178 results on '"Richard Piekarz"'
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152. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report
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Laila Dahmoush, Richard Piekarz, Douglas M. Kingma, Rosemary M. Altemus, Rob Robey, Susan Bakke, Victor Sandor, Maria L. Turner, Susan E. Bates, and Wyndham H. Wilson
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Male ,Skin Neoplasms ,T cell ,Immunology ,Biochemistry ,Peptides, Cyclic ,Romidepsin ,Histones ,Depsipeptides ,Medicine ,T-cell lymphoma ,Humans ,Enzyme Inhibitors ,Aged ,Depsipeptide ,Antibiotics, Antineoplastic ,business.industry ,Cutaneous T-cell lymphoma ,Remission Induction ,Lymphoma, T-Cell, Peripheral ,Acetylation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Peripheral T-cell lymphoma ,Lymphoma ,Anti-Bacterial Agents ,Lymphoma, T-Cell, Cutaneous ,Histone Deacetylase Inhibitors ,medicine.anatomical_structure ,Treatment Outcome ,Cancer research ,Histone deacetylase ,business ,medicine.drug - Abstract
Depsipeptide, FR901228, has demonstrated potent in vitro and in vivo cytotoxic activity against murine and human tumor cell lines. In the laboratory, it has been shown to be a histone deacetylase (HDAC) inhibitor. In a phase I trial of depsipeptide conducted at the National Cancer Institute, 3 patients with cutaneous T-cell lymphoma had a partial response, and 1 patient with peripheral T-cell lymphoma, unspecified, had a complete response. Sézary cells isolated from patients after treatment had increased histone acetylation. These results suggest that inhibition of HDAC is a novel and potentially effective therapy for patients with T-cell lymphoma.
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- 2001
153. Effect of a Histone Deacetylase Inhibitor on Human Cardiac Mass
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Vandana Sachdev, Yukitaka Shizukuda, Douglas R. Rosing, Toren Finkel, Susan E. Bates, and Richard Piekarz
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Oncology ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Antineoplastic Agents ,Depsipeptides ,Neoplasms ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Enzyme Inhibitors ,Pharmacology ,Depsipeptide ,Histone deacetylase 5 ,Chemotherapy ,business.industry ,HDAC11 ,Histone deacetylase inhibitor ,Cancer ,Heart ,Organ Size ,General Medicine ,medicine.disease ,Histone Deacetylase Inhibitors ,Tolerability ,Echocardiography ,Cardiology and Cardiovascular Medicine ,business ,Progressive disease - Abstract
T he histone deacetylase (HDAC) inhibitors are a promising new class of cancer chemotherapeutic agents [1]. Interestingly, growing evidence indicates that this class of drugs can also affect post-mitotic cells such as cardiac myocytes. In particular, both Class I and II HDACs appear to play an important role in regulating cardiac hypertrophy [2,3]. Based on these pre-clinical observations, there is also concern, however, that cardiac mass may be adversely affected by the longterm use of HDAC inhibitors for oncological therapy. Depsipeptide (FR901228 or FK228), a relative class I HDAC inhibitor (inhibiting HDAC1 and HDAC2) [4], is undergoing phase 2 testing for patients with T-cell lymphoma in our Institutes [5]. Thus, we reviewed the cardiac mass determinations in patients who were enrolled in our protocols using depsipeptide as a therapeutic agent. Twelve patients treated at the NIH had the cardiac mass assessment with echocardiograms performed prior to and at set times after initiation of therapy as part of the protocol and had received treatment for a minimum of three months. All patients provided written informed consent for testing and treatment approved by the Institutional Review Board of the National Cancer Institute. Ten patients with cutaneous T-cell lymphoma and two with peripheral T-cell lymphoma were treated with 10.5 or 14 mg/m2 (depending on individual patient tolerability) of depsipeptide once a week for three out of four weeks. As previously described, this amount of drug produced significant EKG changes in all patients and was sufficient to induce changes in histone acetylation levels in circulating blood cells [5]. Seven patients responded to therapy (3 complete responders, 4 partial responders), two patients maintained stable disease for 6 months duration, and three patients had progressive disease (2 after 3 months of therapy and one after 6 months). Despite the observed effect on the patients’ cancer, the cardiac mass, as assessed by two-dimensional echocardiography, did not change significantly during the prolonged course of therapy (Fig. 1). Fig. 1. Cardiac mass during the depsipeptide therapy. Mass was assessed by two-dimensional echocardiography using the recommendations of the American Society of Echocardiography [6]. Mass measurements were made by a single, blinded observer. White circles with a horizontal bar show mean values. The vertical bars at the white circles indicate S.E.M. BL = measurements at baseline before the initiation of treatment.
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- 2005
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154. A Phase I Study Of The Histone Deacetylase Inhibitor Entinostat Plus Clofarabine For Philadelphia Chromosome Negative, Poor Risk (Newly Diagnosed Older Adults or Adults with Relapsed and Refractory Disease) Acute Lymphoblastic Leukemia Or Bilineage/Biphenotypic Leukemia
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Hetty E Carraway, Judith E. Karp, Ivana Gojo, Keith W. Pratz, Nilanjan Ghosh, Steven D. Gore, Margaret M. Showel, Mark Levis, B. Douglas Smith, Jacqueline Greer, James G. Herman, Lia Gore, Min-Jung Lee, Sunmin Lee, Peter Ordentlich, Richard Piekarz, and Jane Trepel
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Combination therapy ,business.industry ,Entinostat ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Fludarabine ,Leukemia ,chemistry.chemical_compound ,chemistry ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,Cytarabine ,Clofarabine ,business ,medicine.drug - Abstract
Introduction Adult patients (pts) diagnosed with acute lymphocytic leukemia (ALL) are known to have a poor clinical outcome as compared to children. Studies report a 2 year event free survival of 30-40% for Philadelphia chromosome negative (Ph-) patients age >30 yrs and 17% for age >50 yrs. In order to improve outcome for adult ALL, agents that are effective, safe and associated with a low morbidity are needed. Clofarabine, a second generation purine nucleoside analog, has clinical activity as a single agent and in combination with cytosine arabinoside (ara-C) against refractory and relapsed ALL. Clofarabine exerts its cytotoxicity through multiple mechanisms of action, with major effects via inhibition of ribonucleotide reductase (RR) and DNA polymerase-alpha, and incorporation into DNA leading to DNA damage and activation of apoptotic pathways. Histone deacetylases (HDACs) are important regulators of chromatin involved in silencing of tumor suppressor genes. HDAC inhibitors are shown to be apoptogenic in vitro for ALL cell lines and have received FDA approval for the treatment of CTCL and peripheral T cell lymphoma. Pre-treatment with entinostat has been shown to enhance the cytotoxic activity of fludarabine in leukemia cell lines in vitro (Maggio et al, Cancer Research 2004). Given the similarity of clofarabine to fludarabine, and its FDA approval for children with refractory ALL, the combination of entinostat with clofarabine was pursued. Methods A Phase I window of opportunity study using overlapping schedule of entinostat and clofarabine was used in adult pts with ALL (B precursor) or Acute Bilineage Leukemia (ABL). Pts were enrolled onto one of two arms; arm “A” received repeated cycles of entinostat-clofarabine every 21 days as long as there was evidence of response (CR, CRi, or PR following cycle 1) and pts on arm “B” received one cycle of entinostat-clofarabine prior to standard multi-agent chemotherapy. Entinostat was administered orally on day 1 and day 8 (with dose escalation from flat dosing of 4mg to 6mg to 8mg from cohort 1 to 3). Clofarabine was administered intravenously at a fixed dose for all dose cohorts at 10mg/m2 for 5 days (day 3-7). Adults >40 yrs with newly diagnosed, Ph- B-lineage ALL or ABL were eligible. Additionally, adults > 21 yrs with relapsed and refractory, Ph- ALL or ABL were eligible. Eligibility criteria included serum creatinine < 2.0 mg/dl, hepatic enzymes < or = 2.5 ULN and bilirubin Results 23 pts from 3 institutions were enrolled on this study (18 at JHH, 3 at UMD, 2 at UColorado). 17 pts were treated on arm A and 6 pts on arm B. 6 pts were treated in each dose level with responses as follows: in dose level one (1 CR, 5 NR) and dose level two (1 CR, 1 CRi, 4NR) and dose level three (3 PR and 3 NR). The dose level 3 cohort was expanded with a total of 5 additional pts to date (1 PR, 1 SD, 3NR). Thus, the overall response rate on dose level 3 was 4PR, 1SD, 6NR. The 4 pts with CR/CRi/PR were all de novo treated elderly pts from Arm A. Notably, one pt on arm A has been in remission for over 1.5 yrs. Toxicities to date included expected but manageable grade (G) 3 and 4 cytopenias. There were G3 elevations of ALT (N=2) and AST (2) and bilirubin (1) and one bacteremia (1) and G4 cellulitis (1). Planned correlative studies are ongoing and include evaluation of acetylation of target proteins using multiparameter flow cytometry and western blot as well as methylation evaluation. Conclusions Combination therapy with entinostat-clofarabine is feasible and is well tolerated with minimal toxicity. Promising durable responses were observed in older pts that were not otherwise able to receive multi-agent induction chemotherapy upfront. This is notable given the low dose of clofarabine used in every cohort. Correlative studies evaluating protein hyperacetylation and DNA methylation in serial samples from treated pts are in progress. Disclosures: Off Label Use: This clinical study is a Phase 1 investigation and it discusses non-FDA approved doses of both clofarabine and entinostat for adults with Acute Lymphocytic Leukemia. The reason for this is that this study examines these agents in combination in a Phase 1 fashion and we started with low doses of each agent. Ordentlich:Syndax: Employment. Trepel:Syndax: Research Funding.
