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  • 1
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 19, No. 2 ( 2013-02), p. S352-S353
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
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  • 2
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2568-2568
    Abstract: Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Vorinostat (SAHA), an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases with preclinical and clinical activity against various forms of lymphoma, is being studied in patients with relapsed or refractory indolent lymphoma. We report the results at the first interim analysis, after accrual of the first 17 evaluable patients according to the two-stage trial design. Methods: Patients with relapsed or refractory follicular, marginal zone, or mantle cell lymphoma are eligible. Vorinostat is dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning is performed after every three cycles, as is marrow biopsy for those with marrow involvement at time of entry into study. Patients may have received up to four prior chemotherapy regimens including Zevalin or Bexxar; previous transplant is allowed. Results: 17 eligible patients (8 female, 9 male) were accrued prior to interim analysis (1 ineligible patient due to wrong histology is excluded from the analysis). The median age at diagnosis was 61 (34–78) years. All patients had progressed or failed to respond to chemotherapy and/or rituximab. Five patients were taken off study due to progression, two came off study due to toxicities (one for fatigue and diarrhea after 10 cycles and the other for diarrhea and dizziness after 2 cycles). One patient stopped therapy due to intercurrent illness, one came off for alternate therapy, 1 completed the treatment per protocol with a CR, and 7 patients remain on treatment. One patient had grade 4 ANC and thrombocytopenia, and one patient had grade 4 thrombocytopenia. Both patients were able to get subsequent cycles. Grade 3 toxicities attributable to study drug were thrombocytopenia, neutropenia, anemia, and fatigue. By the current Cheson criteria, there were 4 patients who achieved complete remission (CR), and 2 patients who achieved partial remission (PR). The two patients with PR as best response subsequently progressed (one at 189 days, one after 462 days). Four other patients are on therapy with stable disease, one patient with stable disease now for over 420 days. Conclusions: The histone deacetylase inhibitor vorinostat shows promising activity against follicular and marginal zone lymphoma, refractory to chemotherapy and rituximab. The target response for stage 1 (4/17) was met and stage 2 is open for accrual.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 29, No. 9 ( 2011-03-20), p. 1198-1203
    Abstract: We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma. Patients and Methods In this open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with ≤ 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability. Results All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses [CR] and five partial responses [PR] ). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue. Conclusion Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 664-664
    Abstract: Abstract 664 Background: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous hematopoietic cell transplantation is poor. Although reduced intensity allogeneic hematopoietic cell transplantation (RIC allo-HCT) can induce durable remissions in some patients with relapsed/refractory HL, its use is limited by a lack of disease control prior to transplantation. Brentuximab vedotin (b-vedotin, SGN-35), a novel antibody-drug conjugate, has a 75% objective response rate in patients with relapsed/refractory HL (Chen 2011). To examine the impact of b-vedotin on RIC allo-HCT, we performed a retrospective analysis of relapsed/refractory HL patients who received b-vedotin at City of Hope National Medical Center (COH) and Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA) and then went on to receive RIC allo-HCT. Methods: Between October 2008 and July 2011, 46 patients with relapsed/refractory HL received b-vedotin at COH and SCCA through Seattle Genetics trials (SGN-35-03, 06, 07, and 08). 16/46 (34.8%) patients subsequently underwent RIC allo-HCT, including 12 at COH (2/12 were transplanted at University of Utah and Wellington Hospital) and 4 at the SCCA. The baseline characteristics are listed in Table 1. All 12 COH patients received fludarabine/melphalan as the conditioning regimen, 5/12 used matched related donors and 7/12 used matched unrelated donors. 10/12 received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis and 2 patients received mycophenolate mofetil (MMF) and cyclosporine (CSP). In contrast, 3/4 patients transplanted at the SCCA received haploidentical donors transplantation using fludarabine/cytoxan/2Gy TBI conditioning and cytoxan/tacrolimus/MMF as GVHD prophylaxis while 1/4 underwent conditioning using 2Gy TBI followed by CSP/MMF prophylaxis. Patients were monitored for engraftment, aGVHD, cGVHD, chimerism, and infectious complications per institutional standards. Each institutional review board approved the retrospective analysis of individual center data and we plan to present combined analysis of COH/SCCA data at ASH. Results: At COH, the 1 year PFS was 90% (95% CI: 54.0, 98.2) and the 1 year OS was 100% with a median follow-up of 13.2 months (range: 2, 20), In addition, the 1 year relapse rate was 10% (95% CI: 1.7, 46) and the non-relapse mortality at 1 year was 0%. Likewise, all 4 of the SCCA patients are alive and progression-free with a median follow up of 7.2 months (range: 2.9, 19). For the entire cohort the rates of aGVHD and cGVHD were 25% and 63%, respectively. There was no grade III-IV aGVHD and only 1/16 (6.3%) with extensive cGVHD. There was no delay of engraftment or increased incidence of CMV/EBV infections (Table 1). The only patient who relapsed after RIC allo-HCT had progressive disease at the time of transplantation, and 276 days had elapsed between the last dose of b-vedotin to RIC allo-HCT. Conclusion: