Mihaela Munteanu - Academia.edu (original) (raw)

Papers by Mihaela Munteanu

Qualitative research in medicine & healthcare, Jul 21, 2017

Medical professional societies each develop specific clinical practice guidelines (CPGs). Based o... more Medical professional societies each develop specific clinical practice guidelines (CPGs). Based on the best available evidence, CPGs are intended to control variability and optimize quality of care in clinical practice. Yet, healthcare providers often do not accept or adhere to guidelines, but their reasons are not fully understood. When providers opt to choose not to follow CPGs, unfavorable patient outcomes including unequal access to treatment become negative consequences. In this small qualitative study, we will explore what causes non-adherence to CPGs and what changes have been made to CPGs from when physicians completed their medical residencies to the present. We interviewed physicians from a variety of medical specialties to assess how these changes may influence guideline adherence as well as the consequences of not following them. We found that guidelines may not be followed in cases where patients have comorbidities that are not described in the guidelines or when physicians do not incorporate new evidence and technology advances into their practice. In some specialties, physicians can develop a poor reputation if they do not adhere to the CPGs, and managed care agencies may deny reimbursement for care they provided. To best serve the physician and the patient, we need to find ways to improve CPG adherence. Tactics such as improving the methodology of CPG formation, using information technology, and creating ways to change physician attitudes and behavior are all viable options.

Ash Annual Meeting Abstracts, Nov 1, 2012

Leukemia, 2002

We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chem... more We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic) in the treatment of 101 patients Ն60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m 2 for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.

Clinical Cancer Research, 2007

Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhib... more Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. Experimental Design: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [18F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. Results: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- an...

Qualitative Research in Medicine and Healthcare, 2017

Medical professional societies each develop specific clinical practice guidelines (CPGs). Based o... more Medical professional societies each develop specific clinical practice guidelines (CPGs). Based on the best available evidence, CPGs are intended to control variability and optimize quality of care in clinical practice. Yet, healthcare providers often do not accept or adhere to guidelines, but their reasons are not fully understood. When providers opt to choose not to follow CPGs, unfavorable patient outcomes including unequal access to treatment become negative consequences. In this small qualitative study, we will explore what causes non-adherence to CPGs and what changes have been made to CPGs from when physicians completed their medical residencies to the present. We interviewed physicians from a variety of medical specialties to assess how these changes may influence guideline adherence as well as the consequences of not following them. We found that guidelines may not be followed in cases where patients have comorbidities that are not described in the guidelines or when physic...

Journal of Clinical Oncology, 2013

8565 Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CV... more 8565 Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CVP in terms of complete remission rate in indolent NHL and MCL. This is the first detailed analysis of the safety and tolerability of the study regimens. Methods: Patients were preselected for R-CHOP or R-CVP, and then randomized to 6-8 cycles of BR (28-d cycle) or the preselected standard regimen (21-d cycles). BR dosing was bendamustine 90 mg/m2/d as a 30-min infusion on days 1 and 2 plus rituximab 375 mg/m2given before bendamustine on day 1. Colony stimulating factors (CSFs) and antiemetics were given per local standards. Results: In patients preselected for R-CHOP, 103 received BR and 98 R-CHOP. In patients preselected for R-CVP, 118 received BR and 116 R-CVP. For all regimens, ≥ 88% of patients received the planned 6 cycles. Main differences in adverse events (AEs), all grades, are shown in the Table. Incidence of grade 3/4 AEs was 69% for R-CHOP vs 56% BR, and 50% for R-CVP vs 56% B...

Journal of Clinical Oncology, 2013

8537 Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for c... more 8537 Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for complete response rate in the treatment of patients with indolent NHL or MCL. Evaluation of time-to-event outcomes is immature. This subanalysis reports response by histology. Methods: Indolent NHL or MCL was histologically confirmed <6 months before study enrollment in patients who were therapy-naïve. Patients were stratified according to predetermined standard treatment (R-CHOP or RECVP) and lymphoma type, then assigned to receive BR (28-day cycles: bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2on day 1) or standard treatment (21-day cycles at standard doses) for 6-8 cycles. Responses were assessed by a blinded independent review committee. The primary efficacy measure was noninferiority of BR complete response (CR) rate for evaluable patients with ≥1 postbaseline efficacy assessment. If the noninferiority threshold was met, superiority was assessed. Secondary measures in...

