding activity of both NF-jB and STAT3 to the promoter of GADD45G, which is one of the most upregulated genes following SRT2183 treatment. Combination of SRT2183 with panobinostat enhanced the anti-growth and anti-survival effects mediated by either compound alone. Quantitative-PCR confirmed that the panobinostat in combination with SRT2183, SRT501 or resveratrol leads to greater upregulation of GADD45G than any of the single agents. Panobinostat plus SRT2183 in combination showed greater inhibition of c-Myc protein levels and phosphorylation of H2A.X, and increased acetylation of p53. Furthermore, EMSA revealed that NF-jB binds directly to the GADD45G promoter, while STAT3 binds indirectly in complexes with NF-jB. In addition, the binding of NF-jB/STAT3 complexes to the GADD45G promoter is inhibited following panobinostat, SRT501 or resveratrol treatment. Moreover, the combination of panobinostat with SRT2183, SRT501 or resveratrol induces a greater binding repression than either agent alone. These data suggest that STAT3 is a corepressor with NF-jB of the GADD45G gene and provides in vitro proofof-concept for the combination of HDACi with SIRT1 activators as a potential new therapeutic strategy in lymphoid malignancies.

Haematologica, Jan 16, 2015

This study examines the activity and tolerability of a regimen combining vorinostat and rituximab... more This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with ≤4 prior therapies were eligible for this open-label phase II study. 200 mg of oral vorinostat was administered twice daily on days 1-14 along with 375 mg/m2 of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, with secondary endpoints of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow-up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months fo...

Leukemia, 2011

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo ant... more Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML.

Cancer Research, 2011

MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G2–M cell-cycle arrest. G... more MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G2–M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-XL and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorino...

Bone Marrow Transplantation, 1998

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow trans... more Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Immunosuppressive treatment regimens carry the potential of causing severe morbidity and mortality, so that additional modes of therapy with fewer sideeffects are clearly needed. Five cGVHD patients (sclerodermoid cGVHD in two patients, lichenoid cGVHD in one patient and intraoral cGVHD in two patients), who had not responded to standard immunosuppressive drugs, were treated with adjuvant UVB phototherapy. The patient with lichenoid cGVHD experienced complete clearing of cutaneous lesions, whereas both patients with sclerodermoid cGVHD experienced significant relief of pruritus, but showed no change of the sclerodermoid skin lesions. Intraoral lesions cleared in one patient. The effects of UVB phototherapy were furthermore documented by measurement of skin viscoelasticity and mouth opening. No sideeffects were encountered. This preliminary study suggests that UVB phototherapy is useful as an adjuvant therapeutic modality in intraoral and cutaneous lichenoid cGVHD.

Blood, 2006

Therapy of Hodgkin disease (HD) is designed to prolong progression-free survival and minimize tox... more Therapy of Hodgkin disease (HD) is designed to prolong progression-free survival and minimize toxicity. The best regimen to achieve this has not yet been defined. A total of 108 patients with newly diagnosed HD and adverse prognostic factors were prospectively studied between 1999 and 2004. They were assigned to therapy according to defined risk stratification. Patients were defined depending on the International Prognostic Score (IPS). Those with IPS of 3 or higher received 2 cycles of escalated therapy, including bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [EB]). All others received 2 cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned following 2 cycles according to results of early interim 67Ga or positron emission tomography/computed tomography (PET/CT). Following a positive interim scan, 4 cycles of EB were administered, whereas 4 cycles of SB were given to patients with a negative scan. The...

Blood, 2008

We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belongin... more We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL). Two model human Ph− ALL cell lines (T-cell MOLT-4 and pre–B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC50: 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph− ALL cells, including those from...

Blood, 2005

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dos... more We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The media...