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- 2013
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155. A Phase II Trial Of Epigenetic Modulators Vorinostat In Combination With Azacitidine (azaC) In Patients With The Myelodysplastic Syndrome (MDS): Initial Results Of Study 6898 Of The New York Cancer Consortium
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Shyamala C. Navada, Erin P. Demakos, Joseph A. Sparano, Maria R. Baer, Amit Verma, Vesna Najfeld, Rosalie Odchimar-Reissig, Lewis R. Silverman, Eric J. Feldman, and Richard Piekarz
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Phases of clinical research ,Cell Biology ,Hematology ,Biochemistry ,Hypomethylating agent ,Internal medicine ,Toxicity ,Cohort ,Medicine ,business ,Adverse effect ,Vorinostat ,medicine.drug ,Lenalidomide - Abstract
Background The hypomethylating agent (HMA) azaC reverses epigenetic silencing and is the first agent demonstrated to improve survival in patients with higher-risk MDS (Silverman et al JCO 2002, Fenaux et al Lancet Oncology 2009). Time to initial response with single agent azaC, is 3 to 4 cycles, the CR rate ranges from 7 to 17% and overall response is 45-50%. Vorinostat, a histone deacetylase inhibitor (HDACI) which inhibits class I and II HDAC, has demonstrated single agent activity in patients with MDS with responses of 20% (Garcia-Manero Blood 2006). In vitro the 2 agents are synergistic in reactivating epigenetically silenced genes. The effect is sequence-dependent requiring exposure to the HMA first followed by the HDAC. We conducted a phase I pilot study of escalating and de-escalating doses of the 2 drugs in combination in 8 cohorts and demonstrated broad activity with responses ranging up to 80% across all of the cohorts tested (Blood 2008). Purpose To determine the response rate of patients treated with the combination of vorinostat and azacitidine at the doses established as safe and effective in Phase I in an expanded cohort of patients with MDS. Methods In the phase II component 3 schedules of the combination were chosen based on response and adverse event profile for further evaluation. Eligible patients were entered into one of 3 cohorts with the combination (see table 1): cohort 1: azaC 55 mg/m2/d 1-7 SC, vorinostat 200mg po Bid d3-16; cohort 2: azaC 75 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3-9; cohort 3: azaC 55 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3- 9. Patients with IPSS int-1, -2 and high-risk disease were eligible. Patients with secondary MDS were eligible, those with AML were excluded. Using a simon 2 stage design 13 patients were entered in each cohort and assessed for response, scored according to IWG 2006 criteria and toxicity. Results 40 patients have been entered and 39 (21 male, 18 female) are evaluable for toxicity and 33 for response, 1 pt was registered but never treated. IPSS classification among the 39 patients: int-1 8; int-2 12; high-risk 12; unclassified 7, with median age 67 (23-79). Responses among evaluable patients have occurred in 23 of 33 (70%); 10 CR, 4 CRi, (CR+CRi=42%) 9 HI, 5 SD, 5 NR. Median time to response is 2 cycles (8 weeks). Responses by cohort (table 1) are 70%, 73% and 67% for cohort 1, 2 and 3, respectively. Analysis for the MDS clone at the time of best response demonstrated the persistence of the clone in 45% of patients as marked by cytogenetic or FISH abnormalities, suggesting a modulating rather than cytotoxic effect of the combination on the clone. Cycles administered, range from 1 to 26+ with a median of 6 cycles. Median duration of response is 16 months overall and 9.5, 23 and 27 months, respectively for cohorts 1, 2 and 3. Eighteen patients have come off study for: death or due to disease complications (6); co-morbidities (2); consent withdrawal (5); and withdrawal for stem cell transplant (3). Median OS is 21.1 months and is 10.1, 37.4 and 19 months for cohorts 1, 2, and 3 respectively (NS). Grade 3 fatigue occurred during cycle 1, 2 or 3 in cohort 1 (8%), cohort 2 (16%) and cohort 3 (8%). GI toxicity grade 3 (vomiting, diarrhea, dehydration) occurred in 8% of patients in each of the cohorts. There was no suggestion of cumulative toxicity for either fatigue or GI adverse events. Correlative biologic study analysis is underway. Conclusion The combination of azaC and vorinostat can be safely administered, and is well tolerated in repetitive cycles. The dose of azaC in cohort 2 adheres to the FDA approved dose and schedule. OR and CR rates and time to initial response are comparable among the cohorts and these data suggest that the combination is superior to published results of azaC alone. Cohorts 2 and 3, with vorinostat administered for 7 days, appears to be associated with longer response duration and OS. An intergroup study (SWOG-S1117) comparing azaC and vorinostat to either azaC alone or combined with lenalidomide is underway utilizing the doses and schedule in cohort 2 from this study. Correlative studies that may shed light on mechanism of action or guide patient selection are being conducted. Supported in part by NYCC- N01 CM-62204 and the Henry and Mickey Taub Foundation. Disclosures: Silverman: Merck: Research Funding. Off Label Use: vorinostat for treatment of patients with a myelodysplastic syndrome investigational use.
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- 2013
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156. Romidepsin Is Effective and Well-Tolerated In Patients ≥ 60 Years Old With Relapsed Or Refractory Peripheral T-Cell Lymphoma (PTCL): Analysis From Phase 2 Trials
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Andrei R. Shustov, Bertrand Coiffier, Steven M. Horwitz, Lubomir Sokol, Barbara Pro, Tina Nielsen, Julie Wolfson, Barbara E Balser, Robin Eisch, Leslie Popplewell, Miles Prince, Steven L. Allen, Richard Piekarz, and Susan E. Bates
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,CHOP ,Biochemistry ,Systemic therapy ,Surgery ,Romidepsin ,Refractory ,Tolerability ,Internal medicine ,Clinical endpoint ,Medicine ,Population study ,business ,Adverse effect ,medicine.drug - Abstract
Background PTCL is a heterogeneous group of mature, post-thymic, T- and natural killer–cell disorders associated with a poor prognosis in most subtypes. Anthracycline-based therapies (eg, CHOP) are most often used in the frontline treatment of PTCL, although they do not typically lead to durable remissions. Older patients may not be eligible for additional chemotherapeutic regimens due to comorbidities and/or poor performance status. Thus, it is important to identify appropriate treatment strategies for older patients with PTCL, particularly in the salvage setting. Romidepsin is a potent class I histone deacetylase inhibitor approved by the FDA for the treatment of patients with PTCL who have received ≥ 1 prior therapy and patients with cutaneous T-cell lymphoma who have received ≥ 1 prior systemic therapy. Approval of PTCL was based on results from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL (N = 131) that demonstrated durable clinical benefit and tolerability and was supported by a similar study from the National Cancer Institute (N = 47). The objective herein is to present efficacy and safety data for romidepsin specific to older patients (≥ 60 years) with relapsed/refractory PTCL in the pivotal and supportive trials. Methods In both trials, patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles. For the pivotal trial, the primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee. For the supportive trial, the primary endpoints were objective response rate (ORR) and rate of CR by investigator assessment. In this analysis, efficacy and safety data for patients ≥ 60 years old were examined and compared with those for the overall study population. Results In the pivotal study, the overall median age was 61 years (range, 20-83); 71/130 patients (55%) were ≥ 60 years old (median 67 years [range, 60-83]) with a median of 2 prior systemic therapies (range, 1-8), including prior stem cell transplant in 7 patients. Response rates in the older population were similar to those seen overall: 25% ORR for both populations, including 14% and 15% with CR/CRu for older vs overall populations, respectively. Also, in both the older and overall populations, the median DOR was 28 months, with the longest response ongoing at 48 months (median follow-up 22.3 months). Of the 10 older patients who achieved CR/CRu, 6 had a DOR of ≥ 12 months. Survival was also similar, with 5 and 4 months PFS and 12 and 11 months OS for the older vs overall populations, respectively. In the supportive trial, the overall median age was 60 (range, 27-84); 23/47 patients (49%) were ≥ 60 years old (median 68 years [range, 61-84]) with a median of 2 prior regimens (range, 1-8), including prior stem cell transplant in 7 patients. Response rates in the older population were similar to those seen overall: 32% and 38% ORR, including 14% and 18% with CR, respectively. The median DOR was 5 months (range, 3-49) and 9 months (range, 2-74+) for the older vs overall populations, respectively. One 79-year-old patient with 6 prior systemic therapies achieved CR on romidepsin and stopped therapy after 6 cycles in consideration of his age. Off therapy, disease progression was observed; romidepsin was restarted per protocol and patient achieved a second CR, receiving an additional 22 cycles of therapy. In both the pivotal and supportive trials, rates of grade ≥ 3 adverse events were similar for the overall vs older patient populations (Table). Conclusions In phase 2 trials of romidepsin for the treatment of relapsed/refractory PTCL, patients aged ≥ 60 years comprised approximately half of patients. Both efficacy and safety were similar for the older vs overall populations. Thus, data were not skewed due to age, and romidepsin is suitable for use in elderly patients with relapsed/refractory PTCL. Disclosures: Shustov: Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Coiffier:Celgene Corporation: Consultancy; Spectrum Pharmaceuticals: Consultancy. Horwitz:Celgene Corporation: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Seattle Gen: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Kyowa Hakko Kirin Pharma: Research Funding; Millenium: Consultancy, Research Funding; Genzyme: Consultancy; Janssen: Consultancy. Sokol:Celgene Corporation: Consultancy, Speakers Bureau; Gloucester: Research Funding. Pro:Celgene Corporation: Honoraria. Nielsen:Celgene Corporation: Employment, Equity Ownership. Balser:Celgene Corporation: Consultancy. Prince:Celgene Corporation: Honoraria, Research Funding. Allen:Celgene Corporation: Honoraria. Bates:Celgene Corporation: Research Funding.