These data suggest that b-vedotin prior to RIC allo-HCT in HL can yield prolonged disease control without a delay in engraftment, increase in non-relapse mortality, aGVHD, cGVHD, and post transplant infectious complications. Such a strategy may allow more patients with relapsed or refractory HL to gain sufficient pre-transplant disease control to undergo this potentially curative procedure. Disclosures: Chen: Seattle Genetics: Consultancy, Research Funding. Off Label Use: SGN-35, a novel antibody drug conjugate, is used as salvage therapy for relapsed hodgkin lymphoma prior to allogeneic hematopoietic cell transplantation. Grove:seattle genetics: Employment. Gopal:Bio Marin: Research Funding; SBio: Research Funding; Pfizer: Research Funding; Abbott: Research Funding; Millenium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Piramal: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Spectrum: Research Funding; GSK: Research Funding; Biogen-Idec: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 55, No. 10 ( 2014-10), p. 2301-2304
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2014
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  • 6
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1564-1564
    Abstract: Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deacetylases with preclinical and clinical activity against various forms of lymphoma. Methods: We report the results of a phase II study of oral vorinostat in patients with relapsed or refractory (to chemotherapy and/or rituximab) follicular, marginal zone, or mantle cell lymphoma. Vorinostat is given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. CT scanning and/or FDG-PET are performed after every three cycles, as is marrow biopsy for those with marrow involvement at time of entry into study. Patients may have received up to four prior chemotherapy regimens including tositumomab or ibritumomab; previous transplant is allowed. Results: 37 patients (14 female, 23 male) were accrued (2 ineligible patient due to wrong histology are excluded from the analysis). The median age for evaluable patients at treatment was 65 (32–79) years. Histologies represented: follicular lymphoma (FL)-20, mantle cell (MC)-8, marginal zone (MZL)- 7. Treatment was well tolerated. Grade 3–4 toxicities possibly attributable to study drug were thrombocytopenia, neutropenia, anemia, diarrhea, anorexia, myalgia, hypokalemia, hypophosphatemia, thrombus (1 patient) and fatigue. 18 patients were taken off study due to progression. Three pts came off study due to toxicities (fatigue and diarrhea after 10 cycles, diarrhea and dizziness after 2 cycles, DVT after 5 cycles), 1 stopped therapy due to intercurrent illness, 1 came off for alternate therapy. By the current Cheson criteria, 6 patients achieved complete remission (CR), and 4 patients achieved partial remission (PR), for an overall response rate (CR+PR) of 29%. By histology, 10 formal responses were seen in patients with follicular (8) or marginal zone lymphoma (2), thus for patients with FL and MZL the response rate is 37%, whereas no responses were seen in mantle cell lymphoma. Two patients with PR as best response subsequently progressed (one at 6 months, one after 16 months), the other two remain on therapy. One CR was achieved after 2 years of stable disease on therapy. At a median follow up of 12 months, median progression-free survival for the 35 eligible patients is 7 months; 5 patients are progression-free for more than 18 months. Eleven patients remain on therapy. Conclusions: The histone deacetylase inhibitor vorinostat is well tolerated over long durations of therapy, and shows promising activity (10 CR+PR out of 27 patients) against relapsed/refractory follicular and marginal zone lymphoma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 7
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 891-891
    Abstract: Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M. RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 8
    Online Resource
    Online Resource
    Oncology Nursing Society (ONS) ; 2018
    In:  Clinical Journal of Oncology Nursing Vol. 22, No. 4 ( 2018-8-1), p. 450-452
    In: Clinical Journal of Oncology Nursing, Oncology Nursing Society (ONS), Vol. 22, No. 4 ( 2018-8-1), p. 450-452
    Type of Medium: Online Resource
    ISSN: 1092-1095 , 1538-067X
    Language: Unknown
    Publisher: Oncology Nursing Society (ONS)
    Publication Date: 2018
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  • 9
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1948-1948
    Abstract: Tipifarnib (R115777, Zarnestra®) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 30 patients have been accrued. with 27 patients evaluable for toxicity. Median age is 64.5 (range 33–75). Grade 3 toxicities were seen at dose levels 1 (400 mg bid)- metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy, and level 5 (1200 mg bid)- grade 3 creatinine elevation. Other grade 1 and 2 toxicities included fatigue, nausea, anorexia, elevated liver enzymes, increased bilirubin, and renal insufficiency. The maximum target treatment dose, 1600 mg PO bid was attained. There were 3 complete responses (CR) out of 9 patients treated at the 1000–1200 mg bid dose level- after cycle 1 in a 47 year old woman with relapsed AML after autologous transplant, with a 10 month continuing remission as of 8/06 (she underwent successful allogeneic transplant); after 2 cycles in a 69 year old man with relapsed AML, who relapsed after 5 months, (with response after retreatment with tipifarnib), and in a 67 year old man with relapsed AML who achieved PR after one cycle and CR after five cycles. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. In AML patients, greater than two fold increase in tipifarnib dosing can be tolerated on this dosing schedule with efficacy perhaps enhanced. Based on these promising results a monotherapy phase 2 or tipifarnib combination study in AML appears warranted.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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    detail.hit.zdb_id: 80069-7
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