Biology of Blood and Marrow Transplantation, 2005

Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or wit... more Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or with added cyclosporine or tacrolimus still has a very high failure and complication rate, and new treatment approaches are needed for both primary and salvage therapy. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently in use for acute graft-versus-host disease prophylaxis. To determine whether MMF had activity in the treatment of cGVHD, we added MMF to standard cyclosporine, tacrolimus, and/or PSE as salvage/second-line (n ‫؍‬ 24) or first-line (n ‫؍‬ 10) therapy in 34 patients. Nine (90%) of 10 patients receiving first-line and 18 (75%) of 24 receiving second-line MMF therapy responded. Twelve (35%) patients had a complete remission, 15 (44%) had a partial remission, 5 (15%) had stable disease, and only 2 (6%) had progressive disease. Out of 30 patients receiving PSE, 22 (73%) were able to decrease PSE doses (median decrease of 50%; range, 25%-100%). With a median follow-up of 24 months (range, 6-28 months), 29 (85%) patients are alive. Three patients had to discontinue MMF because of abdominal cramps within 3 months of starting treatment. These data suggest that MMF is an active, well-tolerated agent in the treatment of cGVHD and may have a beneficial effect on the survival of patients with this complication.

Biology of Blood and Marrow Transplantation, 2008

Allogeneic HCT (Allo-HCT) is an effective treatment option for CLL due to both cytoreductive ther... more Allogeneic HCT (Allo-HCT) is an effective treatment option for CLL due to both cytoreductive therapy from the conditioning regimen as well as the graft versus leukemia (GVL) effect. Traditionally, chemosensitivity is a prerequisite for Allo-HCT; however, this may not be necessary in CLL due to the GVL effect. We identified a consecutive case-series of 29 patients who underwent an Allo-HCT at the City of Hope Medical Center between1993 and 2006. The median age at transplantation was 48 years (38-68). The median time from diagnosis to transplant was 49 months (13-157). Median number of prior chemotherapy regimens was 3(1-6). Twenty four patients had prior fludarabine therapy and 10 were considered refractory. Sixteen patients received prior anthracycline therapy. Twenty two patients had chemosensitive disease, defined as $a partial response to salvage chemotherapy just prior to Allo-HCT. The conditioning regimens used consisted of Fludar

Biology of Blood and Marrow Transplantation, 2006

51%, matched-unrelated (40%), or mismatched related (9%). 41 patients (47%) received PBSC and 45 ... more 51%, matched-unrelated (40%), or mismatched related (9%). 41 patients (47%) received PBSC and 45 patients (51%) received BMSC. Only 2 patients received cord blood transplant. GVHD prophylaxis was tacrolimus (89%) or cyclosporine-based (10%) in 89% and 1. Predictors of NRM and disease progression at one year post HSCT were evaluated using Cox's proportional hazards model for univariate and multivariate analysis. Results: 29 of 88 patients are alive with median follow-up 22 months (1-143). Actuarial estimate of survival at 2 yrs was 29%. Cumulative incidence of progression was 24% and NRM 47% at 2 yrs. Donor type and preparative regimen were significant predictors of NRM on multivariate analysis (Table 1). There was a trend for an increased rate of progression among patients with high risk IPSS (HR ϭ 3.8), yet this did not reach statistical significance (P ϭ .06). None of the other factors evaluated had an impact on the rate of progression. Conclusion: Allogeneic HSCT can provide long-term disease control for a significant proportion of patients with MDS. These results suggest that Flu/Bu may provide optimal cytoreduction with lower toxicity. Progression and late deaths from GVHD remain a significant problem. Strategies aimed at addressing these issues are currently in development (Table 1).

British journal of haematology, Jan 19, 2015

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or periph... more Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction a...

