Randomized Double-Blind Clinical Trial Comparing Safety and Efficacy of the Biosimilar BCD-021 with Reference Bevacizumab

Abstract Background BCD-021 is a bevacizumab biosimilar which was shown to be equivalent to reference bevacizumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to compare efficacy and safety of BCD-021 and reference bevacizumab in combination with paclitaxel and carboplatin in a first-line treatment of inoperable or advanced non-squamous non-small-cell lung cancer (NSCLC). Methods Patients with no previous treatment for advanced non-squamous NSCLC were randomly assigned 3:2 to BCD-021 or reference bevacizumab and were treated with bevacizumab + paclitaxel + carboplatin. Therapy continued for 6 cycles (every 3 weeks), until progression of the disease or unbearable toxicity. The primary study endpoint was the overall response rate. The study goal was to prove the equivalent efficacy of BCD-021 and reference bevacizumab. Equivalence margins for 95% CI for the difference in the overall response rates were set at [-18%; 18%], for 90% CI for the ratio of overall response rate were set at [67%; 150%]. Results In total 357 patients were enrolled in the study, 212 in the BCD-021 group and 145 in the reference bevacizumab group. The ORR was 34.63% in the BCD-022 group and 33.82% in the reference bevacizumab group. Limits of 95% CI for the difference in overall response rates between the groups were [-9.47%; 11.09%]. Limits of 90% CI for the ratio of overall response rate between the groups were [79.6%; 131.73%]. For both approaches CI lied within predetermined equivalence margins. Profile of adverse events (AEs) was similar between the groups (any AEs were reported in 86.89% of patients in BCD-021 group and 89.05% of patients in reference group). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding anti-drug antibody occurrence rate was found between BCD-022 (n = 4; 1.96%) and comparator (n = 5; 3.65%). Both drug products showed low occurrence rate and short life of anti-bevacizumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures. Conclusions Thus, the results of this study demonstrated therapeutic equivalence of bevacizumab biosimilar BCD-021 and referent bevacizumab drug. Trial registration: The trial was registered with ClinicalTrials.gov (Study Number NCT01763645, date of registration 09/01/2013).

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The Effects of a Between-Wave Incentive Experiment on Contact Update and Production Outcomes in a Panel Study

Journal of Official Statistics ◽

10.2478/jos-2013-0022 ◽

2013 ◽

Vol 29 (2) ◽

pp. 261-276 ◽

Cited By ~ 6

Author(s):

Katherine A. McGonagle ◽

Robert F. Schoeni ◽

Mick P. Couper

Keyword(s):

Data Collection ◽

Overall Response Rate ◽

Response Rate ◽

Panel Study ◽

Response Rates ◽

Income Dynamics ◽

Overall Response ◽

Percentage Points ◽

Contact Information ◽

The U.S

Abstract Since 1969, families participating in the U.S. Panel Study of Income Dynamics (PSID) have been sent a mailing asking them to update or verify their contact information in order to keep track of their whereabouts between waves. Having updated contact information prior to data collection is associated with fewer call attempts, less tracking, and lower attrition. Based on these advantages, two experiments were designed to increase response rates to the between wave contact mailing. The first experiment implemented a new protocol that increased the overall response rate by 7-10 percentage points compared to the protocol in place for decades on the PSID. This article provides results from the second experiment which examines the basic utility of the between-wave mailing, investigates how incentives affect article cooperation to the update request and field effort, and attempts to identify an optimal incentive amount. Recommendations for the use of contact update strategies in panel studies are made.

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Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽

10.1182/blood.v110.11.2713.2713 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2713-2713

Author(s):

Rakesh Popat ◽

Catherine Williams ◽

Mark Cook ◽

Charles Craddock ◽

Supratik Basu ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase I ◽

Median Time ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Time To Progression ◽

Overall Response ◽

Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

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Decitabine Is Effective and Safe In Patients with Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v116.21.4032.4032 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4032-4032

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

A. Megan Cornelison ◽

Tapan Kadia ◽

...