Journal of Clinical Oncology, 2013

e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Ben... more e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Bendamustine and rituximab (BR) are commonly combined, and rituximab concentrations are essentially constant ≥1.5 hours due to its long half-life. This BR single-arm study assessed the effects of bendamustine on QTcF over 1.5 hours in previously untreated adults with advanced indolent NHL or MCL. Methods: Patients in this open-label study were aged ≥18 years with QTc on screening electrocardiogram (ECG) ≤450 ms. Exclusion criteria included low serum potassium or magnesium and history of cardiac conditions with QT prolongation risk. Bendamustine 90 mg/m2 was given on days 1 and 2 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. On day 2 of cycle 1, ECGs and blood sampling were performed ~15 min prior to bendamustine infusion (baseline), at the end of infusion (EOI)/Cmax, and 1 h post-EOI. The primary measure was change in QTcF at EOI. Secondary measures included outlier analyses of QTc...

Blood, 2013

Introduction Subcutaneous (SC) omacetaxine mepesuccinate (OMA) is indicated for the treatment of ... more Introduction Subcutaneous (SC) omacetaxine mepesuccinate (OMA) is indicated for the treatment of CP and AP CML in adults with resistance/intolerance (R/I) to ≥2 tyrosine kinase inhibitors (TKIs). Unlike TKIs, OMA inhibits protein synthesis and is not a direct inhibitor of Bcr-Abl kinase activity. The clinical activity of OMA was demonstrated in a combined cohort of patients from 2 single-arm trials. The cohort consisted of patients who had received ≥2 approved TKIs and, at a minimum, documented evidence of R/I to dasatinib and/or nilotinib. This is the final ≥24-month follow-up analysis in a cohort subset from the 2 studies as originally approved by the FDA. Methods Patients received OMA 1.25 mg/m2 bid SC in 28-day cycles: 14 days for induction and 7 days as maintenance, adjusted for tolerability. Primary endpoints were major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP. Secondary objectives included time to onset and duration of response, progress...

Blood, 2011

778 Background: Combination chemo-immunotherapy regimens are used in the majority of patients wit... more 778 Background: Combination chemo-immunotherapy regimens are used in the majority of patients with advanced stage indolent lymphoma who require treatment. Despite high overall response rates following frontline therapy, nearly all patients relapse and many die of their disease. Bendamustine in combination with anti-CD20 monoclonal antibody therapy has been shown to be highly active and well tolerated. Ofatumumab is a fully humanized (IgG1) monoclonal antibody that binds specifically to a unique epitope on CD20, and is active in indolent B-cell non-Hodgkin's lymphoma (NHL). The efficacy and safety of both agents in combination has not been described. The purpose of this phase 2, multicenter study was to determine the efficacy and safety of bendamustine in combination with ofatumumab in first-line treatment of patients with indolent B-cell NHL. Methods: Untreated patients with follicular lymphoma (FL) (grade 1–3a), marginal zone lymphoma (MZL), or lymphoplasmacytic lymphoma (LPL) ...

Blood, 2012

155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combinatio... more 155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). Methods Previously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg...

Blood, 2014

Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma that usually present... more Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma that usually presents as advanced-stage disease. Relapse is common, and management of relapsed/refractory MCL is difficult due to a limited number of approved agents and numerous comorbidities seen in this typically elderly patient population. We conducted a study of bendamustine plus rituximab (BR) in patients with relapsed/refractory MCL and presented preliminary results (Czuczman et al, ASH 2012, Abstract 3662). Final data are being analyzed in a multivariate analysis of baseline demographic and disease factors affecting outcomes for this study, and we present below the final data for individual subgroups for best overall response, DOR, and progression free survival (PFS). Patients and Methods: This multicenter, open-label, single-arm, phase 2 study was conducted to evaluate the efficacy, tolerability, and safety of BR in adults with relapsed or refractory CD20-positive B-cell MCL. Relapsed disease was d...

