The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform

Nathalie Gaspar - One of the best experts on this subject based on the ideXlab platform.

  • Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of Mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma.
    BMJ open, 2019
    Co-Authors: Caroline Brard, Sophie Piperno-neumann, Jessy Delaye, Laurence Brugières, Lisa V. Hampson, Gwénaël Le Teuff, Marie-cécile Le Deley, Nathalie Gaspar
    Abstract:

    Introduction The controversial results on the Mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising drug. The European Commission has granted a marketing authorisation to Mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation. Methods and analysis Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of Mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2 and ≤50 years with newly diagnosed high-risk localised or metastatic osteosarcoma. The main objective is to evaluate the impact on event-free survival (EFS) of Mifamurtide on intention-to-treat population. The secondary objectives are to evaluate the impact of Mifamurtide on overall survival, to evaluate the feasibility and toxicity of the planned treatment, to correlate biology/immunology with the Mifamurtide efficacy/toxicity. With a total of 126 enrolled patients and 51 events, the power is 80% if Mifamurtide is associated with an 18% improvement of the 3-year EFS (52%vs70%, equivalent to an HR=0.55), with a one-sided logrank test alpha=10%. As relevant historical data are available (aggregate treatment effect from the INT-0133 trial and individual data from the control group of the Sarcome-09/OS2006 trial), a Bayesian analysis is also planned. Ethics and dissemination This study was approved by the ‘Comite de Protection des Personnes Ile de France I’ (12/06/2018), complies with the Declaration of Helsinki and French laws and regulations, and follows the International Conference on Harmonisation E6 Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, as well as biological ancillary studies will be presented at appropriate international congresses and published in international peer-review journals. Trial registration number EudraCT 2017-001165-24, NCT03643133

  • sarcome 13 os2016 trial protocol a multicentre randomised open label phase ii trial of Mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high risk osteosarcoma
    BMJ Open, 2019
    Co-Authors: Caroline Brard, Jessy Delaye, Laurence Brugières, Lisa V. Hampson, Gwénaël Le Teuff, Marie-cécile Le Deley, Sophie Pipernoneumann, Nathalie Gaspar
    Abstract:

    Introduction The controversial results on the Mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising drug. The European Commission has granted a marketing authorisation to Mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation. Methods and analysis Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of Mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2 and ≤50 years with newly diagnosed high-risk localised or metastatic osteosarcoma. The main objective is to evaluate the impact on event-free survival (EFS) of Mifamurtide on intention-to-treat population. The secondary objectives are to evaluate the impact of Mifamurtide on overall survival, to evaluate the feasibility and toxicity of the planned treatment, to correlate biology/immunology with the Mifamurtide efficacy/toxicity. With a total of 126 enrolled patients and 51 events, the power is 80% if Mifamurtide is associated with an 18% improvement of the 3-year EFS (52%vs70%, equivalent to an HR=0.55), with a one-sided logrank test alpha=10%. As relevant historical data are available (aggregate treatment effect from the INT-0133 trial and individual data from the control group of the Sarcome-09/OS2006 trial), a Bayesian analysis is also planned. Ethics and dissemination This study was approved by the ‘Comite de Protection des Personnes Ile de France I’ (12/06/2018), complies with the Declaration of Helsinki and French laws and regulations, and follows the International Conference on Harmonisation E6 Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, as well as biological ancillary studies will be presented at appropriate international congresses and published in international peer-review journals. Trial registration number EudraCT 2017-001165-24, NCT03643133

  • Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study
    BMC Medical Research Methodology, 2019
    Co-Authors: Caroline Brard, Nathalie Gaspar, Lisa Hampson, Marie-cécile Le Deley, Gwénaël Le Teuff
    Abstract:

    BACKGROUND: Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial's analysis through a prior distribution. METHODS: Motivated by a RCT intended to evaluate the impact on event-free survival of Mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. RESULTS: The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. CONCLUSION: In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.

  • Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study
    BMC medical research methodology, 2019
    Co-Authors: Caroline Brard, Lisa V. Hampson, Nathalie Gaspar, Marie-cécile Le Deley, Gwénaël Le Teuff
    Abstract:

    Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial’s analysis through a prior distribution. Motivated by a RCT intended to evaluate the impact on event-free survival of Mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.