Keyword(s):

Median Survival ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Chronic Myelomonocytic Leukemia ◽

Phase Iii ◽

White Blood Count ◽

Survival Duration ◽

Overall Response ◽

Myelomonocytic Leukemia

Abstract Abstract 4032 Background: Chronic myelomonocytic leukemia (CMML) is a rare yet indolent disease. The median survival duration in CMML is 12 to 18 months and patients with poor prognostic features do even worse, with median survival time ranging 3 to 6 months. Activity with decitabine in CMML has been previously reported. We sought to analyze the clinical experience of 17 adults with a diagnosis of CMML treated on two decitabine studies. Methods: A subset of patients with CMML from a pivotal phase III 3-day dosing and an open-label trial of 5-day dosing were identified and reviewed to determine the overall response rate (ORR, based on IWG 2006 criteria), duration of response, time to response, and overall survival (OS). Results: A total of 17 patients with CMML were included in this review. Mean age at diagnosis was 71 years (range, 47 to 81 years) with a mean time from diagnosis of 406.4 days. The majority of CMML patients had de novo (94.1%), good risk cytogenetics (58.8%) with an IPSS classification of Intermediate-1 (64.7%). Baseline mean white blood count (WBC), hemoglobin (HGB), and platelets (plts) were 7.5 × 103/μ L, 14.6 g/dL and 81.9 × 103/μ L, respectively. A larger proportion of CMML patients at baseline were plt and RBC transfusion independent. Objective response rate (ORR) was 41% [17.6% complete response (CR) and 23.5% marrowCR (mCR)]; Hematologic improvement (HI) was observed in 11.7% and stable disease in 29.4% of patients. Median survival was 391 (95% CI 239, 678) days and 2 (11.7%) patients progressed to AML. The adverse event profile was similar to observations in previous trials with myelosuppression and infectious complications. Conclusions: This retrospective review of responses in CMML patients supports previous findings of decitabine experience in this population. In this analysis an overall response rate of 41.4% was achieved. Decitabine provided anti-CMML activity with an acceptable safety profile. Disclosures: Jabbour: Eisai Inc.: Editorial and statistical support from Eisai Inc., Honoraria. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy. Ravandi:Eisai Inc.: Research Funding; Eisai Inc.: Honoraria. Borthakur:Eisai Inc.: Research Funding. Cortes:Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding.

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Response to PD-1 inhibition in early- and late-relapsing cutaneous melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e21038 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e21038-e21038

Author(s):

Kelly Fitzgerald ◽

Adil Daud

Keyword(s):

Overall Response Rate ◽

Response Rate ◽

Early Stage ◽

Stage I ◽

Definitive Treatment ◽

Early Stage Disease ◽

Overall Response ◽

Stage Disease ◽

The Difference ◽

Time To Relapse

e21038 Background: Up to 45% of stage I-II melanomas will relapse within 5 years, and some relapses occur more than 10 years after surgical resection. Little is known about the differences in tumor characteristics, including immunogenicity, of early- vs. late-relapsing melanoma, or the implication of these differences in response to PD-1 inhibition. Methods: A retrospective cohort study was conducted to compare time from definitive treatment of localized melanoma to relapse with response to pembrolizumab. Patients with prior stage I-II melanoma who relapsed, and then treated with pembrolizumab, were included in the study. Time to relapse was compared with overall response rate. Results: Among the study population, 66 patients initially presented with early stage disease that relapsed within the study period. The median time to relapse was 5 years (range 0.5-33 years, interquartile range 7.25, Q1 = 2, Q2 = 9.25). 9 patients (14%) relapsed within 2 years of surgery; these patients had a higher overall response rate to pembrolizumab than late-relapsing patients with marginal significance (88% vs 50%, p = 0.056). The difference became less significant when patients who relapsed before or after 5 years (70% vs 47%, respectively, p = 0.20), and before or after 10 years (64% vs 45%, p = .31). Conclusions: Patients with early-relapsing melanoma had higher ORR to pembrolizumab than patients with late-relapsing disease, with early relapse defined as earlier than 2 years from definitive surgical intervention. Late relapsing tumors may harbor mechanisms of resistance to immune checkpoint inhibition.

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SWOG 1609 (DART): A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps2658 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS2658-TPS2658 ◽

Cited By ~ 5

Author(s):

Sandip Pravin Patel ◽

Megan Othus ◽

Young Kwang Chae ◽

Frank Giles ◽

Jourdain Hayward ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Solid Tumors ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Alternative Hypothesis ◽