Blood, 2012

902 Background Bendamustine (B) is an active agent for relapsed and refractory indolent NHL, both... more 902 Background Bendamustine (B) is an active agent for relapsed and refractory indolent NHL, both as monotherapy and combined with rituximab (R), results recently updated by the StiL study group. This study compared efficacy and safety of BR with standard treatment regimens of R-CHOP and R-CVP as first-line treatment for indolent NHL or MCL. Methods Patients were randomized to 6–8 cycles of BR or R-CHOP/R-CVP (R-CHOP or R-CVP determined by investigator prior to randomization). BR regimen was B 90 mg/m2/day on days 1 and 2 plus R 375 mg/m2on day 1 of a 28-day cycle. Standard dosing and 21 day cycles were used for R-CHOP and R-CVP. Primary objective was to demonstrate noninferiority of complete response (CR) rate of BR vs standard treatment (noninferiority margin [ratio] 0.88). Secondary measures included overall response rate (ORR), progression-free survival, and overall survival. Tumor response was determined by a blinded independent review committee (IRC) using International Workin...

Journal of Clinical Pathways, 2019

Journal of Clinical Oncology, 2014

7066 Background: Response milestones are used as prognostic indicators in CML. This analysis comp... more 7066 Background: Response milestones are used as prognostic indicators in CML. This analysis compared OS in patients with/without response to omacetaxine. Methods: This was a post hoc landmark anal...

Leukemia & lymphoma, Jun 10, 2016

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accura... more Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were 'likely correct' in 73% and 25% of cases, respectively (p < .001). Investigators were more likely to make errors by misinterpreting lymph node data and not utilizing PET results. This post hoc finding suggests a possible role for post-training site evaluation/audit, with retraining as needed,...

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 28, 2016

In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall resp... more In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall response rate (ORR) of 82% among 45 patients with relapsed/refractory mantle cell lymphoma (MCL), with manageable tolerability. A prespecified (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) analysis was conducted to assess the predictive value of the metabolic response to BR compared with the response by International Working Group (IWG) criteria. Adult patients with relapsed/refractory MCL underwent FDG-PET at screening and following 6 cycles of BR therapy. Scans were reviewed by a central facility and scored using the 5-point Deauville scale, comparing uptake to the liver and mediastinum in up to 6 lesions, to determine metabolic response rates, indicated by negative posttreatment scans. Metabolic responses were compared with study outcomes assessed by IWG criteria. Complete FDG-PET data were available for 32 of 45 patients. All patients had positive baseline scans, with b...

Investigational new drugs, Oct 25, 2016

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resista... more Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of ...

The Lancet Oncology, 2016

Background-Current treatment options for patients with relapsed or refractory (RR) lymphoma and m... more Background-Current treatment options for patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM) are limited, highlighting the unmet need for effective therapies in these disease settings. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes, which are members of common oncogenic pathways in hematologic malignancies. This study examines CUDC-907 monotherapy in patients with RR lymphoma and MM. Methods-This open-label, non-randomized, first-in-man, phase 1 multi-center trial enrolled adult patients with lymphoma or MM who were refractory to or relapsed after ≥2 prior regimens. CUDC-907 was orally administered in a standard 3+3 dose escalation design using three different dosing schedules which enrolled sequentially as follows: once daily (QD), then intermittent twice (BIW) or thrice weekly (TIW) that enrolled simultaneously, and finally five days on/two days off

Clinical Lymphoma Myeloma and Leukemia, 2016

Comparative chemotherapy-related quality of life data are lacking. Bendamustine-rituximab (BR) de... more Comparative chemotherapy-related quality of life data are lacking. Bendamustine-rituximab (BR) demonstrated noninferiority to R-CHOP

