Early Results of a Phase Ib/II Dose-Escalation Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphomas (PTCL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2673-2673
Author(s):  
Jehan Dupuis ◽  
Rene-Olivier Casasnovas ◽  
Franck Morschhauser ◽  
Herve Ghesquieres ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Phase Ii ◽  
Qt Interval ◽  
Research Funding ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Starting Dose ◽  
Grade 3 ◽  
Previous Phase

Abstract Abstract 2673 Background: Romidepsin is a potent histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior systemic therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 previous phase II studies with overall response rates of 30–38% (Piekarz et al., Blood 2011;117:5827; Coiffier et al., Blood 2010;116(21S):114). The observed toxicity was mainly hematological and digestive. Prolongation of the QT interval has been reported. The aim of the present study was to evaluate the safety, tolerability and efficacy of escalating doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods: Patients with biopsy-proven PTCL are planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1–5) in association with escalating doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 has been chosen as the starting dose. At least 3 patients are to be treated at each dose level, and 3 more at the same dose level if 1 of the first three exhibited dose-limiting toxicity (DLT) during the first 2 cycles. Results: Six patients (3 male, 3 female, aged 47 to 67) have been included so far and are analyzable for toxicity on the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=3), angioimmunoblastic TCL (n=1), primary cutaneous CD4+ small-medium TCL (n=1), enteropathy-associated TCL (n=1). ECOG performance status was good (0–1) in all patients; 5/6 had stage IV disease; IPI score was 1 (n=1), 2 (n=3), 3 (n=1), 4 (n=1). Among the first 3 patients treated at the starting dose of 10 mg/m2, one exhibited a DLT (grade 3 malaise after cycle 2), thus 3 more patients were treated at this dose level. Among those 3, we observed 2 other DLTs: one grade 3 general status deterioration and grade 3 haematological toxicity lasting more than 7 days in the same patient, and one grade 4 hematological toxicity lasting more than 3 days. A total of 269 adverse events (AEs) were observed during 34 analyzable cycles. The most frequent AEs were: neutropenia n=22 (grade 3–4 =12), thrombocytopenia n=28 (grade 3–4 n=5), digestive complaints n=18 (no grade >2), and asymptomatic increase of liver enzymes n=7 (1 grade 3). The mean increase in the corrected QT interval between pre- and post-romidepsin EKGs was 19 ms (range −43 to +79). No clinically relevant cardiac event was reported. One patient progressed after 5 cycles, 2 have finished the 8 planned cycles and are both in CR, and 3 are still under treatment without evidence of progression. Conclusion: Romidepsin can be combined with CHOP without unexpected toxicity. The dose of 10 mg/m2 on days 1& 8 is associated with excessive hematological toxicity. The study is ongoing with a lower dose of 8 mg/m2 on day 1 & 8 of each cycle. Updated results will be presented at the meeting. Disclosures: Coiffier: CELGENE: Consultancy, Research Funding, Speakers Bureau; ALLOS THERAPEUTICS: Consultancy, Research Funding, Speakers Bureau; ESAI: Consultancy, Research Funding, Speakers Bureau.

Phase I study of weekly intraperitoneal paclitaxel combined with S-1 and oxaliplatin for gastric cancer with peritoneal metastasis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Hironori Ishigami ◽  
Shoichi Kaisaki ◽  
Hironori Yamaguchi ◽  
Hiroharu Yamashita ◽  
Shigenobu Emoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Level 3 ◽  
Grade 3 ◽  
Dose Levels