Performance Status ◽

Overall Response ◽

Rare Tumors

TPS2658 Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in advanced rare solid tumors. We sought to investigate the activity of ipilimumab and nivolumab in previously unstudied rare solid tumors, with planned biomarker evaluation pending including whole exome sequencing, RNAseq, and multiplex immune profiling via the NCI CIMACs. Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1mg/kg iv q6weeks) plus nivolumab (240mg iv q2weeks) across 37 cohorts of rare tumors. Eligible patients had incurable rare cancer, defined histologically with an incidence of less than 6 in 100,000 per year, and did not have an approved or standard therapy available that had been shown to prolong overall survival. Patients were required to be 18 years of age or older, have a Zubrod performance status of 0-2, with absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 75,000/mcL, hemoglobin ≥ 8 g/dL, creatinine clearance ≥ 50 mL/min, total bilirubin ≤ 2.0 x institutional upper limit of normal (IULN), AST and ALT ≤ 3.0 x IULN, TSH or free T4 serum ≤ IULN, and normal adrenocorticotropic hormone (ACTH) ≤ IULN. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) ≥ 6 months, and toxicity. The primary objective of this Phase II trial was to evaluate the overall response rate (ORR, confirmed complete and partial responses [CR and PR]) by RECIST v1.1. Our objective was to distinguish between a true ORR 15% (null hypothesis) versus 30% (alternative hypothesis). A Simon’s two-stage design was used, which required an analysis on the first 6 eligible patients who received therapy. If 1 or more of the 6 patients had a response (confirmed CR or PR), an additional 10 patients were to be accrued. The study was activated on 1/13/17 with the first patient treated on 3/1/17. The trial is currently open at 862 sites across the NCTN (with 352 sites having enrolled patients) and 554 patients enrolled to date. Clinical trial information: NCT02834013.

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An Open-Label Phase II Study to Investigate the Safety and Efficacy of Rituximab Plus Chlorambucil in Previously Untreated Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukaemia (CLL).

Blood ◽

10.1182/blood.v114.22.3428.3428 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3428-3428 ◽

Cited By ~ 4

Author(s):

Peter Hillmen ◽

John G. Gribben ◽

George A Follows ◽

Donald W. Milligan ◽

Hazem A. Sayala ◽

...

Keyword(s):

Interim Analysis ◽

Overall Response Rate ◽

Response Rate ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Open Label ◽

Overall Response ◽

Binet Stage ◽

The Uk

Abstract Abstract 3428 Poster Board III-316 Introduction Despite the increasing use of fludarabine (F) plus cyclophosphamide (C), and recently rituximab (R)-FC combinations in CLL, chlorambucil (Chl) remains a first-line treatment option, particularly for elderly patients and those with co-morbidities with chronic lymphocytic leukemia (CLL). However, rates of complete response (CR) are relatively low (up to 7%) as are overall responses (approximately 65%) with Chl. In this study we assessed the feasibility of adding R to Chl in order to improve outcomes. Methods Previously untreated patients with CLL who required therapy according to IWCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1-7; 10mg/m2/day p.o.) repeated every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in patients with continuing clinical response at 6 cycles. The primary endpoint was the adverse event (AE) profile. Secondary endpoints included response rates, progression-free and overall survival and assessment of minimal residual disease. Efficacy results from this study were compared with historical data from patients in the UK LRF CLL4 study who received Chl at the same dose but as monotherapy between 1999 and 2004. Each of the 50 patients in the Chl-R trial were matched to 3 patients from the CLL4 trial by Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age. Results This is a planned interim analysis (IA) based on the first 50 patients out of the total 100 patients from 12 centres. Of these 47 patients were evaluable (2 missing bone marrow at time of IA; 1 protocol violation received only 1 cycle). The median age of patients was 70.5 years (range 48–86), 62% were male and 52% had Binet stage C CLL. The most common AEs were gastrointestinal disorders. There were 25 serious AEs (SAEs) reported in 17 patients. The most common SAEs were infections (10 SAEs, in 6 patients). Additionally there were 3 SAEs (in 3 patients) of febrile neutropenia – grade 3 or 4 neutropenia was reported in 40% of patients. Overall response rate on an intent-to-treat analysis was 84%. When compared with the well matched subset of Chl patients from the UK LRF CLL4 study, the overall response rate was 17.3% higher (95% CI 4.7% - 30.0%), indicating that the Chl-R patients have improved responses. Conclusions Based on this planned interim analysis, the addition of R to Chl is a feasible combination with no unexpected AEs. The combination of R and Chl was effective for untreated patients with CLL. It is important to note that the median age of patients in this study was considerably greater than the median age of patients in the UK LRF CLL4 and other large trials in CLL, and more representative of the typical age of patients presenting with CLL in the clinic. The combination of R and Chl was well-tolerated and effective for untreated patients with CLL who cannot tolerate a more intensive regimen, and suggest investigation in a Phase III study is warranted. Disclosures Hillmen: Alexion Pharmaceuticals: Consultancy; F.Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Schering: Consultancy. Hayward:F.Hoffmann-La Roche Ltd: Former Employee.

