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Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.

ABSTRACT: PURPOSE:EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-?-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. PATIENTS AND METHODS:At diagnosis, patients age ? 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ? two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-?-2b (0.5 to 1.0 ?g/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). RESULTS:Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-?-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-?-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-?-2b and for stopping prematurely, respectively. Median IFN-?-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-?-2b and provided toxicity information reported grade ? 3 toxicity during IFN-?-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-?-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. CONCLUSION:At the preplanned analysis time, MAP plus IFN-?-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-?-2b or stopped prematurely. Long-term follow-up for events and survival continues.

SUBMITTER: Bielack SS

PROVIDER: S-EPMC4486345 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.

Bielack Stefan S SS Smeland Sigbjørn S Whelan Jeremy S JS Marina Neyssa N Jovic Gordana G Hook Jane M JM Krailo Mark D MD Gebhardt Mark M Pápai Zsuzsanna Z Meyer James J Nadel Helen H Randall R Lor RL Deffenbaugh Claudia C Nagarajan Rajaram R Brennan Bernadette B Letson G Douglas GD Teot Lisa A LA Goorin Allen A Baumhoer Daniel D Kager Leo L Werner Mathias M Lau Ching C CC Sundby Hall Kirsten K Gelderblom Hans H Meyers Paul P Gorlick Richard R Windhager Reinhard R Helmke Knut K Eriksson Mikael M Hoogerbrugge Peter M PM Schomberg Paula P Tunn Per-Ulf PU Kühne Thomas T Jürgens Heribert H van den Berg Henk H Böhling Tom T Picton Susan S Renard Marleen M Reichardt Peter P Gerss Joachim J Butterfass-Bahloul Trude T Morris Carol C Hogendoorn Pancras C W PC Seddon Beatrice B Calaminus Gabriele G Michelagnoli Maria M Dhooge Catharina C Sydes Matthew R MR Bernstein Mark M

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20150601 20

<h4>Purpose</h4>EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy.<h4>Patients and methods</h4>At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, d ...[more]

PMID: 26033801

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Project description:Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG-IFN) alfa-2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG-IFN alfa-2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non-Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ?3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups.This post hoc analysis of HCV patients treated with PEG-IFN alfa-2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response.

Project description:BACKGROUND:Several countries have used pegylation technology to improve the pharmacokinetic properties of essential drugs. Recently, a novel interferon alfa-2b protein conjugated to four-branched 12 kDa polyethylene glycol molecules was developed jointly between Cuba and Brazil. The aim of this study was to compare the pharmacokinetic properties of BIP48 (pegylated interferon alfa-2b from Bio-Manguinhos/Fiocruz, Brazil) to those of PEGASYS® (commercially available pegylated interferon alfa-2a from Roche Pharmaceutical). METHODS:This phase I, single-centre, randomized, double-blind crossover trial enrolled 31 healthy male volunteers aged 19 to 35 who were allocated to two stages, either side of a 5-week wash-out period, with each arm lasting 14 consecutive days after subcutaneous administration of 180 ?g of one formulation or the other (study or comparator). The main outcome variable was serum pegylated interferon concentrations in 15 samples collected during the course of the study and tested using an enzyme immunoassay. RESULTS:There were no differences between formulations in terms of magnitude or absorption parameters. Analysis of time parameters revealed that BIP48 remained in the body significantly longer than PEGASYS® (Tmax: 73 vs. 54 h [p =?0.0010]; MRT: 133 vs. 115 h [p =?0.0324]; ke: 0.011 vs. 0.013 h(-1) [p =?0.0153]; t1/2: 192 vs. 108 h [p =?0.0218]). CONCLUSION:BIP48 showed the expected pharmacokinetic profile for a pegylated product with a branched molecular structure. Compared to PEGASYS®, the magnitude absorption was similar, but time parameters were consistent with slower elimination. Further studies should be conducted to evaluate the clinical implications of these findings. A phase II-III repeated-dose clinical trial is ongoing to study these findings in patients with chronic hepatitis C virus infection. TRIAL REGISTRATION:This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 ). This trial was retrospectively registered in June 2013.

Dataset Information

Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.

Publications

Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.

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