146 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX in phase I and phase II studies. S-1 plus oxaliplatin (SOX) demonstrated efficacy in a phase II study, and is regarded as a candidate for the next-generation standard regimen for gastric cancer. We designed a new regimen combining weekly IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. A dose-escalation study of IP PTX in combination with fixed doses of SOX was carried out to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: PTX was administered intraperitoneally on days 1 and 8 with an initial dose of 20 mg/m2 (level 1), stepped up to 30 mg/m2 (level 2) or 40 mg/m2 (level 3) depending on observed toxicity. S-1 was administered orally at a dose of 80 mg/m2/day (b.i.d.) for 14 days followed by a 7-day rest. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. This treatment was repeated every 3 weeks. Toxicity was graded according to CTCAE v4.0. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 non-hematological toxicity. The MTD was defined as the dose level at which 2 or more of 3 or 6 patients developed DLTs during two courses of treatment. The RD was defined as one dose level under the MTD. Results: A total of 12 gastric cancer patients with peritoneal metastasis were enrolled. No DLTs were observed at all dose levels. Neutropenia in one patient at dose level 3 was the only grade 3 toxicity observed. Grade 2/3 leukopenia, neutropenia and thrombocytopenia were observed only in 2 patients at dose level 3. Regarding grade 2 non-hematological toxicities, anorexia, fatigue and nausea were observed in 6, 4 and 2 patients, respectively, independent of dose levels. Consequently, the MTD was not reached, and the RD of IP PTX was determined to be 40 mg/m2 (level 3). Conclusions: Combination chemotherapy of IP PTX with SOX was shown to be a safe regimen that should be further explored in clinical trials.

scholarly journals Final Analysis of the RO-CHOP Phase Ib/II Study: Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 504-504 ◽  
Author(s):  
Jehan Dupuis ◽  
Franck Morschhauser ◽  
Herve Ghesquieres ◽  
Herve Tilly ◽  
Olivier Casasnovas ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
T Cell Lymphoma ◽  
Phase Iii ◽  
Hematological Toxicity ◽  
Phase Ib ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Background: Romidepsin is a histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 phase II studies with overall response rates of 25-38%(Piekarz, Blood 2011 & Coiffier, J Clin Oncol 2012). Toxicity is mainly hematologic and digestive. We here present the final analysis of a phase Ib/II trial aiming to evaluate the safety, tolerability and efficacy of romidepsin in association with CHOP in patients with previously untreated PTCL. Patients & methods: Patients with PTCL were planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1 – 5) in association with varying doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 days 1 & 8 was chosen. The dose-variation scheme followed a traditional “3+3” design. Dose-limiting toxicities (DLT) were considered during the first 2 cycles. DLT was initially defined as: Non hematological toxicity grade 3-4 or hematological toxicity grade 3 lasting more than 7 days or grade 4 lasting more than 3 days. The protocol was subsequently amended to tolerate if lasting less than 10 (grade 3) or 7 days (grade 4). Results: Eighteen patients have been treated in phase Ib of the study (Dupuis, Hematol Oncol 2013). Significant, albeit tolerable hematological toxicity having been observed in the first two cohorts, the definition of DLT was modified during the course of the study. The dose of 12 mg/m2 was chosen as the recommended dose for phase II. Nineteen patients were treated in the phase II part of the study. Two patients had an early cardiac event (myocardial infarction) and were excluded from the efficacy analysis. A third patient had a cardiac event (acute cardiac failure) after cycle 1 day one and continued on CHOP alone. There were no deaths attributable to toxicity. Late hematological toxicity was observed, thus some cycles after cycle 2 were delivered with only one administration of romidepsin at day 1: Among 509 planned romidepsin administrations, 93 (18%) were cancelled on decision of the investigator, mainly during the last 2 cycles and mainly because of hematological toxicity. Sixty-seven percent of patients had at least on serious adverse event (SAE). The most frequent SAEs were: Febrile neutropenia (13.5%), general physical health deterioration (13.5%), lung infection (10.8%), vomiting (8%). Thirty-eight percent of patients had Grade 3-4 neutropenia at any time of the study, 19% grade 3-4 thrombocytopenia, 8% grade 3-4 anemia. Observed response rates (IHP 2007 criteria) were (n=35): Complete response 51%, partial response 17%, and progressive disease 25%. With a median follow-up of 17.5 months, the estimated progression-free survival is 57% at 18 months with 5 progressions among the 24 responding patients. The overall survival rate at 18 months is 76,5%. Longer follow-up will be presented during the meeting. Conclusion: Romidepsin can be combined with CHOP at the price of foreseeable hematological toxicity. Some cardiovascular events have been observed but the relationship with romidepsin is questionable. The progression-free survival rates seem promising, and the combination of romidepsin and CHOP is actually compared with CHOP alone in the setting of a phase III randomized trial (phase III RO-CHOP study). References : 1. Piekarz R, Blood. 2011;117(22):5827-34. 2. Coiffier B, J Clin Oncol. 2012;30(6):631-6 3. Dupuis J, Hematological Oncology 2013;31(Suppl.1):96-150 Disclosures Off Label Use: Romidepsin in association with CHOP for first line treatment of peripheral T-cell lymphoma. Morschhauser:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tilly:Celgene: Research Funding. Coiffier:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Clofarabine (CLO) Has Single Agent Activity in Relapsed and Refractory Non-Hodgkin Lymphoma (NHL) Including Rituximab (R)-Refractory Patients (pts).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 921-921
Author(s):  
Chadi Nabhan ◽  
Jacob David Bitran ◽  
Walter Fried ◽  
Angel G. Galvez ◽  
Laura Magid ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Large Cell ◽  
Median Number ◽  
Low Grade ◽  
Grade 3