Qualitative research in medicine & healthcare, Jul 21, 2017

Medical professional societies each develop specific clinical practice guidelines (CPGs). Based o... more Medical professional societies each develop specific clinical practice guidelines (CPGs). Based on the best available evidence, CPGs are intended to control variability and optimize quality of care in clinical practice. Yet, healthcare providers often do not accept or adhere to guidelines, but their reasons are not fully understood. When providers opt to choose not to follow CPGs, unfavorable patient outcomes including unequal access to treatment become negative consequences. In this small qualitative study, we will explore what causes non-adherence to CPGs and what changes have been made to CPGs from when physicians completed their medical residencies to the present. We interviewed physicians from a variety of medical specialties to assess how these changes may influence guideline adherence as well as the consequences of not following them. We found that guidelines may not be followed in cases where patients have comorbidities that are not described in the guidelines or when physicians do not incorporate new evidence and technology advances into their practice. In some specialties, physicians can develop a poor reputation if they do not adhere to the CPGs, and managed care agencies may deny reimbursement for care they provided. To best serve the physician and the patient, we need to find ways to improve CPG adherence. Tactics such as improving the methodology of CPG formation, using information technology, and creating ways to change physician attitudes and behavior are all viable options.

Ash Annual Meeting Abstracts, Nov 1, 2012

Leukemia, 2002

We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chem... more We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic) in the treatment of 101 patients Ն60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m 2 for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.

Clinical Cancer Research, 2007

Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhib... more Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. Experimental Design: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [18F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. Results: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- an...

Qualitative Research in Medicine and Healthcare, 2017

Medical professional societies each develop specific clinical practice guidelines (CPGs). Based o... more Medical professional societies each develop specific clinical practice guidelines (CPGs). Based on the best available evidence, CPGs are intended to control variability and optimize quality of care in clinical practice. Yet, healthcare providers often do not accept or adhere to guidelines, but their reasons are not fully understood. When providers opt to choose not to follow CPGs, unfavorable patient outcomes including unequal access to treatment become negative consequences. In this small qualitative study, we will explore what causes non-adherence to CPGs and what changes have been made to CPGs from when physicians completed their medical residencies to the present. We interviewed physicians from a variety of medical specialties to assess how these changes may influence guideline adherence as well as the consequences of not following them. We found that guidelines may not be followed in cases where patients have comorbidities that are not described in the guidelines or when physic...

Journal of Clinical Oncology, 2013

8565 Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CV... more 8565 Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CVP in terms of complete remission rate in indolent NHL and MCL. This is the first detailed analysis of the safety and tolerability of the study regimens. Methods: Patients were preselected for R-CHOP or R-CVP, and then randomized to 6-8 cycles of BR (28-d cycle) or the preselected standard regimen (21-d cycles). BR dosing was bendamustine 90 mg/m2/d as a 30-min infusion on days 1 and 2 plus rituximab 375 mg/m2given before bendamustine on day 1. Colony stimulating factors (CSFs) and antiemetics were given per local standards. Results: In patients preselected for R-CHOP, 103 received BR and 98 R-CHOP. In patients preselected for R-CVP, 118 received BR and 116 R-CVP. For all regimens, ≥ 88% of patients received the planned 6 cycles. Main differences in adverse events (AEs), all grades, are shown in the Table. Incidence of grade 3/4 AEs was 69% for R-CHOP vs 56% BR, and 50% for R-CVP vs 56% B...

Journal of Clinical Oncology, 2013

8537 Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for c... more 8537 Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for complete response rate in the treatment of patients with indolent NHL or MCL. Evaluation of time-to-event outcomes is immature. This subanalysis reports response by histology. Methods: Indolent NHL or MCL was histologically confirmed <6 months before study enrollment in patients who were therapy-naïve. Patients were stratified according to predetermined standard treatment (R-CHOP or RECVP) and lymphoma type, then assigned to receive BR (28-day cycles: bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2on day 1) or standard treatment (21-day cycles at standard doses) for 6-8 cycles. Responses were assessed by a blinded independent review committee. The primary efficacy measure was noninferiority of BR complete response (CR) rate for evaluable patients with ≥1 postbaseline efficacy assessment. If the noninferiority threshold was met, superiority was assessed. Secondary measures in...