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- 2013
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157. Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop)
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Min-Jung Lee, William M. Bonner, Susan E. Bates, Antonio Tito Fojo, Sanjeeve Balasubramaniam, Arun Rajan, Christophe E. Redon, Cody J. Peer, Richard Piekarz, Jane B. Trepel, Giuseppe Giaccone, William D. Figg, and Christina Bryla
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Cisplatin ,Cancer Research ,Chemotherapy ,DNA repair ,business.industry ,medicine.medical_treatment ,Pharmacology ,chemistry.chemical_compound ,Oncology ,chemistry ,medicine ,Epigenetics ,Histone deacetylase ,business ,Belinostat ,Etoposide ,medicine.drug - Abstract
2527 Background: Histone deacetylase inhibitors (HDIs) are epigenetic therapies in development. To exploit the unique activity in impairing DNA repair, HDIs have been combined with chemotherapy. Belinostat is a potent HDI combined with Cis and Etop based on enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Methods: Patients with relapsed/refractory cancer or previously untreated advanced stage SCLC were eligible. Belinostat was administered by continuous infusion (CIV) over 48h, from 400 mg/m2/24h, in cohorts of 3. Cis was administered on day 1 and Etop daily X3. Belinostat pharmacokinetics (PK) and several pharmacodynamic (PD) measures were assessed, including lysine acetylation in peripheral blood mononuclear cells (PBMCs) and γH2Ax staining in PBMCs and in hair follicles. Results: Five dose levels were explored in 20 patients with solid tumors, including 5 patients with SCLC, two who had no prior therapy. At the first dose level, dose-limiting toxicities (DLT) of gr 4 ANC in 1, and gr 3 HTN in 1 were observed. Cis and Etop were reduced to 60 mg/m2 and 80 mg/m2, respectively, and the dose level repeated without DLT. At the next dose level, 800 mg/m2/24h belinostat, grade 3 HTN and grade 4 pneumonitis were observed. At the MTD of 600 mg/m2/24h belinostat, DLT was seen in 1 of 6 pts; however, all 6 pts required later dose reductions. We thus considered 500 mg/m2/24h in combination with Cis and Etop to be the recommended Phase II dose; confirmation ongoing. PKs show belinostat levels at 1 uM over the 48h infusion, decreasing rapidly to the 60h timepoint. In total 11 pts, 3 with SCLC, completed 6 cycles. PR was seen in 6 pts (3 with SCLC). PD studies confirmed γH2AX staining in PBMCs and hair follicles, peaking at 36h and 60h, respectively. Tubulin and lysine acetylation (Ac-K) in PBMCs peaked at 36h; Ac-K recovered more rapidly than tubulin, mirroring γH2AX. Conclusions: The MTD of belinostat over 48h by CIV was 600 mg/m2/24h, in combination with Cis 60 mg/m2 on day 1 and Etop 80 mg/m2 on days 1 - 3. PD endpoints indicate that belinostat is active in promoting both acetylation and DNA damage. The HDI combined with chemotherapy requires dose reduction and likely represents an on-target increase in DNA damage. Clinical trial information: NCT00926640.
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- 2013
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158. Abstract 3399: Resistance to the histone deacetylase inhibitor romidepsin is associated with degradation of Bim following MAPK pathway activation
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Zhirong Zhan, Nathan L. Collie, Arup R. Chakraborty, Andrew V. Kossenkov, Michael M. Gottesman, Louise Showe, Jean-Pierre Gillet, Susan E. Bates, Richard Piekarz, Victoria Luchenko, and Rob Robey
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Cancer Research ,Entinostat ,medicine.drug_class ,MEK inhibitor ,Histone deacetylase inhibitor ,Biology ,Romidepsin ,chemistry.chemical_compound ,Oncology ,chemistry ,Panobinostat ,Immunology ,medicine ,Cancer research ,Apicidin ,Vorinostat ,Belinostat ,medicine.drug - Abstract
Inhibition of histone deacetylase (HDAC) enzymes represents a promising therapeutic approach in clinical oncology, as aberrant gene expression and alterations in histone acetylation due to HDACs have been implicated in tumor development and progression. Even though several histone deacetylase inhibitors (HDIs) are currently in clinical trials, so far only the HDIs romidepsin and vorinostat have been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL). During clinical trials with romidepsin in CTCL, disease progression was noted in some patients who initially responded to therapy, while the disease in other patients did not respond to therapy suggesting that both de novo and acquired resistance to romidepsin were observed. To identify molecular determinants of resistance, we selected HuT78 CTCL cells with romidepsin in the presence of inhibitors of P-glycoprotein (Pgp) to prevent upregulation of Pgp as a mechanism of resistance. Resistant sublines were approximately 250- to 385-fold resistant to romidepsin; the Pgp inhibitor tariquidar did not significantly reverse resistance. The sublines also exhibited resistance to apoptosis following treatment with the HDIs apicidin, belinostat, entinostat, panobinostat, and vorinostat. A custom gene-expression array detected elevated expression of insulin receptor (INSR) in romidepsin resistant cells compared to parental cells. Immunoblot analysis of downstream effectors of the IR pathway demonstrated a 4- to 8-fold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation. Even though resistant cells did not respond to 48 h treatment with inhibitors of the insulin receptor, they exhibited exquisite sensitivity to treatment with as little as 1 nM of the MEK inhibitor PD0325901. Sensitivity to MEK inhibition in resistant cells was associated with restoration of the pro-apoptotic protein Bim. Combined treatment of romidepsin with MEK inhibitors also significantly yielded greater apoptosis in resistant cells compared to romidepsin and MEK inhibitor treatment alone. Gene expression analysis of circulating tumor samples obtained from patients with CTCL enrolled on the NCI 1312 Phase II romidepsin study suggested interaction of romidepsin with the MAPK pathway, indicated by altered expression of genes demonstrated to be under its control. These findings implicate activation of MEK as a resistance mechanism to romidepsin, and suggest combination of romidepsin with MEK inhibitors in clinical trials. Citation Format: Arup R. Chakraborty, Rob Robey, Zhirong Zhan, Victoria Luchenko, Michael Gottesman, Nathan Collie, Jean-Pierre Gillet, Richard Piekarz, Andrew Kossenkov, Louise Showe, Susan Bates. Resistance to the histone deacetylase inhibitor romidepsin is associated with degradation of Bim following MAPK pathway activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3399. doi:10.1158/1538-7445.AM2013-3399
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- 2013
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159. Abstract 4666: A phase 2 study investigating the safety, efficacy and surrogate biomarkers of response of 5-azacitidine (5-AZA) andentinostat (MS-275) in patients with triple-negative advanced breast cancer
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George Somlo, Roisin M. Connolly, Shannon Slater, Adam Brufsky, Cynthia A. Zahnow, Rachel C. Jankowitz, Zhe Zhang, A. A. Garcia, Steven Baylin, John H. Fetting, Antonio C. Wolff, Richard Piekarz, Vered Stearns, Michelle A. Rudek, Penny Powers, Nancy E. Davidson, Stacie Jeter, and Nita Ahuja
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Entinostat ,Cancer ,medicine.disease ,Interim analysis ,Surgery ,chemistry.chemical_compound ,Breast cancer ,chemistry ,Tolerability ,Internal medicine ,Clinical endpoint ,Medicine ,Hormonal therapy ,business ,Tamoxifen ,medicine.drug - Abstract
Background: In preclinical breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor (DNMTI) and a histone deacetylase inhibitor (HDACI) yield superior estrogen receptor (ER) re-expression and greater restoration of tamoxifen responsiveness than either agent alone. We conducted a multicenter phase II clinical trial to evaluate the DNMTI 5-azacitidine (5-AZA) and the HDACI entinostat in women with advanced breast cancer. Methods: Women with advanced HER2-negative, either triple-negative (TN; ER/progesterone receptor [PR]/HER2-negative) or hormone-resistant breast cancer received 5-AZA 40 mg/m2 (SQ, days 1-5, 8-10) and entinostat 7 mg (PO, days 3,10) every 28 days. Primary endpoint: objective response rate (ORR) in each group. Secondary endpoints: safety, tolerability, survival, clinical benefit rate. Exploratory endpoints: pharmacokinetics, pharmacogenetics, change in candidate gene re-expression/methylation in circulating DNA and mandatory tumor samples. Patients are offered ongoing study therapy at progression with addition of hormonal therapy (optional continuation phase). Sample size: Simon two-stage design with interim analysis after 13 patients per cohort (1st stage). If ≥1 response, accrual will continue for total of 27 per cohort (2nd stage). Null hypothesis: ORR at most 5% against alternative hypothesis that is at least 20% with type I error 4% and power 90%. Preclinical TN/ ER-positive xenograft studies assessing 5-AZA impact were also performed. Results: Thirteen evaluable patients were enrolled in 1st stage of TN cohort. Median age was 47 (31-67), median prior chemotherapies 3 (1-5), 77% white/33% black, 77% visceral disease. Median cycles received 2 (1-4). Therapy was well tolerated, most common grade 3/4 treatment related adverse events leucopenia and neutropenia (23% each). No responses observed following 1st stage and this cohort was closed. Median 1.5 additional cycles (optional continuation phase) received by 4 patients with no responses to date. Exposure to 5-AZA (Cmax=1134±1670ng/mL; AUCINF=939±724 ng*h/mL) was slightly higher than previous studies, entinostat (Cmin=0.78±0.65ng/mL) was similar. Hormone-resistant cohort proceeded to 2nd stage as 1 partial response observed. Final results will be reported once accrual complete. Ongoing preclinical studies suggest that ER-positive is more sensitive than TN breast cancer to 5-AZA. Conclusion: Combination epigenetic therapy with agents, dose and schedule described was well tolerated but not associated with clinical activity in advanced TN breast cancer. Correlative analyses will be presented at meeting. Promising preclinical findings suggest epigenetic therapy may be efficacious in ER-positive breast cancer. Citation Format: Roisin M. Connolly, Rachel C. Jankowitz, Cynthia A. Zahnow, Zhe Zhang, Michelle A. Rudek, Stacie C. Jeter, Shannon Slater, Penny Powers, Antonio C. Wolff, John Fetting, Adam M. Brufsky, Richard Piekarz, Nita Ahuja, George Somlo, Augustin Garcia, Steven Baylin, Nancy E. Davidson, Vered Stearns. A phase 2 study investigating the safety, efficacy and surrogate biomarkers of response of 5-azacitidine (5-AZA) andentinostat (MS-275) in patients with triple-negative advanced breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4666. doi:10.1158/1538-7445.AM2013-4666
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- 2013
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160. A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of advanced or recurrent thymic malignancies
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Arlene Berman, Giuseppe Giaccone, David S. Schrump, Michell Manu, Eva Szabo, Arun Rajan, Udayan Guha, Corey A. Carter, Richard Piekarz, Anish Thomas, Sean Khozin, and Tricia F. Kunst
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Cancer Research ,Pathology ,medicine.medical_specialty ,Hydroxamic acid ,Cyclophosphamide ,business.industry ,Cisplatin/doxorubicin ,Thymic cancer ,First line treatment ,chemistry.chemical_compound ,Oncology ,chemistry ,medicine ,Cancer research ,Single agent ,Histone deacetylase ,business ,Belinostat ,medicine.drug - Abstract
7103 Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) pan-inhibitor with single agent activity in thymic malignancies. PAC has activity against thymic cancers. Synergy between Bel and several chemotherapeutic agents, including P, A, and C, has been demonstrated in preclinical models. Methods: Patients with histologically confirmed, treatment naive advanced thymic malignancies, PS2+ PAC) and 2 patients at DL2 (Bel 2000 mg/m2+ PAC). Dose Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 neutropenia and thrombocytopenia. Recommended phase II dose (RP2D) was set at DL1. Most common grade 3/4 treatment-related adverse events (AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, hypokalemia, elevated AST, prolonged QTc and infusion-catheter related thromboembolic complications (23% each). Outcomes included one complete response (CR; T at DL1), 6 partial responses (PR; 4 T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in Ph1 and Ph2). Four patients previously deemed unresectable underwent surgical resection. Conclusions: Belinostat in combination with PAC has activity in thymic malignancies with a predicable AE profile. ORR was 54% including 33% PR in the TC subgroup. RP2D of the combination has been defined. Accrual to Ph2 part and molecular profiling of patient tumors is ongoing.