Blood, 2008

Background. Ispinesib is a novel polycylic, nitrogen-containing heterocycle small molecule that a... more Background. Ispinesib is a novel polycylic, nitrogen-containing heterocycle small molecule that acts by inhibition of the mitotic kinesin spindle protein (KSP) HsEg5. Pre-clinical studies demonstrate activity against both murine and human solid tumor and leukemia cell lines by inhibition of adenosine diphosphate release from KSP, causing monopolar spindle formation and programmed cell death. Methods. This was a single agent, phase I dose-escalation trial in patients with relapsed/refractory acute myeloid (AML) or lymphoid leukemia (ALL) or advanced myelodysplastic syndrome (MDS). Intravenous ispinesib was given for 3 consecutive days every 21 days. Doses were escalated from 1.5 mg/m2/day to 13.3 mg/m2/day in cohorts of 3 patients. Clinical and peripheral blood responses were monitored on at least a weekly basis and bone marrow evaluations were done every three weeks. Grade 3 or greater non-hematologic toxicities were considered dose limiting toxicities (DLT) with the exception of in...

Blood, 2007

Background: Patients with Hodgkin’s Lymphoma with relapse or refractory disease after salvage the... more Background: Patients with Hodgkin’s Lymphoma with relapse or refractory disease after salvage therapy and transplant face a paucity of active agents. New modalities of treatment are necessary. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases. After initial phase I data (Kelley WK, et al 2005) showed prolonged stable disease in patients with Hodgkin’s, a Phase II study of this agent was launched in patients with relapsed or refractory Hodgkin’s lymphoma. Methods: Eligible patients had relapsed or refractory Hodgkin’s lymphoma, bidimensionally measurable disease, and performance status 0-2. Patients may have received up to five prior chemotherapy regimens; previous autologous transplant is allowed. Vorinostat was dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning was performed after every three cycles, as was marrow biopsy for those with marrow involvement at ti...

Blood, 2007

The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last th... more The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last three decades, despite the improvement in the outcome of younger adults during this same time due to the use of hematopoietic stem cell transplantation and intensive cytarabine consolidation. Older adults can not tolerate intensive therapy due to poor performance status, impaired organ function, and comorbid illnesses. Tipifarnib is an oral farnesyl transferase inhibitor with activity in the treatment of myelodysplastic syndrome (MDS) and high-risk AML patients. The primary objective of study S0432 was to test whether any of four different regimens of tipifarnib is sufficiently effective and tolerable therapy for previously untreated AML in patients of age 70 or over to warrant phase III study. Patients could not be considered candidates for, or must have declined, conventional induction chemotherapy. Patients had to have adequate renal and hepatic function, and the white blood cell (WBC) ...

Journal of Clinical Oncology, 2012

Purpose Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refr... more Purpose Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population. Patients and Methods Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed. Results The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 pa...

Clinical Cancer Research, 2019

Purpose: Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize t... more Purpose: Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize that ipilimumab would augment the efficacy of rituximab (R) in patients with relapsed/refractory (R/R) CD20+non-Hodgkin's lymphoma (NHL). This phase I study aimed to identify a recommended phase 2 dose, document toxicities, and preliminarily assess efficacy and potential predictive biomarkers. Patients and Methods: Thirty-three patients with R/R CD20+B-cell lymphoma received R at 375 mg/m2weekly for 4 weeks and I at 3 mg/kg on day 1 and every 3 weeks for four doses. Responding patients went on to maintenance with each agent given every 12 weeks. To facilitate correlative analysis, the expansion phase randomized patients to simultaneous R+I versus R with I delayed 2 weeks. Results: Toxicity was manageable; no dose-limiting toxicity was observed at the doses studied. When considering the entire cohort, efficacy was modest, with an objective response rate (ORR) of 24% and median progress...

Leukemia & lymphoma, Oct 19, 2016

We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide red... more We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1-4 and 15-18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 12, 2015

RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor ... more RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a Phase I study of RG7112 in patients with hematologic malignancies was conducted. Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, such as TP53-mutation status and MDM2 expression, and preliminary clinical activity. Patients were divided into 2 cohorts: Stratum A (relapsed/refractory AML (except APL), ALL, and CML) and Stratum B (relapsed/refractory CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 DLTs were reported. PK analysis indicated that twice-daily dosing enhanced daily exposure. Anti-leukemia activity was observed in t...