Abstract Abstract 921 Background: CLO is a second generation nucleoside analogue with known activity in acute leukemia and myelodysplasia. As there is no standard therapy for refractory and transplant-ineligible relapsed NHL, and given the activity that purine analogues have in lymphoid malignancies, we sought to investigate the activity of CLO in this pt population regardless of histology. Methods: Eligible pts had measurable disease by CT and/or PET, ECOG performance status ≤ 2, and adequate renal, cardiac, liver, and bone marrow function (unless cytopenias were disease-related). CLO was given in the outpatient setting intravenously over 1-hour days 1-5 every 28 days for 6 cycles maximum. All pts received anti-viral and anti-pneumocystis jiroveci prophylaxis. First, we initiated a phase I portion using a standard 3×3 study design. CLO was given at 4 mg/m2 in cohort 1 with subsequent cohorts to be escalated by 2 mg/m2 each. Once the maximum tolerated dose (MTD) was determined, the phase II portion of this study was initiated at the MTD. All pts were followed until disease progression. Results: Thirty-three pts (18 females, 15 males) have been enrolled (7 in the phase I portion and 26 in the phase II), of which 29 are evaluable for response and/or toxicity (2 just started therapy, 1 taken off due to persistent cytopenias, and 1 withdrew consent). Median age was 69 years (range 27-88), median number of prior therapies was 3 (range 1-8), with 21% failing prior stem cell transplantation and 74% being R-refractory. Median time from original diagnosis to first CLO treatment was 36 months (range 6-216). Histologies included 12 diffuse large cell, 5 follicular, 5 small lymphocytic, 4 anaplastic large T-cell, and 1 each for Richter, mantle cell, marginal zone, peripheral T-cell, transformed, non-specific T-cell, and mixed histology. Median number of CLO cycles was 4 (range 1-6). Thrombocytopenia was the dose-limiting toxicity at 6 mg/m2 in 2/6 pts. The MTD recommended for phase II was 4 mg/m2. With a median follow up of 8 months (range 1-33), 7 pts (24%) showed complete response (CR) and 8 (27%) had partial response (PR) for an overall response rate of 51%. Four pts (13%) demonstrated stable disease and 10 (34%) showed progression. Median duration of response was 7 months (range 2-33+) with 6 pts continuing in remission including a patient who is undergoing stem cell transplantation. Median time to progression (TTP) was 3.5 months with median overall survival of 8 months. sEVEN pts (24%) remain progression-free. Of patients who were followed for more than 12 months, 60% were alive at 1-year. Five of the CR pts were of low-grade histology while only 2 had large cell lymphoma. All pts required growth factor support. Toxicity was mainly hematologic with 63% experiencing grade 3/4 thrombocytopenia, 60% grade 3/4 neutropenia, and 39% grade3/4 anemia, and 63%. Grade 3 and/or 4 non-hematologic toxicity included 2 (6%) with tumor lysis syndrome, 2 (6%) infectious episodes (pneumonia and bilateral cellulitis), 2 (6%) renal insufficiency, 2 (6%) fatigue, 1 (3%) seizure activity, 1 (3%) pleural effusion, and 1 hypokalemia (3%). No treatment-related mortality. Conclusions: CLO is active in heavily pre-treated B-cell NHL including R-refractory pts. Activity appears more pronounced in low-grade histology. The drug is well-tolerated and can be administered as an outpatient. Reversible myelosuppression is the major toxicity. Future studies in front-line in combination with R are warranted. Disclosures: Nabhan: Bayer: Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding; Genentech: Honoraria, Speakers Bureau. Venugopal:Genzyme: Honoraria, Research Funding; Genentech: Honoraria, Research Funding, Speakers Bureau.