Cristina Oliva - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetics and pharmacodynamics of liposomal Mifamurtide in adult volunteers with mild or moderate renal impairment.
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: Karthik Venkatakrishnan, Thomas Marbury, Yi Liu, Dennis Noe, Jaime Mertz, Michael Bargfrede, Kambiz Farbakhsh, Cristina Oliva, Ashley Milton
    Abstract:

    Aims To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal Mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT®) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. Methods Subjects received a 4 mg dose of liposomal Mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). Results Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total Mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6–132%) and 119% (90% confidence interval, 94.1–151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered Mifamurtide (4 mg). Conclusions These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of Mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.

  • Pharmacokinetics and pharmacodynamics of liposomal Mifamurtide in adult volunteers with mild or moderate hepatic impairment: Liposomal Mifamurtide in adults with hepatic impairment
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: Karthik Venkatakrishnan, Thomas Marbury, Yi Liu, Dennis Noe, Jaime Mertz, Michael Bargfrede, Kambiz Farbakhsh, Cristina Oliva, Ashley Milton
    Abstract:

    To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal Mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. Subjects received a 4 mg dose of liposomal Mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total Mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered Mifamurtide (4 mg). These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of Mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations. © 2013 The British Pharmacological Society.

  • A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal Mifamurtide (L-MTP-PE) in healthy adult volunteers
    European Journal of Clinical Pharmacology, 2012
    Co-Authors: Karthik Venkatakrishnan, William G. Kramer, Timothy W. Synold, Daniel B. Goodman, Evin Sides, Cristina Oliva
    Abstract:

    Purpose This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [Mifamurtide (L-MTP-PE)] in healthy adults. Methods L-MTP-PE 4 mg was administered intravenously over 30 min. Study participants were monitored from 24 h preinfusion until 72 h postinfusion. Blood samples were drawn over 0–72 h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24 h predose through 24 h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90 % confidence intervals were calculated. Results Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05 ± 0.40 h. PK variability was low, with

  • A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal Mifamurtide (L-MTP-PE) in healthy adult volunteers.
    European journal of clinical pharmacology, 2012
    Co-Authors: Karthik Venkatakrishnan, William G. Kramer, Timothy W. Synold, Daniel B. Goodman, Evin Sides, Cristina Oliva
    Abstract:

    Purpose This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [Mifamurtide (L-MTP-PE)] in healthy adults.

  • Observational, Noninterventional Surveillance Study of Patients with High-Grade Osteosarcoma who are Candidates for Liposomal Mifamurtide Treatment
    Annals of Oncology, 2012
    Co-Authors: I.j. Lewis, Cristina Oliva, Y. Liu
    Abstract:

    ABSTRACT Background Although surgery is the mainstay of osteosarcoma treatment, it is generally not curative and prognosis is poor. Survival rates improved with the introduction of adjuvant and neoadjuvant chemotherapy but have remained largely unchanged since the 1980s. Mifamurtide is a liposomal formulation of muramyl tripeptide phosphatidyl ethanolamine, which stimulates macrophages and monocytes, resulting in tumoricidal effects. In a phase 3 trial in 678 patients with newly diagnosed high-grade osteosarcoma, Mifamurtide given post-resection in combination with chemotherapy improved 6-year overall survival probability to 77% vs. 66% with chemotherapy alone (p = 0.03; Mifamurtide assessment report [www.ema.europa.eu]). The most common grade 3/4 adverse events (AEs) were cytopenias, stomatitis and infections, with no difference between the treatment arms for most toxicities reported (www.ema.europa.eu). Methods This phase 4 study will assess osteosarcoma patients who are candidates for Mifamurtide therapy at European centres. (EudraCT: 2009-017204-89;NCT01194284). Eligible patients are aged 2–30 years, with a confirmed diagnosis of high-grade osteosarcoma. Approximately 150 patients are planned to be entered, and recruited over a 2-year period. Patients will receive the standard schedule of 2 mg/m2 IV Mifamurtide, administered twice weekly for 12 weeks then once weekly for 24 weeks (total 36 weeks). The primary objectives are to assess the short- (during treatment) and long-term (≤5 years from last Mifamurtide dose or until death) safety profile of Mifamurtide, including evaluation of AEs of special interest (defined as important identified and potential risks) to take into account the risk of recurrence and comorbidities with chemotherapy. Secondary objectives include assessment of disease status, disease-free survival and overall survival. Disclosure C. Oliva: Employment: Takeda. Y. Liu: Employment: Millennium. All other authors have declared no conflicts of interest.

Caroline Brard - One of the best experts on this subject based on the ideXlab platform.

  • Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of Mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma.
    BMJ open, 2019
    Co-Authors: Caroline Brard, Sophie Piperno-neumann, Jessy Delaye, Laurence Brugières, Lisa V. Hampson, Gwénaël Le Teuff, Marie-cécile Le Deley, Nathalie Gaspar
    Abstract:

    Introduction The controversial results on the Mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising drug. The European Commission has granted a marketing authorisation to Mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation. Methods and analysis Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of Mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2 and ≤50 years with newly diagnosed high-risk localised or metastatic osteosarcoma. The main objective is to evaluate the impact on event-free survival (EFS) of Mifamurtide on intention-to-treat population. The secondary objectives are to evaluate the impact of Mifamurtide on overall survival, to evaluate the feasibility and toxicity of the planned treatment, to correlate biology/immunology with the Mifamurtide efficacy/toxicity. With a total of 126 enrolled patients and 51 events, the power is 80% if Mifamurtide is associated with an 18% improvement of the 3-year EFS (52%vs70%, equivalent to an HR=0.55), with a one-sided logrank test alpha=10%. As relevant historical data are available (aggregate treatment effect from the INT-0133 trial and individual data from the control group of the Sarcome-09/OS2006 trial), a Bayesian analysis is also planned. Ethics and dissemination This study was approved by the ‘Comite de Protection des Personnes Ile de France I’ (12/06/2018), complies with the Declaration of Helsinki and French laws and regulations, and follows the International Conference on Harmonisation E6 Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, as well as biological ancillary studies will be presented at appropriate international congresses and published in international peer-review journals. Trial registration number EudraCT 2017-001165-24, NCT03643133

  • sarcome 13 os2016 trial protocol a multicentre randomised open label phase ii trial of Mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high risk osteosarcoma
    BMJ Open, 2019
    Co-Authors: Caroline Brard, Jessy Delaye, Laurence Brugières, Lisa V. Hampson, Gwénaël Le Teuff, Marie-cécile Le Deley, Sophie Pipernoneumann, Nathalie Gaspar
    Abstract:

    Introduction The controversial results on the Mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising drug. The European Commission has granted a marketing authorisation to Mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation. Methods and analysis Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of Mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2 and ≤50 years with newly diagnosed high-risk localised or metastatic osteosarcoma. The main objective is to evaluate the impact on event-free survival (EFS) of Mifamurtide on intention-to-treat population. The secondary objectives are to evaluate the impact of Mifamurtide on overall survival, to evaluate the feasibility and toxicity of the planned treatment, to correlate biology/immunology with the Mifamurtide efficacy/toxicity. With a total of 126 enrolled patients and 51 events, the power is 80% if Mifamurtide is associated with an 18% improvement of the 3-year EFS (52%vs70%, equivalent to an HR=0.55), with a one-sided logrank test alpha=10%. As relevant historical data are available (aggregate treatment effect from the INT-0133 trial and individual data from the control group of the Sarcome-09/OS2006 trial), a Bayesian analysis is also planned. Ethics and dissemination This study was approved by the ‘Comite de Protection des Personnes Ile de France I’ (12/06/2018), complies with the Declaration of Helsinki and French laws and regulations, and follows the International Conference on Harmonisation E6 Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, as well as biological ancillary studies will be presented at appropriate international congresses and published in international peer-review journals. Trial registration number EudraCT 2017-001165-24, NCT03643133

  • Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study
    BMC Medical Research Methodology, 2019
    Co-Authors: Caroline Brard, Nathalie Gaspar, Lisa Hampson, Marie-cécile Le Deley, Gwénaël Le Teuff
    Abstract:

    BACKGROUND: Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial's analysis through a prior distribution. METHODS: Motivated by a RCT intended to evaluate the impact on event-free survival of Mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. RESULTS: The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. CONCLUSION: In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.

  • Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study
    BMC medical research methodology, 2019
    Co-Authors: Caroline Brard, Lisa V. Hampson, Nathalie Gaspar, Marie-cécile Le Deley, Gwénaël Le Teuff
    Abstract:

    Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial’s analysis through a prior distribution. Motivated by a RCT intended to evaluate the impact on event-free survival of Mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.

Karthik Venkatakrishnan - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetics and pharmacodynamics of liposomal Mifamurtide in adult volunteers with mild or moderate renal impairment.
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: Karthik Venkatakrishnan, Thomas Marbury, Yi Liu, Dennis Noe, Jaime Mertz, Michael Bargfrede, Kambiz Farbakhsh, Cristina Oliva, Ashley Milton
    Abstract:

    Aims To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal Mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT®) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. Methods Subjects received a 4 mg dose of liposomal Mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). Results Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total Mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6–132%) and 119% (90% confidence interval, 94.1–151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered Mifamurtide (4 mg). Conclusions These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of Mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.