Anticancer research

DNA methylation can influence histone modification and gene expression. The growth-arrest DNA dam... more DNA methylation can influence histone modification and gene expression. The growth-arrest DNA damage inducible gene 45beta (Gadd45beta) has been reported as a potential diagnostic marker for aggressive hepatocellular carcinoma. In this study, the synergistic effect of the histone deacetylase inhibitor depsipeptide and the DNA methyltransferase inhibitor 5-azacytidine on the Gadd45beta gene expression in human liver cells was examined. The effects of depsipeptide and 5-azacytidine in CL-48, HepG2 and Hep3B cells were examined by PCR, cell viability test, Western blot and chromatin immunoprecipitation assay. Two microM depsipeptide reactivated Gadd45beta gene expression considerably within 4 h in HepG2 cells, but not in CL-48 or Hep3B cells. Up to 10 microM 5-azacytidine had no reactivation effect on Gadd45beta. A sequential treatment of depsipeptide+5-azacytidine (but not 5-azacytidine+depsipeptide) exhibited a synergistic effect on Gadd45beta gene reactivation in the HepG2 cells. Th...

Cell Death & Disease, 2013

We explored the activity of SIRT1 activators (SRT501 and SRT2183) alone and in combination with p... more We explored the activity of SIRT1 activators (SRT501 and SRT2183) alone and in combination with panobinostat in a panel of malignant lymphoid cell lines in terms of biological and gene expression responses. SRT501 and SRT2183 induced growth arrest and apoptosis, concomitant with deacetylation of STAT3 and NF-jB, and reduction of c-Myc protein levels. PCR arrays revealed that SRT2183 leads to increased mRNA levels of pro-apoptosis and DNA-damage-response genes, accompanied by accumulation of phospho-H2A.X levels. Next, ChIP assays revealed that SRT2183 reduces the DNA-binding activity of both NF-jB and STAT3 to the promoter of GADD45G, which is one of the most upregulated genes following SRT2183 treatment. Combination of SRT2183 with panobinostat enhanced the anti-growth and anti-survival effects mediated by either compound alone. Quantitative-PCR confirmed that the panobinostat in combination with SRT2183, SRT501 or resveratrol leads to greater upregulation of GADD45G than any of the single agents. Panobinostat plus SRT2183 in combination showed greater inhibition of c-Myc protein levels and phosphorylation of H2A.X, and increased acetylation of p53. Furthermore, EMSA revealed that NF-jB binds directly to the GADD45G promoter, while STAT3 binds indirectly in complexes with NF-jB. In addition, the binding of NF-jB/STAT3 complexes to the GADD45G promoter is inhibited following panobinostat, SRT501 or resveratrol treatment. Moreover, the combination of panobinostat with SRT2183, SRT501 or resveratrol induces a greater binding repression than either agent alone. These data suggest that STAT3 is a corepressor with NF-jB of the GADD45G gene and provides in vitro proofof-concept for the combination of HDACi with SIRT1 activators as a potential new therapeutic strategy in lymphoid malignancies.

Haematologica, Jan 16, 2015

This study examines the activity and tolerability of a regimen combining vorinostat and rituximab... more This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with ≤4 prior therapies were eligible for this open-label phase II study. 200 mg of oral vorinostat was administered twice daily on days 1-14 along with 375 mg/m2 of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, with secondary endpoints of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow-up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months fo...

Leukemia, 2011

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo ant... more Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML.

Cancer Research, 2011

MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G2–M cell-cycle arrest. G... more MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G2–M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-XL and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorino...

Bone Marrow Transplantation, 1998

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow trans... more Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Immunosuppressive treatment regimens carry the potential of causing severe morbidity and mortality, so that additional modes of therapy with fewer sideeffects are clearly needed. Five cGVHD patients (sclerodermoid cGVHD in two patients, lichenoid cGVHD in one patient and intraoral cGVHD in two patients), who had not responded to standard immunosuppressive drugs, were treated with adjuvant UVB phototherapy. The patient with lichenoid cGVHD experienced complete clearing of cutaneous lesions, whereas both patients with sclerodermoid cGVHD experienced significant relief of pruritus, but showed no change of the sclerodermoid skin lesions. Intraoral lesions cleared in one patient. The effects of UVB phototherapy were furthermore documented by measurement of skin viscoelasticity and mouth opening. No sideeffects were encountered. This preliminary study suggests that UVB phototherapy is useful as an adjuvant therapeutic modality in intraoral and cutaneous lichenoid cGVHD.