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- 2012
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161. Validation of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women receiving treatment for metastatic breast cancer
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Richard Piekarz, Thomas M. Atkinson, Lauren J. Rogak, Ann M. O'Mara, Christine I. Nichols, Andrea Denicoff, K Lang, Sandra A. Mitchell, Victoria Federico, Debu Tripathy, Deepa Lalla, Sara A. Hurvitz, Antonia V. Bennett, Bryce B. Reeve, Kathleen Castro, Alice P. Chen, Lori M. Minasian, Ethan Basch, and Steven B. Clauser
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Common Terminology Criteria for Adverse Events ,medicine.disease ,business ,Adverse effect ,Metastatic breast cancer ,Pro ctcae - Abstract
9144 Background: NCI PRO-CTCAE is designed to enhance adverse event reporting by integrating patients’ self-report of the frequency (F), severity (S) and interference (I) with usual activities of 78 symptomatic treatment toxicities. This study examined the construct validity of a subset of PRO-CTCAE items in women with metastatic breast cancer (MBC). Methods: 207 women (70% aged 45-59 years; 94% White;71% college-educated) with HER2+ MBC who had received treatment in the past month were recruited from 6 U.S. breast cancer support groups and completed a web survey that collected 18 PRO-CTCAE symptoms, and the Rotterdam Symptom Checklist (RSC). Pairwise concordance among PRO-CTCAE symptom dimensions was examined using weighted Kappa and Bowker’s test for symmetry. Results: Respondents were a median of 47 months since MBC diagnosis and 61% rated their health-related quality of life (HRQL) as good to excellent. Symptom prevalence was similar for PRO-CTCAE and RSC, with respondents more likely to endorse mood disturbance on PRO-CTCAE (Anxiety/Worry 90%; Sad/Unhappy Feelings 86%) vs. RSC (Anxiety 63%; Depressed Mood 61%). There was parallel rank-ordering of fatigue, anxiety, insomnia, depression, difficulty concentrating and neuropathy as the symptoms that were most severe, interfered most and caused the greatest bother. Within PRO-CTCAE, pairwise agreement among F, S and I was moderate for most symptoms (κw=.42 to .54). Agreement between F and S was highest for pain, nausea and arm/leg swelling (κw=.61 to .80), and lowest for anxiety/worry and sad/unhappy feelings (κw= .27-.37). Except for arm/leg swelling, endorsement patterns by the dimensions of F, S and I were distinct (Bowker’s p all
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- 2012
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162. Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced malignancies
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Christina Bryla, Christophe E. Redon, Yixing Jiang, Susan E. Bates, Leonard Joseph Appleman, Asako J. Nakamura, Robert A. Parise, Edward Chu, Julie L. Eiseman, William M. Bonner, Jan H. Beumer, Chandra P. Belani, John Wright, Sanjeeve Balasubramaniam, and Richard Piekarz
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,ECOG Performance Status ,Pharmacology ,medicine.disease ,Immunofluorescence ,Lymphoma ,Pharmacokinetics ,Renal cell carcinoma ,Pharmacodynamics ,Internal medicine ,Toxicity ,medicine ,Cytotoxic T cell ,business - Abstract
2553 Background: DMS612 is a dimethane sulfonate compound that was identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines in a chemical screen of the NCI-60 panel. DMS612 has bifunctional alkylating activity in vitro. Objectives of this first-in-human phase I study included determining the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), PK and PD of DMS612 administered by 10 minute intravenous infusion on day 1, 8 and 15 of a 28 day cycle. Methods: Eligibility criteria included adults with advanced solid malignancies or lymphoma with ECOG performance status 0-2, life expectancy > 3 months and adequate organ and marrow function. Patients were enrolled using a standard “3+3” dose escalation scheme. Plasma PK of DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD was assessed by γ-H2AX immunofluorescence. Results: 35 subjects were enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses administered were 1.5, 3, 5, 7, 9 and 12 mg/m2. The MTD was determined to be 9 mg/m2, with only one DLT of grade 4 thrombocytopenia in 12 subjects enrolled. The maximum administered dose of 12 mg/m2 was considered to be intolerable after 1 of 3 subjects had grade 4 neutropenia and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia in later cycles was observed in other subjects, including one patient naïve to prior cytotoxic chemotherapy. One subject with RCC had a confirmed partial response at 7 mg/m2. DMS612 was rapidly converted into carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides, some of which retained alkylating activity in vitro. Dose-dependent pharmacodynamic evidence of DNA damage induced by DMS612 in vivo was observed by γ-H2AX immunofluorescance in both peripheral blood lymphocytes and plucked scalp hairs. Conclusions: The MTD of DMS12 administered by intravenous infusion on day 1, 8 and 15 of a 28-day cycle was 9 mg/m2. Pre-clinical and clinical observations suggest that further study of DMS612 in RCC is warranted.
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- 2012
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163. Acceptability of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women with metastatic breast cancer (MBC)
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Victoria Federico, Christine I. Nichols, Kathleen Castro, Alice P. Chen, Ann M. O'Mara, Melissa Brammer, Lori M. Minasian, Ethan Basch, Musa Mayer, Richard Piekarz, Laura Sit, Thomas M. Atkinson, Andrea Denicoff, Bryce B. Reeve, Lauren J. Rogak, K Lang, Deepa Lalla, Steven B. Clauser, and Sandra A. Mitchell
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Outcome measures ,Common Terminology Criteria for Adverse Events ,medicine.disease ,Metastatic breast cancer ,Pro ctcae ,Clinical trial ,Internal medicine ,Patient experience ,medicine ,business ,Adverse effect - Abstract
e19633 Background: NCI PRO-CTCAE is a new patient-reported outcome measure designed to enhance adverse event (AE) reporting in clinical trials by integrating the patient experience. The PRO-CTCAE item bank includes items representing the frequency (F), severity (S) and interference (I) with usual activities of 78 symptomatic AEs. The aim of this study was to examine the acceptability of a subset of PRO-CTCAE items to women receiving treatment for HER2+ MBC. Methods: 207 women on active treatment for HER2+ MBC (median 47 months since MBC diagnosis) were recruited from 6 U.S. breast cancer support groups and completed a web survey that included 18 PRO-CTCAE symptoms. Respondents were aged 45-64 years (71%), white (94%), college-educated (72%), with health-related quality of life rated good to excellent (61%) and median EQ5D utility score of 0.8. To explore PRO-CTCAE acceptability and data quality, we examined item level missingness, endorsement frequencies and binary and free-text responses about the comprehensibility of PRO-CTCAE items. Results: Item level missingness across all symptoms for each PRO-CTCAE dimension (F, S and I) ranged from 1.0% to 5.3%, with a median of 2.9%; interference associated with decreased appetite had the greatest missingness (5.3%). Excluding this outlier, maximum missingness was 3.9%. Endorsement frequencies of response choices for S of insomnia, constipation, fatigue, pain, anxiety/worry and sad/unhappy feelings support acceptable instrument sensitivity (all adjacent response points endorsed by >7% of respondents). Most respondents (92%) thought the items were easy to understand; a few were uncertain about how to rate symptoms such as anxiety, depression, insomnia and nausea if they were present but partially controlled with medication. Conclusions: These findings confirm and extend those of other studies demonstrating the acceptability of PRO-CTCAE. Evaluation in a more heterogeneous sample, particularly with respect to education and cancer site, is underway.