  • Pharmacokinetics and pharmacodynamics of liposomal Mifamurtide in adult volunteers with mild or moderate hepatic impairment: Liposomal Mifamurtide in adults with hepatic impairment
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: Karthik Venkatakrishnan, Thomas Marbury, Yi Liu, Dennis Noe, Jaime Mertz, Michael Bargfrede, Kambiz Farbakhsh, Cristina Oliva, Ashley Milton
    Abstract:

    To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal Mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. Subjects received a 4 mg dose of liposomal Mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total Mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered Mifamurtide (4 mg). These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of Mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations. © 2013 The British Pharmacological Society.

  • Mifamurtide in metastatic and recurrent osteosarcoma: A patient access study with pharmacokinetic, pharmacodynamic, and safety assessments
    Pediatric blood & cancer, 2013
    Co-Authors: Pete Anderson, Karthik Venkatakrishnan, Paul A. Meyers, Eugenie S. Kleinerman, Dennis P.m. Hughes, C. Herzog, Winston W. Huh, Robert M. Sutphin, Yatin M. Vyas, V. Shen
    Abstract:

    Purpose This non-randomized, patient-access protocol, assessed both safety and efficacy outcomes following liposomal muramyl-tripeptide-phosphatidylethanolamine (L-MTP-PE; Mifamurtide) in patients with high-risk, recurrent and/or metastatic osteosarcoma. Methods Patients received Mifamurtide 2 mg/m2 intravenously twice-weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration-time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion-related adverse events (IRAE); other AEs and overall survival (OS) were assessed. Results The study began therapy in January 2008; the last patient completed therapy in October 2012. Two hundred five patients were enrolled; median age was 16.0 years and 146/205 (71%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a log-linear manner 2–6 hours post-dose; t1/2 was 2 hours. There were no readily apparent relationships between age and BSA-normalized clearance, half-life, or pharmacodynamic effects, supporting the dose of 2 mg/m2 Mifamurtide across the age range. Patients reported 3,679 IRAE after 7,482 Mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills + fever or headache + fatigue symptom clusters. One- and 2-year OS was 71.7% and 45.9%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N = 40) had similar 2-year OS (39.9%) as the entire cohort (45.9%) Conclusions Mifamurtide had a manageable safety profile; PK/PD of Mifamurtide in this patient access study was consistent with prior studies. Two-year OS was 45.9%. A randomized clinical trial would be required to definitively determine impact on patient outcomes. Pediatr Blood Cancer 2014;61:238–244. © 2013 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

  • A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal Mifamurtide (L-MTP-PE) in healthy adult volunteers
    European Journal of Clinical Pharmacology, 2012
    Co-Authors: Karthik Venkatakrishnan, William G. Kramer, Timothy W. Synold, Daniel B. Goodman, Evin Sides, Cristina Oliva
    Abstract:

    Purpose This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [Mifamurtide (L-MTP-PE)] in healthy adults. Methods L-MTP-PE 4 mg was administered intravenously over 30 min. Study participants were monitored from 24 h preinfusion until 72 h postinfusion. Blood samples were drawn over 0–72 h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24 h predose through 24 h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90 % confidence intervals were calculated. Results Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05 ± 0.40 h. PK variability was low, with

  • A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal Mifamurtide (L-MTP-PE) in healthy adult volunteers.
    European journal of clinical pharmacology, 2012
    Co-Authors: Karthik Venkatakrishnan, William G. Kramer, Timothy W. Synold, Daniel B. Goodman, Evin Sides, Cristina Oliva
    Abstract:

    Purpose This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [Mifamurtide (L-MTP-PE)] in healthy adults.

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  • muramyl tripeptide phosphatidyl ethanolamine encapsulated in liposomes l mtp pe in the treatment of osteosarcoma
    Advances in Experimental Medicine and Biology, 2014
    Co-Authors: Paul A. Meyers, Alexander Jaho Chou
    Abstract:

    Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or Mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received Mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.