Blood, 2006

Therapy of Hodgkin disease (HD) is designed to prolong progression-free survival and minimize tox... more Therapy of Hodgkin disease (HD) is designed to prolong progression-free survival and minimize toxicity. The best regimen to achieve this has not yet been defined. A total of 108 patients with newly diagnosed HD and adverse prognostic factors were prospectively studied between 1999 and 2004. They were assigned to therapy according to defined risk stratification. Patients were defined depending on the International Prognostic Score (IPS). Those with IPS of 3 or higher received 2 cycles of escalated therapy, including bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [EB]). All others received 2 cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned following 2 cycles according to results of early interim 67Ga or positron emission tomography/computed tomography (PET/CT). Following a positive interim scan, 4 cycles of EB were administered, whereas 4 cycles of SB were given to patients with a negative scan. The...

Blood, 2008

We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belongin... more We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL). Two model human Ph− ALL cell lines (T-cell MOLT-4 and pre–B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC50: 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph− ALL cells, including those from...

Blood, 2005

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dos... more We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The media...

Biology of Blood and Marrow Transplantation, 2005

Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or wit... more Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or with added cyclosporine or tacrolimus still has a very high failure and complication rate, and new treatment approaches are needed for both primary and salvage therapy. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently in use for acute graft-versus-host disease prophylaxis. To determine whether MMF had activity in the treatment of cGVHD, we added MMF to standard cyclosporine, tacrolimus, and/or PSE as salvage/second-line (n ‫؍‬ 24) or first-line (n ‫؍‬ 10) therapy in 34 patients. Nine (90%) of 10 patients receiving first-line and 18 (75%) of 24 receiving second-line MMF therapy responded. Twelve (35%) patients had a complete remission, 15 (44%) had a partial remission, 5 (15%) had stable disease, and only 2 (6%) had progressive disease. Out of 30 patients receiving PSE, 22 (73%) were able to decrease PSE doses (median decrease of 50%; range, 25%-100%). With a median follow-up of 24 months (range, 6-28 months), 29 (85%) patients are alive. Three patients had to discontinue MMF because of abdominal cramps within 3 months of starting treatment. These data suggest that MMF is an active, well-tolerated agent in the treatment of cGVHD and may have a beneficial effect on the survival of patients with this complication.

Biology of Blood and Marrow Transplantation, 2008

Allogeneic HCT (Allo-HCT) is an effective treatment option for CLL due to both cytoreductive ther... more Allogeneic HCT (Allo-HCT) is an effective treatment option for CLL due to both cytoreductive therapy from the conditioning regimen as well as the graft versus leukemia (GVL) effect. Traditionally, chemosensitivity is a prerequisite for Allo-HCT; however, this may not be necessary in CLL due to the GVL effect. We identified a consecutive case-series of 29 patients who underwent an Allo-HCT at the City of Hope Medical Center between1993 and 2006. The median age at transplantation was 48 years (38-68). The median time from diagnosis to transplant was 49 months (13-157). Median number of prior chemotherapy regimens was 3(1-6). Twenty four patients had prior fludarabine therapy and 10 were considered refractory. Sixteen patients received prior anthracycline therapy. Twenty two patients had chemosensitive disease, defined as $a partial response to salvage chemotherapy just prior to Allo-HCT. The conditioning regimens used consisted of Fludar