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- 2012
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164. Abstract B9: Activated MAPK Pathway Mediates Resistance to Romidepsin via Bim Degradation in Romidepsin-Selected HuT 78 Cells
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Susan E. Bates, Victoria Luchenko, Richard Piekarz, Robert W. Robey, Jean-Pierre Gillet, Michael M. Gottesman, Arup R. Chakraborty, and Nathan Collie
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MAPK/ERK pathway ,Cancer Research ,biology ,Mitogen-activated protein kinase kinase ,Molecular biology ,Romidepsin ,Insulin receptor ,chemistry.chemical_compound ,Oncology ,chemistry ,Downregulation and upregulation ,Cell culture ,biology.protein ,medicine ,Histone deacetylase ,Valspodar ,medicine.drug - Abstract
Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50 < 10 nM) but not to phosphatidylinositol 3-kinase (PI3K) inhibition. Combined treatment of romidepsin with low concentrations (1- 3 nM) of MEK inhibitor also resulted in increased cell death in romidepsin-resistant HuT 78 cells. The exquisite sensitivity to MEK inhibition in the resistant sublines was found to correlate with restoration of the expression of Bim (BCL2L11), a Bcl-2-homology domain-3 only (BH-3) proapoptotic protein. In the resistant cells, the MAPK pathway appeared to regulate Bim expression posttranslationally as we did not detect any gene induction of BCL2L11 or FOXO3, a transcription factor known to activate BCL2L11 expression, following MEK inhibition. These findings implicate increased activation of the MAPK pathway as a mechanism of resistance to romidepsin, and suggest that combining romidepsin with MEK inhibitors may be an effective strategy to overcome resistance.
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- 2012
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165. Abstract 4709: Combined mitogen-activated protein kinase pathway inhibition with short-term romidepsin treatment induces proapoptotic Bim and cell death in BRAF mutant cancers
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Julian C. Bahr, Arup R. Chakraborty, Robert W. Robey, Susan E. Bates, Victoria Luchenko, Alexandra S. Zimmer, and Richard Piekarz
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MAPK/ERK pathway ,Cancer Research ,Kinase ,Romidepsin ,chemistry.chemical_compound ,Oncology ,chemistry ,Apoptosis ,Annexin ,Cancer research ,medicine ,Propidium iodide ,Protein kinase A ,V600E ,medicine.drug - Abstract
Solid tumor trials with histone deacetylase inhibitors (HDIs) have been largely disappointing. We recently characterized a romidepsin-resistant T-cell lymphoma cell line that was found to have activation of the mitogen-activated protein kinase (MAPK) pathway, leading to subsequent phosphorylation and degradation of the proapoptotic protein Bim, suggesting that activation of this pathway may also confer resistance to romidepsin and other HDIs. The V600E BRAF mutation has been found in approximately 60% of melanomas and approximately 15% of colon cancers and leads to constitutive activation of the MAPK pathway. We thus hypothesized that combined treatment with romidepsin and BRAF or mitogen-activated protein kinase kinase (MEK) inhibitors may be effective in cancers that harbor the V600E BRAF mutation. To more closely simulate clinical administration of romidepsin, 11 V600E BRAF mutant cell lines (8 melanomas and 3 colorectal cancers) were exposed to 25 ng/ml romidepsin for 6 h after which romidepsin was removed, cells were incubated in fresh medium for an additional 42 h and subsequently apoptosis was measured by Annexin V and propidium iodide staining. Of the 11 cell lines, 10 exhibited significantly higher annexin staining after short-term romidepsin treatment (control 7.1% ± 3.8% vs. treated 34.7% ± 17.8%, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4709. doi:1538-7445.AM2012-4709
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- 2012
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166. Abstract 2624: Elevated expression of phosphorylated mitogen activated protein kinase kinase (MEK) as a mechanism of resistance to the histone deacetylase inhibitor romidepsin in HUT 78 cutaneous T-cell lymphoma cells
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Jean-Pierre Gillet, Arup R. Chakraborty, Nathan L. Collie, Robert W. Robey, Susan E. Bates, Michael M. Gottesman, and Richard Piekarz
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MAPK/ERK pathway ,Cancer Research ,medicine.drug_class ,MEK inhibitor ,Histone deacetylase inhibitor ,Biology ,Mitogen-activated protein kinase kinase ,Molecular biology ,Romidepsin ,chemistry.chemical_compound ,Oncology ,chemistry ,Panobinostat ,medicine ,Belinostat ,Vorinostat ,medicine.drug - Abstract
Elevated expression of phosphorylated mitogen activated protein kinase kinase (MEK) as a mechanism of resistance to the histone deacetylase inhibitor romidepsin in HUT 78 cutaneous T-cell lymphoma cells. Histone deacetylase inhibitors (HDIs) have shown promise in the treatment of T-cell lymphomas including cutaneous and peripheral T-cell lymphomas. However, resistance to romidepsin limits its activity in some patients. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To study mechanisms of resistance to the HDI romidepsin, the HUT78 cutaneous T-cell lymphoma cell line was exposed to increasing concentrations of romidepsin in the presence of the P-glycoprotein (P-gp) inhibitors verapamil or valspodar (PSC-833) to prevent the emergence of P-gp, a known resistance mechanism. The DpVp35 and DpVp50 sublines are maintained in 35 ng/ml and 50 ng/ml romidepsin, respectively, in the presence of 5 µg/ml verapamil while DpP75 is maintained in 75 ng/ml romidepsin and 3 µg/ml valspodar. In 4-day cytotoxicity assays, the sublines are approximately 55-fold resistant to romidepsin and are not cross resistant to the HDIs belinostat, panobinostat or vorinostat. Low but detectable levels of P-gp do not explain the resistance. We used a custom drug resistance gene expression array and found increased expression of insulin receptor (IR) in the resistant cells that was confirmed by immunoblot analysis. Elevated expression of phosphorylated mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. Interestingly, resistant cells were found to be exquisitely sensitive to MEK inhibition, as significant apoptosis was observed after 48 h in the presence of 5 nM of the MEK inhibitor PD0325901 and 10 nM of the MEK inhibitor AZD 6244 as measured by flow cytometry with annexin V and by immunoblot examining poly (ADP-ribose) polymerase (PARP) cleavage. No significant apoptosis was observed in parental cells at concentrations up to 500 nM. Resistant cells were not, however, sensitive to extracellular related kinase (ERK) inhibition or phosphatidylinositol 3-kinase (PI3K) inhibition in as determined by annexin V assay. In summary, we hypothesize that activated MEK can mediate resistance to romidepsin, but may also lead to collateral sensitivity to MEK inhibitors. The emerging role of activated MEK as a mechanism of resistance to romidepsin suggests combination of romidepsin with MEK inhibitors in future clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2011-2624
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- 2011
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167. Religious Tradition and Concern for the Welfare of All Living Beings
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Ari Z. Zivotofsky and Richard Piekarz
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business.industry ,media_common.quotation_subject ,Medicine ,Environmental ethics ,General Medicine ,business ,Welfare ,media_common - Published
- 2010
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168. Abstract 3527: A pharmacodynamic study of docetaxel in combination with the p-glycoprotein antagonist, tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer
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William D. Figg, Tito Fojo, Deborah Draper, Robert W. Robey, Erin R. Gardner, Aradhana M. Venkatesan, Susan E. Bates, Richard Piekarz, Ronan J. Kelly, Clara Chen, and Frank M. Balis
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Cancer Research ,education.field_of_study ,Chemotherapy ,business.industry ,Tariquidar ,medicine.medical_treatment ,Population ,Area under the curve ,Phases of clinical research ,Cancer ,Pharmacology ,medicine.disease ,Oncology ,Docetaxel ,medicine ,Lung cancer ,education ,business ,medicine.drug - Abstract
Purpose: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to demonstrate meaningful results. However, data highlighting Pgp-mediated drug efflux continues to be reported. A growing body of evidence suggests that sestamibi uptake in lung cancer correlates with disease response to chemotherapy and has been proposed as a pre-selection technique to identify tumors that will respond to chemotherapy. We report the results of a clinical trial using tariquidar (XR9576), a potent Pgp antagonist, in combination with docetaxel. Experimental Design: Patients first received either 40 mg/m2 of docetaxel alone or 40 mg/m2 docetaxel administered in combination with 150 mg tariquidar. In the first cycle, the pharmacokinetics of docetaxel were monitored after the day 1 and day 8 doses with or without tariquidar. 99mTc-sestamibi scanning and rhodamine efflux from CD56+ mononuclear cells were performed to establish whether tariquidar modulates Pgp. In subsequent cycles, 75 mg/m2 of docetaxel was administered with 150mg of tariquidar every three weeks. Results: Forty-eight patients were enrolled onto the trial. Twenty-nine percent of the patients (14/48) had previously treated metastatic non-small cell lung cancer (NSCLC). Three partial responses were seen in the NSCLC cohort, measuring 40%, 57% and 67% reduction in tumor size by RECIST. Two patients remained on study for 7 and 24 months, respectively. Non-hematologic grade 3/4 toxicities in 235 cycles included fatigue (6%), nausea (4%), and diarrhea (1%). Tariquidar blocked Pgp-mediated rhodamine efflux from CD56+ cells and reduced 99mTc-sestamibi clearance from the liver. Sestamibi results were available in 32 of the 48 patients, and an increased area under the curve for the liver was noted, ranging from 5.8% to 251% over the pre-tariquidar scan. A 12% to 25% increase in sestamibi uptake was noted in 8 of 10 patients with lung cancer with visible lesions. A pharmacokinetic analysis evaluating potential interaction between tariquidar and docetaxel will be presented; previous reports suggest minimal interaction with anticancer agents. Conclusions: Tariquidar is a Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Surrogate studies show increased retention of the Pgp substrate sestamibi following tariquidar in imagable lung cancers. Although the percentage increase was less than 25%, we have previously noted that quantitation by planar sestamibi imaging tends to underestimate actual change in accumulation. While response in this trial was designed as an exploratory endpoint only, three responses among 14 in a heavily pretreated population with NSCLC are somewhat surprising and suggest that a follow-up phase II study may be worthwhile. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3527.