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AOP2014, a Novel Peg-Proline-Interferon Alpha-2b with Improved Pharmacokinetic Properties, Is Safe and Well Tolerated and Shows Promising Efficacy in Patients with Polycythemia Vera (PV)

Blood ◽

10.1182/blood.v120.21.175.175 ◽

2012 ◽

Vol 120 (21) ◽

pp. 175-175 ◽

Cited By ~ 3

Author(s):

Heinz Gisslinger ◽

Robert Kralovics ◽

Bettina Gisslinger ◽

Daniel Lechner ◽

Veronika Buxhofer-Ausch ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Phase Iii ◽

Molecular Response ◽

Overall Response ◽

Long Term Treatment

Abstract Abstract 175 AOP2014 is a next generation long-acting pegylated IFNa-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. AOP2014 has a distinct pharmacokinetic and pharmacodynamic profile which may potentially allow reduced dosing frequencies compared to other pegylated IFNs. This is being expected to result in improved tolerability, better compliance, and, finally, favorable long-term treatment outcomes. AOP2014 is a designated Orphan Drug in EU for treatment of patients with PV. The maximum tolerated dose (MTD), long term safety and efficacy of AOP2014, administered subcutaneously every 14 days, are the main objectives of the study. Patients with confirmed PV diagnosis, age equal or older 18 years, both naïve and cytoreduction pre-treated are eligible. After establishing the MTD, an extended cohort of 25 additional patients was planned to be recruited. European LeukemiaNet criteria were used for response assessment. 34 patients, treated by March 31, 2012 were included into this analysis: 25 in Phase I (dose-finding) and 9 in the Phase II (cohort extension). Median time from diagnosis was 24 months (range 0–180). 12 patients (35%) were HU pre-treated (mean past duration of HU pre-treatment 39 months, mean daily HU dose 950 mg). Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 21 patients (62%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (32%) had a history of thrombotic complications. Median Hct at baseline was 42% (range 36–51). Median WBC and platelet counts were 10.6*109/l (range 3.9–20.4) and 452*109/l (range 141–1019), respectively. 17 patients (50%) had splenomegaly at baseline. The median reported treatment duration was 41 weeks (range: 1 day – 80 weeks), 11 patients completed 1 year on treatment. Doses from 50 to 540 ug every two weeks were tested, 540 ug has been concluded as MTD as the highest tested dose, since no DLTs occurred in the study. The mean administered dose (both Phase I and II patients) was 287 ug. After 28 weeks of treatment (21 evaluable patients), 71% of patients had hematological response (7 CR, 33%; 8 PR, 38%), at week 36 (19 evaluable patients) 8 patients (42%) achieved a CR and 8 patients (42%) a PR, overall response rate (ORR, CR+PR) was 84%. At week 52 (1 year; 11 evaluable patients), 5 patients (46%) had CR and 5 (46%) PR, ORR was 91%; 8 (73%) patients presented with completely normalized blood values, all evaluable patients were phlebotomy free at this timepoint. 4 patients (of 12 evaluable for this measurement, 33%) had still enlarged spleen at week 52. At week 76, 2 evaluable patients were complete responders. At week 52, 1 patient (of 9 evaluable, 11%) developed partial molecular response, at week 68 3 patients (of 7 evaluable, 43%) had partial molecular response. One patient with allelic burden of 22% at baseline developed complete molecular response at week 36 (still ongoing). Mainly grade 1 and 2 adverse events were reported. A total of 358 adverse events occurred. 27 patients (79%) suffered from drug-related adverse events. 9 patients (26%) developed serious adverse events; 4 SAEs were considered to be treatment related. 5 patients (15%) discontinued their study participation prematurely, 3 of them due to adverse events (deterioration of underlying disease and two cases of depression). Acceptable tolerability and durable clinical benefits have been demonstrated in PV patients measured as overall response rate of above 90% with CRs of 46% at one year after treatment start. Phlebotomy independence and normalization of hematological parameters could be seen in most of the patients. The study continues to recruit and collect long term follow up information. Presented data support further development of AOP2014 in PV, a Phase III study is planned to start early 2013. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Lechner:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

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Head-to-Head Comparison of 5-Azacitidine Versus Decitabine for the Treatment of Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v120.21.2843.2843 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2843-2843