Journal of Clinical Oncology, 2013

e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Ben... more e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Bendamustine and rituximab (BR) are commonly combined, and rituximab concentrations are essentially constant ≥1.5 hours due to its long half-life. This BR single-arm study assessed the effects of bendamustine on QTcF over 1.5 hours in previously untreated adults with advanced indolent NHL or MCL. Methods: Patients in this open-label study were aged ≥18 years with QTc on screening electrocardiogram (ECG) ≤450 ms. Exclusion criteria included low serum potassium or magnesium and history of cardiac conditions with QT prolongation risk. Bendamustine 90 mg/m2 was given on days 1 and 2 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. On day 2 of cycle 1, ECGs and blood sampling were performed ~15 min prior to bendamustine infusion (baseline), at the end of infusion (EOI)/Cmax, and 1 h post-EOI. The primary measure was change in QTcF at EOI. Secondary measures included outlier analyses of QTc...

Blood, 2013

Introduction Subcutaneous (SC) omacetaxine mepesuccinate (OMA) is indicated for the treatment of ... more Introduction Subcutaneous (SC) omacetaxine mepesuccinate (OMA) is indicated for the treatment of CP and AP CML in adults with resistance/intolerance (R/I) to ≥2 tyrosine kinase inhibitors (TKIs). Unlike TKIs, OMA inhibits protein synthesis and is not a direct inhibitor of Bcr-Abl kinase activity. The clinical activity of OMA was demonstrated in a combined cohort of patients from 2 single-arm trials. The cohort consisted of patients who had received ≥2 approved TKIs and, at a minimum, documented evidence of R/I to dasatinib and/or nilotinib. This is the final ≥24-month follow-up analysis in a cohort subset from the 2 studies as originally approved by the FDA. Methods Patients received OMA 1.25 mg/m2 bid SC in 28-day cycles: 14 days for induction and 7 days as maintenance, adjusted for tolerability. Primary endpoints were major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP. Secondary objectives included time to onset and duration of response, progress...

Blood, 2011

778 Background: Combination chemo-immunotherapy regimens are used in the majority of patients wit... more 778 Background: Combination chemo-immunotherapy regimens are used in the majority of patients with advanced stage indolent lymphoma who require treatment. Despite high overall response rates following frontline therapy, nearly all patients relapse and many die of their disease. Bendamustine in combination with anti-CD20 monoclonal antibody therapy has been shown to be highly active and well tolerated. Ofatumumab is a fully humanized (IgG1) monoclonal antibody that binds specifically to a unique epitope on CD20, and is active in indolent B-cell non-Hodgkin's lymphoma (NHL). The efficacy and safety of both agents in combination has not been described. The purpose of this phase 2, multicenter study was to determine the efficacy and safety of bendamustine in combination with ofatumumab in first-line treatment of patients with indolent B-cell NHL. Methods: Untreated patients with follicular lymphoma (FL) (grade 1–3a), marginal zone lymphoma (MZL), or lymphoplasmacytic lymphoma (LPL) ...

Blood, 2012

155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combinatio... more 155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). Methods Previously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg...

Blood, 2014

Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma that usually present... more Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma that usually presents as advanced-stage disease. Relapse is common, and management of relapsed/refractory MCL is difficult due to a limited number of approved agents and numerous comorbidities seen in this typically elderly patient population. We conducted a study of bendamustine plus rituximab (BR) in patients with relapsed/refractory MCL and presented preliminary results (Czuczman et al, ASH 2012, Abstract 3662). Final data are being analyzed in a multivariate analysis of baseline demographic and disease factors affecting outcomes for this study, and we present below the final data for individual subgroups for best overall response, DOR, and progression free survival (PFS). Patients and Methods: This multicenter, open-label, single-arm, phase 2 study was conducted to evaluate the efficacy, tolerability, and safety of BR in adults with relapsed or refractory CD20-positive B-cell MCL. Relapsed disease was d...