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- 2010
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169. Final Results of a Phase 2 NCI Multicenter Study of Romidepsin in Patients with Relapsed Peripheral T-Cell Lymphoma (PTCL)
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Richard Piekarz, John Wright, Robin Frye, Steven L Allen, David Joske, Mark Kirschbaum, Ian D. Lewis, Miles Prince, Sonali Smith, Elaine S Jaffe, and Susan Bates
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Abstract 1657 Poster Board I-683 Background The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel pan-HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with cutaneous T-cell lymphoma (CTCL) in two phase 2 studies. Aims To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and CTCL. Methods This Phase 2, open-label, multi-arm, multicenter study enrolled 46 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. This study is now closed to accrual. Pts with relapsed or refractory PTCL who had received at least one prior standard chemotherapy regimen were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results 46 pts (24 [52%] men and 22 [48%] women) with a mean age of 59 (range: 28 to 84) years were treated with romidepsin. 32 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 4.8 (range 1 to 14). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1-47) and the overall median duration of response was 9.0 months (range 1.8 months to 5.8 yrs) for all pts. The median duration of response for the 5 pts who achieved CR was 6.0 months (range 2.8 months to 5.8 yrs).The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (74%; 9% ≥grade 3), fatigue (72%; 20% ≥grade 3), decreased platelets (72%; 35% ≥grade 3), cardiovascular/general-other (72%; 0% ≥grade 3) and decreased AGC (65%; 43% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions This study demonstrates tolerability and durable clinical benefit (ORR of 33% and median duration of response of 9.0 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with relapsed or refractory PTCL is ongoing at multiple international centers. Disclosures Kirschbaum: Gloucester Pharmaceuticals: Consultancy.
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- 2009
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170. Systematic Assessment of Potential Cardiac Effects of the Novel Histone Deacetylase (HDAC) Inhibitor Romidepsin
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Darrell Nix, Jean Nichols, Susan E. Bates, Christopher Schoonmaker, Sean Whittaker, Michelle Currie, Youn H. Kim, Richard Piekarz, Christopher H. Cabell, C. J Godfrey, and Howard A. Burris
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,QT interval ,Asymptomatic ,Hypokalemia ,Hypomagnesemia ,Romidepsin ,Pharmacodynamics ,Internal medicine ,Cardiology ,Medicine ,Dosing ,medicine.symptom ,business ,Depression (differential diagnoses) ,medicine.drug - Abstract
3709 Poster Board III-645 Background Romidepsin is an anti-neoplastic agent that has been identified as a novel pan-HDAC inhibitor with single-agent activity in cutaneous T-cell lymphoma (CTCL) in 2 studies (GPI-04-0001 and NCI 1312). In the GPI study the overall response rate (ORR) was 34% including 6 complete clinical responses (CCRs) in 96 pts with CTCL and the median duration of response (DOR) was 14.9 months (mo). In the NCI study, the ORR was 35% including 4 CCR in 71 pts and the median DOR was 11 mo. NCI 1312 has also reported single-agent activity in patients with peripheral T-cell lymphoma with an ORR of 31% including 4 CRs in the 48 pts analyzed. HDAC inhibitors have variably been reported to have cardiovascular effects, in particular, QTc prolongation. To systemically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA Division of Oncology Drug Products. Subsequently, a romidepsin QTc Clinical/Statisitcal Analysis Plan was developed following the ICH E14 Guidelines, to provide a comprehensive evaluation of the cardiac effects of romidepsin. Methods An analysis of romidepsin cardiac safety, including review and analysis of ECG findings, was performed. The primary objective of these analyses was to evaluate the effect of romidepsin on the change from baseline on the corrected QT interval of the ECG using the Fridericia QT correction method (QTcF) during Cycle 1 Day 1 exposure to study drug. A total of 4909 ECGs from 110 patients in 3 clinical studies, GPI study, NCI study, and Study GPI-06-0005 (a Phase 1 PK study) were evaluated. The 110 patients comprised 103 patients with T-cell lymphoma and 7 patients with advanced cancer treated with romidepsin at 14 mg/m2 as a 4-hour infusion on Days 1, 8, and 15 of a 28-day cycle. Using a nonlinear mixed effects model the pharmacodynamics of romidepsin was characterized for exposure-QTc effects. Results In an analysis of ECG data, a mean increase of 5.0 msec (90% CI upper bound 7.7 msec) in QTcF interval was measured following infusion of romidepsin; this value includes a contribution to QTc prolongation by pre-dose antiemetics. Data from the NCI study showed that the QTcF change persisted to 24 hours, with a return to baseline by 48 hours, whereas in the smaller GPI-06-0005 study, QTcF peaked 2 hours post infusion and there was no QTcF effect seen at 24 hours. Categorical analyses showed no patients with a change from baseline >60 msec or an absolute QTcF >480 msec. No cardiac events of Torsade de Pointes were reported. Per the ICH E14 guidance,56 a threshold for regulatory concern for mean QTc prolongation is 5 msec with an upper bound of the 95% CI of 10 msec. Prolongations of >60 msec over baseline or a value >500 msec are also considered cautionary. Treatment-emergent morphological changes on ECG (minor ST-segment depression, T-wave flattening, biphasic T-waves, and T-wave inversion) have been observed during treatment with romidepsin; however the overall frequency of these minor, asymptomatic changes was similar to the frequency of pre-exposure abnormalities on each dosing day, suggesting a high degree of background noise in these data. Furthermore, there was no association between these ECG findings and any clinical, functional, or laboratory findings of cardiac abnormalities. | Category | Study | | |:------------------------------- | -------------------- | --------------------- | ----------------- | | GPI Study N=87 n (%) | NCI Study N=41 n (%) | GPI-06-0005 N=7 n (%) | Total N=135 n (%) | | QTcF change from baseline[1][1] | | No increase | 31 (36) | 10 (24) | 2 (29) | 43 (32) | | 1-29 msec increase | 46 (53) | 27 (66) | 4 (57) | 77 (57) | | 30-60 msec increase | 2 (2) | 4 (10) | 1 (14) | 7 (5) | | >60 msec increase | | | | | | QTcF not available | 8 (9) | | | 8 (6) | | QTcF absolute value: | | >450 msec | 2 (2) | 2 (5) | | 4 (3) | | >480 msec | | | | | | >500 msec | | | | | * [↵][2]1 For GPI studies, baseline values are those post co-med, or if missing post co-med, then pre-comed baseline is used. Categorical Analysis of QTc Change on Cycle 1, Day 1 Conclusions The findings from the romidepsin studies show that the observed QTc changes were below the threshold levels of concern outlined in ICH E14. Pharmacodynamic modeling showed no evidence of a relationship between the plasma concentration of romidepsin and changes in the QTc interval. Since hypokalemia and hypomagnesemia are associated with ECG abnormalities, supplementation with potassium and magnesium to achieve normal levels prior to romidepsin administration is recommended. Disclosures: Cabell: Gloucester Pharmaceuticals: Consultancy. Whittaker: Gloucester Pharmaceuticals: Research Funding. Nichols: Gloucester Pharmaceuticals: Employment, Equity Ownership. Nix: Gloucester Pharmaceuticals: Employment. Burris: Gloucester Pharmaceutcals: Research Funding. [1]: #fn-1 [2]: #xref-fn-1-1
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- 2009
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171. Characterization of Cyclic Hematologic Changes Observed in Patients with Cutaneous T-Cell Lymphoma (CTCL) Receiving Romidepsin, a Novel Histone Deacetylase (HDAC) Inhibitor
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Sean Whittaker, Ellen J Kim, Miles Prince, Marie France Demierre, Cynthia Giver, Sagar Lonial, Richard Piekarz, Youn H Kim, Jean Nichols, Darrell Nix, and Susan Bates
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medicine.medical_specialty ,business.industry ,Anemia ,Immunology ,Cutaneous T-cell lymphoma ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Romidepsin ,medicine.anatomical_structure ,Internal medicine ,Medicine ,T-cell lymphoma ,Platelet ,Bone marrow ,business ,Thrombopoietin ,medicine.drug - Abstract
Abstract 3701 Poster Board III-637 Background Romidepsin is an anti-neoplastic agent that has been identified as a novel pan-HDAC inhibitor with single-agent activity in T-cell lymphoma. In a combined analysis of 167 patients (pts) with cutaneous T-cell lymphoma (CTCL) from 2 clinical studies (GPI and NCI studies), the overall response rate was 35%, including 10 pts with a complete clinical response (CCR). Median duration of response was 13.8 months and 42% of pts with advanced disease (stage ≥IIB) responded [Demierre et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8546)]. The most common hematologic abnormalities in these pts included anemia (41%), thrombocytopenia (34%), neutropenia (27%), and lymphopenia (26%). Most hematologic toxicities were Grade 1 or 2, although 'Grade 3 events were observed. These events were reversible and a small portion of the patients discontinued the study drug because of these events (2%). This report details an analysis of platelet counts in pts receiving romidepsin and an investigation into the mechanism of thrombocytopenia in nonclinical studies. Methods Pts with CTCL who received ≥1 prior systemic therapy failure and had an ECOG PS of 0-2 were enrolled in 2 single-arm, open-label, multicenter and international clinical studies. Treatment with QTc prolonging therapies or CYP34A inhibitors was prohibited and pts with significant cardiovascular abnormalities were excluded. Romidepsin at 14 mg/m2 was administered as a 4-hr IV infusion on days 1, 8, and 15 of a 28 day cycle. Nonclinical studies were conducted in mice to investigate the mechanism of romidepsin effects on platelets. Romidepsin was administered to female BALB/c mice at doses of 1 or 4 mg/kg by tail-vein injection on days 1, 5 and 9. Blood samples were collected every 2 days from alternating groups of mice to minimize effects of bleeding on platelet counts. Results In clinical studies, there is a mean decrease in platelet counts during the treatment period of each cycle, and a return to baseline levels or above between cycles observed in both clinical studies as described in the table below. No clinically meaningful change has been observed in the central tendency over 4 cycles of treatment in both studies. In the mouse studies, dose-dependent effects were seen on both WBC and platelet counts. Day 2 WBC counts dropped to 45% and 10% of normal at the 1 and 4 mg/kg doses, respectively. WBC counts remained low until after the dosing period in the 1 mg/kg romidepsin group, but recovered more quickly in the 4 mg/kg group. Day 2 platelet counts were 70% of normal at the 1 mg/kg dose and remained near this level until day 10, followed by recovery to normal at day 15. At the 4 mg/kg dose, profound thrombycytopenia was induced, with platelet counts only 20% of normal on days 4-6. Platelet counts slowly recovered to 70% of normal by day 15. Plasma thrombopoietin levels were normal throughout the experiment for the 1 mg/kg group, and showed a large increase to 275% of normal on day 6 in the 4 mg/kg group, which is the expected response to thrombocytopenia as a signal to increase platelet production and indicates that platelet reduction is not attributable to defective TPO production. Bone marrow megakaryocyte populations are being examined to determine the effects of romidepsin on these platelet-producing cells. Conclusions Following romidepsin administration, a saw tooth pattern is observed in the reduction and recovery of platelets. Recovery of platelets appears to occur more rapidly in humans than in mice; however, the effects are reversible after dosing in clinical studies and in murine models. In the clinical data the recovery pattern suggests that the transient effects are direct and are not effects on bone marrow. Disclosures: Whittaker: Gloucester Pharmaceuticals: Research Funding. Prince:Gloucester Pharmaceuticals: Consultancy. Demierre:Gloucester Pharmaceuticals: Consultancy, Honoraria. Lonial:Gloucester Pharmaceuticals: Honoraria. Kim:Gloucester Pharmaceuticals: Consultancy, Honoraria. Nichols:Gloucester Pharmaceuticals: Employment, Equity Ownership. Nix:Gloucester Pharmaceuticals: Employment.