Author(s):

Yun-Gyoo Lee ◽

Inho Kim ◽

Sung-Soo Yoon ◽

Seonyang Park ◽

June-Won Cheong ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Lower Risk ◽

Overall Response Rate ◽

Response Rate ◽

Hazard Ratio ◽

Phase Iii ◽

Comparable Efficacy ◽

Overall Response ◽

Risk Of Death ◽

Grade 3

Abstract Abstract 2843 Introduction The hypomethylating agents (HMAs) 5-azacitidine (AZA) and decitabine (DAC) provided significant overall response rates (40–60%) in myelodysplastic syndrome (MDS), and improved the outcome of higher risk MDS. However, phase III trials comparing AZA or DAC to conventional treatment including best supportive care have shown discrepant results. The aim of this study is to compare the efficacy and safety between AZA and DAC in patients with MDS. Methods We evaluated 203 patients in lower risk with significant cytopenia and higher risk MDS who received AZA and 97 patients who received DAC in Korea between January 2004 and December 2011. AZA 75mg/m2/day was given subcutaneously for 7 days every 4 weeks. DAC 20mg/m2/day was given intravenously over one hour for 5 days every 4 weeks. We compared overall response rate (complete responses, partial responses, marrow complete responses, and hematologic improvements), overall survival (OS) and adverse outcomes with the use of propensity-score matching in the overall cohort according to HMAs. Results Among 300 patients, propensity matching for the entire cohort created 97 matched pairs of patients. The International Prognostic Scoring System risk category was Intermediate-2/High in 40.2%. A median of 5 courses (range 1–24) were delivered in AZA and 5 courses (range 1–14) in DAC. In the overall matched cohort, there was no significant difference between AZA and DAC in overall response rate (44.2% vs. 52.1%, P=.28), OS (28 vs. 23 months; hazard ratio for AZA, 1.14; 95% confidence interval [CI], 0.75 to 1.72, P=.54) with a median follow-up duration of 29.6 months. Among the patient under 65, no significant differences were noted for OS between AZA and DAC group. Among the patient over 65, however, the patients who received DAC showed higher risk of death than those who received AZA with borderline significance (hazard ratio for AZA, 1.58; 95% CI 0.91 to 2.73, P=.10). The cumulative hazard of transformation to acute myeloid leukemia (AML) was 16.3% in AZA and 21.9% in DAC at one year, and 32.2% in AZA and 55.3% in DAC at two year. The incidence of grade 3 & 4 neutropenia was significantly higher in DAC than AZA (P=.026). Among 1151 assessable treatment courses (604 in AZA, 547 in DAC), AZA group have less likely to experience fever episodes requiring intravenous antibiotics than DAC group (8.6 vs. 15.7 episodes per 100 courses; risk ratio, 0.55; P<.001). Conclusions In a cohort of patients in lower risk with significant cytopenia and higher risk MDS, AZA and DAC showed comparable efficacy in terms of overall response rate, OS and risk of transformation to AML. However, patients receiving DAC experienced more frequent grade 3 & 4 neutropenia and fever episodes than patient receiving AZA. When both AZA and DAC are available, safety profiles as well as treatment efficacy need to be considered. Disclosures: No relevant conflicts of interest to declare.

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Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.0221 ◽

2006 ◽

Vol 24 (3) ◽

pp. 431-436 ◽

Cited By ~ 618

Author(s):

S. Vincent Rajkumar ◽

Emily Blood ◽

David Vesole ◽

Rafael Fonseca ◽

Philip R. Greipp

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Response Rate ◽

Eastern Cooperative Oncology Group ◽

Response Rates ◽

Incidence Rates ◽

Phase Iii ◽

Newly Diagnosed ◽

Monoclonal Protein ◽

Grade 3

Purpose To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma. Patients and Methods Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A. Results Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively). Conclusion Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.

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Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.4.1470 ◽

1997 ◽

Vol 15 (4) ◽

pp. 1470-1477 ◽

Cited By ~ 21

Author(s):

N A Dawson ◽

W D Figg ◽

M R Cooper ◽

O Sartor ◽

R C Bergan ◽

...

Keyword(s):

Prostate Cancer ◽

Poor Prognosis ◽

Metastatic Prostate Cancer ◽

Overall Response Rate ◽

Response Rate ◽

Karnofsky Performance Status ◽

Severe Disease ◽

Performance Status ◽

Phase Iii ◽

Overall Response

PURPOSE To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

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