Biology of Blood and Marrow Transplantation, 2006

51%, matched-unrelated (40%), or mismatched related (9%). 41 patients (47%) received PBSC and 45 ... more 51%, matched-unrelated (40%), or mismatched related (9%). 41 patients (47%) received PBSC and 45 patients (51%) received BMSC. Only 2 patients received cord blood transplant. GVHD prophylaxis was tacrolimus (89%) or cyclosporine-based (10%) in 89% and 1. Predictors of NRM and disease progression at one year post HSCT were evaluated using Cox's proportional hazards model for univariate and multivariate analysis. Results: 29 of 88 patients are alive with median follow-up 22 months (1-143). Actuarial estimate of survival at 2 yrs was 29%. Cumulative incidence of progression was 24% and NRM 47% at 2 yrs. Donor type and preparative regimen were significant predictors of NRM on multivariate analysis (Table 1). There was a trend for an increased rate of progression among patients with high risk IPSS (HR ϭ 3.8), yet this did not reach statistical significance (P ϭ .06). None of the other factors evaluated had an impact on the rate of progression. Conclusion: Allogeneic HSCT can provide long-term disease control for a significant proportion of patients with MDS. These results suggest that Flu/Bu may provide optimal cytoreduction with lower toxicity. Progression and late deaths from GVHD remain a significant problem. Strategies aimed at addressing these issues are currently in development (Table 1).

British journal of haematology, Jan 19, 2015

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or periph... more Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction a...

Blood, 2008

Background. Ispinesib is a novel polycylic, nitrogen-containing heterocycle small molecule that a... more Background. Ispinesib is a novel polycylic, nitrogen-containing heterocycle small molecule that acts by inhibition of the mitotic kinesin spindle protein (KSP) HsEg5. Pre-clinical studies demonstrate activity against both murine and human solid tumor and leukemia cell lines by inhibition of adenosine diphosphate release from KSP, causing monopolar spindle formation and programmed cell death. Methods. This was a single agent, phase I dose-escalation trial in patients with relapsed/refractory acute myeloid (AML) or lymphoid leukemia (ALL) or advanced myelodysplastic syndrome (MDS). Intravenous ispinesib was given for 3 consecutive days every 21 days. Doses were escalated from 1.5 mg/m2/day to 13.3 mg/m2/day in cohorts of 3 patients. Clinical and peripheral blood responses were monitored on at least a weekly basis and bone marrow evaluations were done every three weeks. Grade 3 or greater non-hematologic toxicities were considered dose limiting toxicities (DLT) with the exception of in...

Blood, 2007

Background: Patients with Hodgkin’s Lymphoma with relapse or refractory disease after salvage the... more Background: Patients with Hodgkin’s Lymphoma with relapse or refractory disease after salvage therapy and transplant face a paucity of active agents. New modalities of treatment are necessary. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases. After initial phase I data (Kelley WK, et al 2005) showed prolonged stable disease in patients with Hodgkin’s, a Phase II study of this agent was launched in patients with relapsed or refractory Hodgkin’s lymphoma. Methods: Eligible patients had relapsed or refractory Hodgkin’s lymphoma, bidimensionally measurable disease, and performance status 0-2. Patients may have received up to five prior chemotherapy regimens; previous autologous transplant is allowed. Vorinostat was dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning was performed after every three cycles, as was marrow biopsy for those with marrow involvement at ti...

Blood, 2007

The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last th... more The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last three decades, despite the improvement in the outcome of younger adults during this same time due to the use of hematopoietic stem cell transplantation and intensive cytarabine consolidation. Older adults can not tolerate intensive therapy due to poor performance status, impaired organ function, and comorbid illnesses. Tipifarnib is an oral farnesyl transferase inhibitor with activity in the treatment of myelodysplastic syndrome (MDS) and high-risk AML patients. The primary objective of study S0432 was to test whether any of four different regimens of tipifarnib is sufficiently effective and tolerable therapy for previously untreated AML in patients of age 70 or over to warrant phase III study. Patients could not be considered candidates for, or must have declined, conventional induction chemotherapy. Patients had to have adequate renal and hepatic function, and the white blood cell (WBC) ...