Blood, 2012

902 Background Bendamustine (B) is an active agent for relapsed and refractory indolent NHL, both... more 902 Background Bendamustine (B) is an active agent for relapsed and refractory indolent NHL, both as monotherapy and combined with rituximab (R), results recently updated by the StiL study group. This study compared efficacy and safety of BR with standard treatment regimens of R-CHOP and R-CVP as first-line treatment for indolent NHL or MCL. Methods Patients were randomized to 6–8 cycles of BR or R-CHOP/R-CVP (R-CHOP or R-CVP determined by investigator prior to randomization). BR regimen was B 90 mg/m2/day on days 1 and 2 plus R 375 mg/m2on day 1 of a 28-day cycle. Standard dosing and 21 day cycles were used for R-CHOP and R-CVP. Primary objective was to demonstrate noninferiority of complete response (CR) rate of BR vs standard treatment (noninferiority margin [ratio] 0.88). Secondary measures included overall response rate (ORR), progression-free survival, and overall survival. Tumor response was determined by a blinded independent review committee (IRC) using International Workin...

Journal of Clinical Pathways, 2019

Journal of Clinical Oncology, 2014

7066 Background: Response milestones are used as prognostic indicators in CML. This analysis comp... more 7066 Background: Response milestones are used as prognostic indicators in CML. This analysis compared OS in patients with/without response to omacetaxine. Methods: This was a post hoc landmark anal...

Leukemia & lymphoma, Jun 10, 2016

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accura... more Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were 'likely correct' in 73% and 25% of cases, respectively (p < .001). Investigators were more likely to make errors by misinterpreting lymph node data and not utilizing PET results. This post hoc finding suggests a possible role for post-training site evaluation/audit, with retraining as needed,...

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 28, 2016

In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall resp... more In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall response rate (ORR) of 82% among 45 patients with relapsed/refractory mantle cell lymphoma (MCL), with manageable tolerability. A prespecified (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) analysis was conducted to assess the predictive value of the metabolic response to BR compared with the response by International Working Group (IWG) criteria. Adult patients with relapsed/refractory MCL underwent FDG-PET at screening and following 6 cycles of BR therapy. Scans were reviewed by a central facility and scored using the 5-point Deauville scale, comparing uptake to the liver and mediastinum in up to 6 lesions, to determine metabolic response rates, indicated by negative posttreatment scans. Metabolic responses were compared with study outcomes assessed by IWG criteria. Complete FDG-PET data were available for 32 of 45 patients. All patients had positive baseline scans, with b...

Investigational new drugs, Oct 25, 2016

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resista... more Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of ...

The Lancet Oncology, 2016

Background-Current treatment options for patients with relapsed or refractory (RR) lymphoma and m... more Background-Current treatment options for patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM) are limited, highlighting the unmet need for effective therapies in these disease settings. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes, which are members of common oncogenic pathways in hematologic malignancies. This study examines CUDC-907 monotherapy in patients with RR lymphoma and MM. Methods-This open-label, non-randomized, first-in-man, phase 1 multi-center trial enrolled adult patients with lymphoma or MM who were refractory to or relapsed after ≥2 prior regimens. CUDC-907 was orally administered in a standard 3+3 dose escalation design using three different dosing schedules which enrolled sequentially as follows: once daily (QD), then intermittent twice (BIW) or thrice weekly (TIW) that enrolled simultaneously, and finally five days on/two days off

Clinical Lymphoma Myeloma and Leukemia, 2016

Comparative chemotherapy-related quality of life data are lacking. Bendamustine-rituximab (BR) de... more Comparative chemotherapy-related quality of life data are lacking. Bendamustine-rituximab (BR) demonstrated noninferiority to R-CHOP