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- 2009
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172. Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma (CTCL)
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Youn H. Kim, Ellen Kim, Miles Prince, J. Balser, Jean Nichols, Marie-France Demierre, Sean Whittaker, Archie G. Prentice, Susan E. Bates, and Richard Piekarz
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Oncology ,Cancer Research ,medicine.medical_specialty ,Mycosis fungoides ,education.field_of_study ,business.industry ,Cutaneous T-cell lymphoma ,Population ,medicine.disease ,Surgery ,Romidepsin ,medicine.anatomical_structure ,Internal medicine ,Medicine ,Stage (cooking) ,business ,Until Disease Progression ,education ,Lymph node ,Sezary Cell ,medicine.drug - Abstract
8546 Background: Romidepsin is a novel pan-HDAC inhibitor with demonstrated single-agent activity in 2 open-label clinical studies of 167 patients (pts) with CTCL [mycosis fungoides or Sézary Syndrome (SS)]. Data for these 2 studies were pooled for more accurate estimates of endpoints and investigation of subpopulations. Methods: GPI-04–0001 (pivotal study) enrolled 96 pts with confirmed CTCL who had recieved ≥1 prior systemic therapy. NCI 1312 (supportive study) enrolled 71 pts with CTCL. Pts recieved romidepsin, 14mg/m2 as a 4-hr infusion on days 1, 8, and 15 every 28 days until disease progression (≥25% increase). The primary efficacy endpoint for both studies was overall response rate (ORR) using a composite endpoint that included skin assessment, lymph node and visceral involvement and abnormal circulating T-cells/Sézary cells. Results: 167 pts received romidepsin (as-treated); 135 pts (81%) were in the efficacy evaluable population. Mean age was 57±12 yrs, 67% men, 87% white. 103 pts (76%) had stage ≥IIB disease. Median number of prior systemic therapies was 2 (range 1–8). ORR in the table. Responses were noted in: 42% of pts with stage ≥IIB; 11 (58%) of 19 pts with SS (erythroderma + Sézary cells, >1000/ml or >20% ); and 20 (38%) of 52 pts who received prior bexarotene and 8 (40%) of 20 pts who had received denileukin diftitox. Most common drug-related adverse events (AE), all grades, included: nausea (67%), fatigue (49%), anorexia (37%), ECG T-wave changes (29%), anemia (26%), dysgeusia (23%), neutropenia (22%), leucopenia (20%). Related serious AEs in 2% of pts: supraventicular arrhythmia, ventricular arrhythmia, infection, neutropenia, WBC decreased, hyperuricemia, hypotension; all other serious AEs in ≤1 pt. 3 deaths reported as possibly related. Conclusions: Romidepsin is a valuable new therapy for pts with CTCL based on the ORR, CR, durability of response, improvement in all disease compartments and responses at all stages and in all subpopulations analyzed. [Table: see text] [Table: see text]
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- 2009
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173. Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin
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Richard Piekarz, Jean Nichols, Sean Whittaker, William McCulloch, C. Schoonmaker, Christopher H. Cabell, C. J Godfrey, Susan E. Bates, Youn H. Kim, and Howard A. Burris
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QTC PROLONGATION ,Cancer Research ,Oncology ,business.industry ,medicine ,HDAC inhibitor ,Histone deacetylase ,Pharmacology ,medicine.disease ,business ,Lymphoma ,Romidepsin ,medicine.drug - Abstract
e19533 Background: Romidepsin is a novel pan-HDAC inhibitor with single-agent activity in T-cell lymphoma. HDAC inhibitors reportedly have cardiovascular effects, in particular, QTc prolongation. To systematically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA. Methods: The effect of romidepsin on the change from baseline QTcF (Fridericia's correction) at key pharmacokinetic and pharmacodynamic (PD) time points was investigated. ECGs from 110 pts with advanced malignancies in 3 open-label, clinical studies of romidepsin 14 mg/m2 administered on days 1, 8 and 15 of a 28 day cycle were evaluated by blinded, independent assessors. Results: A mean 2.7 msec increase (90% confidence interval [CI]: 0.2, 5.3) in QTcF interval from a baseline post-antiemetic administration to after infusion of romidepsin was measured. A subanalysis of 74 patients (pts) evaluated QTcF from pre-antiemetic to post-romidepsin showed a mean change in QTcF of 5.0 msec (90% CI: 2.3, 7.7). Thus, antiemetic comedications likely accounts for a portion of the clinically apparent QTc effect. The QTc returned to baseline within 48 hrs. No absolute QTc values >480 msec and no QTc changes >60 msec were observed. No relationship was observed in an analysis of romidepsin plasma concentration versus QT changes. Mean heart rate (HR) increased 10.1±9.0 bpm after romidepsin administration, with a return to baseline by 24 hrs. Several treatment-emergent morphological changes in ECGs (including T wave and ST-segment) were reported. Many of the ECG morphologic abnormalities (determined by automated machine reading) were also observed at baseline. These ECG changes were transient and were not associated with functional cardiovascular changes or with symptoms. Conclusions: Romidepsin has a slight effect on the QT interval but rigorous ECG evaluation found this effect to be mild, below the threshold of regulatory and clinical concern, and not associated with any observed clinical cardiovascular events. Concentration response modeling found no PD relationship between romidepsin concentration and changes in QTcF, but did suggest a relationship between romidepsin concentration and HR. [Table: see text]
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- 2009
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174. Final Clinical Results of a Phase 2 NCI Multicenter Study of Romidepsin in Recurrent Cutaneous T-Cell Lymphoma (Molecular Analyses Included)
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Craig B. Reeder, Miles Prince, John P. Leonard, Laura F. Hutchins, Mark Kirschbaum, Susan E. Bates, Maryalice Stetler Stevenson, Robin Frye, Steven L. Allen, Larisa J. Geskin, Michael Craig, John Wright, William D. Figg, David Joske, Alexander Ling, Jean Nichols, and Richard Piekarz
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medicine.medical_specialty ,business.industry ,Surrogate endpoint ,Immunology ,Cmax ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Romidepsin ,Surgery ,Lymphoma ,Tolerability ,Internal medicine ,medicine ,T-cell lymphoma ,business ,Histone H3 acetylation ,medicine.drug - Abstract
Background: Responses to the novel HDAC inhibitor romidepsin were observed in patients (pts) with T-cell lymphoma in a phase 1 NCI trial. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced cutaneous T-cell lymphoma (CTCL). As an exploratory endpoint, to examine the molecular effects of romidepsin in both CTCL and peripheral T-cell lymphoma (PTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 71 CTCL pts from the NCI and 9 extramural sites. PTCL pts were also enrolled. Clinical results for pts with CTCL and biomarker analyses for both PTCL and CTCL are presented here; clinical results for the PTCL pts are presented elsewhere. This study is now closed to accrual. Pts with recurrent CTCL (Stages IA-IVB) received romidepsin at 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 q 28 days. Responses were assessed using a composite endpoint that evaluated overall changes in skin (modified Physicians Global Assessment), lymph nodes, extranodal visceral lesions and abnormal circulating T-cells. Molecular endpoints evaluated in NCI pts were: histone acetylation in peripheral blood mononuclear cells (PBMCs); MDR-1 gene expression in PBMCs and in biopsy samples; and blood fetal hemoglobin levels. Results: 71 pts (48 men and 23 women) with a mean age of 56 yrs (range 28–84) were enrolled and received romidepsin; 63 pts received ≥2 cycles of therapy. Mean number of prior therapies was 3.4 (range 1–10). Objective disease response rates (ORR) are presented in the table. Overall disease control (CR+PR+SD90) was 62% in all pts and 70% in pts who received ≥2 cycles. Target skin lesions were followed and changes were generally similar to overall skin changes. Median duration of response (DOR) was 11 months (mo) and the maximum DOR as of data cut-off was 5.5+ yrs. The most frequent drug-related AEs (all grades, all cycles) were generally mild, including nausea (82%; 4% ≥grade 3), fatigue (73%; 14% ≥ grade 3), electrocardiogram T-wave amplitude decreased (69%, 0% ≥grade 3); hemoglobin decreased (59%, 9% ≥grade 3), and platelet count decreased (59%; 13% ≥grade 3). Six pts died within 30 days of study drug administration: 2 after salvage chemotherapy, 1 with ARDS due to PD, 2 with infection, and 1 of unknown cause; 2 of these deaths were considered possibly related to treatment. An increase in all biomarkers measured was observed, although not in all pts. Correlation between global histone H3 acetylation (AcH3) at the 24-hr time point and Cmax, AUC, and clearance was observed (r = 0.37, 0.36, and −0.44, respectively, p = 0.03). Pts with major responses were more likely to have higher levels of AcH3 at 24 hr. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 35% and median DOR of 11 mo in all pts) of romidepsin in pts with recurrent CTCL. Significant responses were observed at all stages of disease, including an ORR of 32% in all pts with stage ≥IIB and 20% in all pts with stage IV. Time to response was rapid, within 2 mo in most pts, and responses were durable, >6 mo in most pts. Molecular analyses confirmed that romidepsin inhibits its target deacetylases in pts. Increases were not observed in all pts, perhaps reflecting, in part, variable drug exposure or variable response to HDAC inhibition. Correlation of global acetylation with PK parameters suggests that increased drug exposure results in increased global acetylation. All Pts N=71 Pts ≥ 2 cycles N=63 ORR (CR+PR), n (%) 25 (35%) 25 (40%) PR, n (%) 21 (30%) 21 (33%) CR, n (%) 4 (6%) 4 (6%) SD90, n(%) 19 (27%) 19 (30%) Overall disease control (CR+PR+ SD90) 44 (62%) 44 (70%) DOR 11 (1+ mo, 5.5+ yrs) 11 (1+ mo, 5.5+ yrs) OR for pts with stage ≥ IIB, n (%) 20/62 (32%) 20/55 (36%) SD90= stable disease for ≥90 days
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- 2008
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175. Phase I trial of romidepsin, a histone deacetylase inhibitor, given on days one, three and five in patients with thyroid and other advanced cancers
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Antonio Tito Fojo, D. Draper, V. Luchenko, Susan E. Bates, William D. Figg, John Wright, and Richard Piekarz
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Depsipeptide ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Thyroid ,Histone deacetylase inhibitor ,Romidepsin ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Internal medicine ,medicine ,Cancer research ,Cytotoxic T cell ,In patient ,business ,medicine.drug - Abstract
3571 Background: Romidepsin (FK228 or depsipeptide) is a potent histone deacetylase inhibitor (HDI) with cytotoxic activity in preclinical models and significant activity in patients with cutaneous...