A Phase II Open-Label, Multi-Center Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab (KW-0761) in Patients with Previously Treated Peripheral T-Cell Lymphoma(PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1763-1763 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Bertrand Coiffier ◽  
John Radford ◽  
Dolores Caballero ◽  
Paul Fields ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Median Number ◽  
Advisory Board ◽  
Japanese Study ◽  
Duration Of Response ◽  
Previously Treated ◽  
Grade 3

Abstract Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Makoto Onizuka ◽  
Kiyoshi Ando ◽  
Makoto Yoshimitsu ◽  
Takashi Ishida ◽  
S Yoshida ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
Dose Cohort ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Background: HBI-8000 is an orally bioavailable member of the benzamide class of histone deacetylase inhibitors (HDACi), that inhibits cancer-associated HDAC enzymes (Class I and IIb). HBI-8000 has anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It was recently approved by the Chinese FDA under the name chidamide (Epidaza) for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). HBI-8000 is also being manufactured in the USA for clinical development outside of China. The preliminary results of a phase I trial of HBI-8000 to confirm the safety and maximum tolerated dose (MTD) in Japanese patients (pts) with advanced NHL are presented (NCT02697552). Methods: This is a multicenter, prospective phase I trial in Japan. Inclusion criteria: patients are eligible if they have histologically or cytologically proven NHL and no other standard therapy is available. The primary endpoint is the MTD based on the frequency of dose-limiting toxicities (DLTs) observed within 28 days of the first dose. Secondary endpoints include pharmacokinetic (PK) profile and anti-tumor activity. At the time of this abstract submission, the trial is still ongoing. Results: Thirteen out of 14 pts were eligible for the 1st cycle DLT assessment (6 pts in the 30 mg, 7 pts in the 40 mg cohort). Median age was 68 years, gender well balanced, and the majority of pts had ≥ 2 prior treatment regimens. Five pts had the diagnosis of adult T-cell leukemia-lymphoma (ATL), 2 pts presented with PTCL, 3 with diffuse large B-cell lymphoma (DLBLC), 2 with follicular lymphoma (FL), 1 with cutaneous T-cell lymphoma (CTCL), and 1 with marginal zone lymphoma. Overall, the treatment was well tolerated, and adverse drug reactions (ADRs) were predominantly hematologic, consistent with the previous experiences. There were 7 pts in the 40 mg dose cohort because one of the first 3 pts had to be replaced for incomplete dosing due to grade 3 hypertriglyceridemia which was not regarded as DLT by the Data Monitoring Safety Committee (DMC/SMC). In the 40 mg cohort, 2 pts were considered as DLTs by definition in the protocol: grade 4 neutropenia and grade 3 alanine transaminase (ALT) increase. Both pts were asymptomatic. The grade 4 neutropenia promptly resolved with the administration of G-CSF and the grade 3 ALT elevation resolved with dose interruption. The 30 mg dose cohort completed with no DLT after the 1st cycle in 6 pts. The following hematologic grade 3/4 toxicities were noted in the 40 mg dose cohort (N=7): leukopenia (2 pts, 29%), neutropenia (3 pts, 43%), and thrombocytopenia (3 pts, 43%). Non-hematologic ADRs included fatigue, nausea, diarrhea, decreased appetite, erythema and pyrexia. The preliminary pharmacokinetic (PK) results from the 3 patients in the 30 mg cohort, and 7 patients in the 40 mg dose cohort show inter-patient variability as expected of an oral agent. Mean half-life (t ½ ) was between16.5 and 20 hours (h) with a Tmax between 2.5 and 3.5h and consistent with previous findings. Mean Cmax and AUC increased with dose (30 mg: 210 ng/mL; 3660 h*ng/mL and 40 mg: 590 ng/mL; 7200 h*ng/mL). The patient with neutropenia as DLT presented with the highest exposure. Cardiovascular assessments including serial ECGs and troponin assessments did not reveal clinically relevant findings. Best overall response was noted in 40 mg BIW cohort (N=7): 1 CR (10%), 5 PR (30%), 1 SD (20%). Four of the partial responders were ATL patients. In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle. Summary: In this phase l trial evaluating the safety of twice weekly 30 mg and 40 mg doses, HBI-8000 was well tolerated with expected toxicities that could be managed with dose interruptions/reductions. Tumor response results in pts who completed at least one cycle of treatment indicate some clinical benefit especially in pts who started with the 40 mg dose level. The DMC/SMC has provided an opinion that the 2 observed DLTs with HBI-8000 in the phase I trial were clinically manageable and that 40 mg BIW would be recommended as the dosage for subsequent phase II studies. Registration enabling phase II trials to evaluate efficacy and safety in R/R ATL pts (Japan) and R/R PTCL pts (Japan and Korea) are being initiated. Disclosures Ando: SymBio Pharmaceuticals: Research Funding. Yoshimitsu:HUYA Bioscience International: Research Funding. Ishida:Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding; Bayer Pharma AG: Research Funding. Hidaka:Chugai-pharm: Research Funding. Nagashima:HUYA Bioscience International: Employment. Miyazato:HUYA Bioscience International: Employment. Schupp:HUYA Bioscience International: Employment. Rolland:HUYA Bioscience International: Employment. Gillings:HUYA Bioscience International: Employment. Lee:HUYA Bioscience International: Employment. Tobinai:Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; HUYA Bioscience: Honoraria; Janssen Pharmaceuticals: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceuticals: Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