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- 2008
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176. Phase II Trial of Romidepsin, FK228, in Cutaneous and Peripheral T-Cell Lymphoma: Clinical Activity and Molecular Markers
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Susan E. Bates, Robin Frye, Laura F. Hutchins, Louise C. Showe, Miles Prince, John Wright, Mark Kirschbaum, Steven L. Allen, Richard Piekarz, Maria L. Turner, Tito Fojo, William D. Figg, and Jasmine Zain
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Oncology ,medicine.medical_specialty ,CD30 ,business.industry ,Immunology ,Cell Biology ,Hematology ,Gene signature ,medicine.disease ,Biochemistry ,Peripheral T-cell lymphoma ,Lymphoma ,Romidepsin ,Internal medicine ,Fetal hemoglobin ,medicine ,Enteropathy-associated T-cell lymphoma ,business ,Anaplastic large-cell lymphoma ,medicine.drug - Abstract
Histone deacetylase inhibitors induce changes in gene expression that lead to cellular differentiation and reversal of the transformed phenotype. Interest in clinical development of these agents has been spurred by the responses observed in patients with T-cell lymphoma to romidepsin, previously FK228 and depsipeptide. To date, 61 patients with CTCL and 34 with PTCL have been accrued to our ongoing multiinstitutional trial of romidepsin for patients with recurrent or refractory cutaneous or peripheral T-cell lymphoma. Romidepsin is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14 mg/m2. Complete and partial responses have been observed in patients with CTCL, with a complete response in a patient with Sézary syndrome ongoing for over 45 months and a partial response ongoing for over 60 months. Both complete and partial responses were observed in patients with various subtypes of PTCL, including PTCL, unspecified, ALK-/CD30+ anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma, with a complete response ongoing for over 34 months. Responses will be updated for presentation. Molecular endpoint analysis was performed in normal and malignant circulating peripheral mononuclear cells, PBMCs, and in tumor samples. Immunoblot analysis demonstrated increased histone acetylation in PBMCs of 2-fold or greater from 19 of 33 patients at 4 or 24 hrs. RT-PCR of RNA demonstrated a 2-fold or greater increased expression of MDR-1 in PBMCs from 27 of 45 patients, 11 of which were greater than 4-fold. Microarray performed on CTCL patient samples detected significant changes with treatment. In addition, changes in the 5 gene signature for CTCL previously published (Nebozhyn et al. Blood2006; 107:3189) were also detected when analyzed by QPCR. MDR1 expression was evaluated by RT-PCR in 30 patient’s tumors. MDR1 expression level was not significantly increased at the time of progression, mean 3.2 and 4.9 (s.d. 3.1 and 5.5, respectively) in MDR1 units as defined in Zhan et al. Blood 1997 89:3795. Since differentiating agents have been shown to induce expression of fetal hemoglobin in the laboratory, fetal hemoglobin levels were assayed in patients on this clinical trial. Increased circulating fetal hemoglobin of 2, 5, and 10 fold was observed in 34, 24, and 15 patients, respectively, from 44 patients evaluated. SNP analysis is being performed on the MDR1 gene for comparison with pharmacokinetics and induction of fetal hemoglobin and MDR1 itself. In conclusion, romidepsin has significant single agent activity in patients with CTCL or PTCL. Molecular effects can be assayed in patients treated with romidepsin and related agents. Further clinical development of these agents should include combination trials and the identification of molecular markers of response.
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- 2006
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177. Completion of the First Cohort of Patients with Cutaneous T-Cell Lymphoma Enrolled on a Phase II Trial of Depsipeptide
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Miles Prince, Mark Kirschbaum, Jasmine Zain, Richard Piekarz, Susan E. Bates, Maria L. Turner, Steven L. Allen, John Wright, and Robin Frye
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Bexarotene ,Depsipeptide ,Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cutaneous T-cell lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Romidepsin ,Denileukin diftitox ,Internal medicine ,Cohort ,medicine ,T-cell lymphoma ,Exfoliative dermatitis ,business ,medicine.drug - Abstract
Histone deacetylase inhibitors, such as depsipeptide or FK228 (Gloucester Pharmaceuticals), form a new class of antineoplastic agents found to have activity in T-cell lymphoma. A multi-institutional phase II trial of depsipeptide is ongoing; accrual is complete for the first cohort, comprised of patients with cutaneous T-cell lymphoma who had disease that had progressed or was refractory to prior therapy and who had fewer than three prior regimens of systemic cytotoxic chemotherapy. Depsipeptide is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14 mg/m2. The first 3 patients enrolled were treated on the earlier NCI schedule, on days 1 and 5 of a 21 day cycle. Twenty-seven patients with a median age of 57 (31–77) were enrolled in this cohort and received a median of 5 (1–56) cycles and 14 (2–111) doses. Patients had received a median of 3 (1–11) prior therapies. These included PUVA in 15 patients, interferon in 8, bexarotene in 13, denileukin diftitox in 6, oral steroids in 6, topical nitrogen mustard in 7, or cytotoxic chemotherapy in 15. Disease extent at time of enrollment included 6 patients with tumor stage, 6 with generalized erythroderma and 3 with Sézary syndrome. Three patients, all with Sézary syndrome, achieved a complete response and five patients had partial responses for an overall response rate of 30%. With patients continuing to respond, the median duration of response is 18 (6–48) months. Partial responses were observed in patients with plaque/patch stage (1), generalized erythroderma (1), and tumor stage disease (3). An additional five patients had stable disease with a median duration to date of 6 months (4–14). Two patients had unconfirmed partial responses, three patients were not evaluable for response, one patient is too early to evaluate for response and seven patients had documented progression of disease. Overall depsipeptide was well tolerated, the main toxicities observed were nausea, taste changes, fatigue, neutropenia, thrombocytopenia. Non-specific ST-T wave changes were noted by ECG, without changes in cardiac function. No evidence of cardiac damage has been detected by serial echocardiograms, MUGA scans or troponin assays. Eight patients with objective responses receiving depsipeptide were followed for 12 to 53 months without evidence of cumulative toxicity. Induction of histone acetylation of more than two-fold was observed in paired samples of PBMNCs obtained from 9 of the 18 individual patients tested. RT-PCR analysis of MDR-1 demonstrated unchanged expression in tumor biopsies taken from 8 patients at the time of tumor progression when compared to prior to treatment initiation. While it is generally recognized that patients with Sézary syndrome are more refractory to available therapies, remarkably all patients enrolled with Sézary syndrome achieved a complete response to single agent depsipeptide. In conclusion, depsipeptide is the first of a new generation of histone deacetylase inhibitors to demonstrate consistent clinical activity with durable responses achieved in patients with CTCL. Patients are being accrued to a replicate arm for the purpose of confirming the observed response rate.
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- 2005
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178. Responses and molecular markers in patients with peripheral T-cell lymphoma treated on a phase II trial of depsipeptide, FK228
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Jasmine Zain, Susan E. Bates, Robin Frye, Maria L. Turner, Sonali M. Smith, John Wright, M. Kischbaum, Steven L. Allen, John P. Leonard, and Richard Piekarz
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Depsipeptide ,Cancer Research ,Oncology ,Differentiating Agents ,business.industry ,medicine ,In patient ,Histone deacetylase ,Pharmacology ,medicine.disease ,business ,Peripheral T-cell lymphoma - Abstract
3061 Background: The histone deacetylase inhibitors (HDIs) are a class of differentiating agents undergoing clinical testing. Depsipeptide, FK228 (Gloucester and Fujisawa Pharmaceuticals), is an HD...
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- 2005
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