scholarly journals Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2x2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1455-1455 ◽  
Author(s):  
Peter Westervelt ◽  
Gail J. Roboz ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Level ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Activation ◽  
Phase 1 ◽  
Disease Stage ◽  
Molecular Abnormalities ◽  
Grade 3

Abstract Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR. Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level. Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. Disclosures Roboz: Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

Gemcitabine and carboplatin in the treatment of metastatic cholangiocarcinoma and gallbladder cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15102-15102
Author(s):  
R. Suresh ◽  
J. Picus ◽  
S. Sorscher ◽  
C. Fournier ◽  
B. R. Tan
Keyword(s):  
Gallbladder Cancer ◽  
Phase Ii ◽  
Stable Disease ◽  
Liver Enzymes ◽  
Phase Ii Study ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Elevated Liver Enzymes ◽  
Grade 3 ◽  
Electrolyte Abnormalities

15102 Background: There is currently no standard therapy for patients with unresectable or metastatic biliary tract cancers. Gemcitabine has been shown to be active against these tumors with a 20–30% response in various phase II studies. Gemcitabine is also synergistic with platinum compounds. Aim: We conducted a Phase II study of gemcitabine plus carboplatin in patients with unresectable or metastatic choloangiocarcinoma or gallbladder cancer to assess the regimen’s safety and efficacy. Methods: Since 3/2002, 49 (48 evaluable) patients were treated with gemcitabine at 1000 mg/m2 IV over 30 minutes days 1 and 8 with carboplatin at AUC 5 IV on day 1 of a 21 day cycle. There were 34 women and 15 men enrolled. Ages ranged from 34 to 87 with a median age of 65 years. Results: Best radiologic responses - 5CR, 9 PR, 24 stable disease and 10 progression. CR+PR 14/48 (29.2%) and stable disease 24/48 (50%). Toxicity: Hematological toxicities: Grade 3 neutropenia 33%, febrile neutropenia 0.02%, anemia 12.5% and thrombocytopenia 14.6%. Grade 4 hematological toxicites were rare - neutropenia 0.04%, and thrombocytopenia 0.06%. Non-hematologic toxicities were generally mild (fatigue, edema, nausea, vomiting, elevated liver enzymes, electrolyte abnormalities). Except for one patient who had depression there were no grade 4 non-hematological toxicity. Grade 3 non- hematological toxicites were also rare occurring only in 1 to 3 patients. Conclusions: Gemcitabine and carboplatin is active against biliary cancer and is highly tolerable. This study is being supported by Eli Lilly & Co. No significant financial relationships to disclose.

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

A Phase I Safety Study of Enzastaurin Plus Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1870-1870
Author(s):  
Irene M Ghobrial ◽  
Nikhil C Munshi ◽  
Brianna N Harris ◽  
Zheng Yuan ◽  
Nichole M Porter ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Loading Dose ◽  
Advisory Committees ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3

Abstract Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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