  • Mifamurtide in metastatic and recurrent osteosarcoma: A patient access study with pharmacokinetic, pharmacodynamic, and safety assessments
    Pediatric blood & cancer, 2013
    Co-Authors: Pete Anderson, Karthik Venkatakrishnan, Paul A. Meyers, Eugenie S. Kleinerman, Dennis P.m. Hughes, C. Herzog, Winston W. Huh, Robert M. Sutphin, Yatin M. Vyas, V. Shen
    Abstract:

    Purpose This non-randomized, patient-access protocol, assessed both safety and efficacy outcomes following liposomal muramyl-tripeptide-phosphatidylethanolamine (L-MTP-PE; Mifamurtide) in patients with high-risk, recurrent and/or metastatic osteosarcoma. Methods Patients received Mifamurtide 2 mg/m2 intravenously twice-weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration-time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion-related adverse events (IRAE); other AEs and overall survival (OS) were assessed. Results The study began therapy in January 2008; the last patient completed therapy in October 2012. Two hundred five patients were enrolled; median age was 16.0 years and 146/205 (71%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a log-linear manner 2–6 hours post-dose; t1/2 was 2 hours. There were no readily apparent relationships between age and BSA-normalized clearance, half-life, or pharmacodynamic effects, supporting the dose of 2 mg/m2 Mifamurtide across the age range. Patients reported 3,679 IRAE after 7,482 Mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills + fever or headache + fatigue symptom clusters. One- and 2-year OS was 71.7% and 45.9%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N = 40) had similar 2-year OS (39.9%) as the entire cohort (45.9%) Conclusions Mifamurtide had a manageable safety profile; PK/PD of Mifamurtide in this patient access study was consistent with prior studies. Two-year OS was 45.9%. A randomized clinical trial would be required to definitively determine impact on patient outcomes. Pediatr Blood Cancer 2014;61:238–244. © 2013 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

  • Mifamurtide (L-MTP-PE) for Metastatic and Recurrent Osteosarcoma (OS): Survival and Safety Profile from a Patient Access Study
    Annals of Oncology, 2012
    Co-Authors: Pete Anderson, Cristina Oliva, Paul A. Meyers, Eugenie S. Kleinerman, Y. Liu
    Abstract:

    ABSTRACT Introduction and research objectives Liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE; Mifamurtide) is approved for treatment of non-metastatic osteosarcoma (OS) in Europe, Israel, and Mexico. The primary objective of MTP-OS-403 was to collect information regarding the safety and tolerability of MTP in patients with high-risk OS. The open label access study called for L-MTP-PE 2mg/m2 twice /week x 24 doses, then weekly (total doses= 48 in 9 months). OS patients could receive MTP as a single agent or with appropriate chemotherapy. Results As of April 2012, 202 patients were registered at 8 participating centers. Most had metastases at initial presentation or recurrent OS. Median age was 16 yr. Time from initial diagnosis to L-MTP-PE treatment was 29 +/- 23 months (median 24 mo). Although >88% had metastases, 27% had been resected to no evidence of disease (NED) before study entry. The most common Infusion related AE (IRAE) within 24 hours of infusion were chills (37%), fever (25%), nausea (21%), headache (19%), and fatigue (15%). The most common AE (grade 3-4) other than IRAE were chemotherapy-related and included thrombocytopenia (22%), neutropenia (19%), leukopenia (18%), febrile neutropenia (16%), lymphopenia (15%), and anaemia (15%). At MDACC, there was 1 episode of pleural effusion and one episode of pericardial effusion that were possibly L-MTP-PE related. The median number of L-MTP-PE doses given was 34 (mean 30.1 +/- 17.5); 32% of these high risk OS patients received 48 doses. As of April 2012 45% (90/202) of these high risk OS patients continue to be followed for survival. Conclusion The safety profile of L-MTP-PE in high-risk OS patients is consistent with the known toxicity of the product. The infusion related AEs were generally mild to moderate. Since survival benefit in high-grade OS from MTP may be related to disease burden (i.e. achieving NED status using local control measures such as surgery and/or radiotherapy), L-MTP-PE may be more effective when used in the adjuvant setting. A randomized multi-institutional clinical trial in OS patients presenting with metastases at diagnosis should be considered. Disclosure C. Oliva: Cristina Oliva is a Takeda employee. Y. Liu: I am a Millennium employee. All other authors have declared no conflicts of interest.

  • muramyl tripeptide Mifamurtide for the treatment of osteosarcoma
    Expert Review of Anticancer Therapy, 2009
    Co-Authors: Paul A. Meyers
    Abstract:

    Osteosarcoma is an ultraorphan disease. There are approximately 1000 new patients diagnosed with osteosarcoma each year in the USA and Europe. Current treatment for osteosarcoma utilizes multiagent chemotherapy and surgical resection of all clinically detectable disease. Current treatments for osteosarcoma achieve 60–70% event-free survival (EFS) for patients with localized disease and approximately 20% EFS for patients who present with metastasis. These results have been stable for two decades. The addition of muramyl tripeptide (Mifamurtide) to chemotherapy resulted in a trend towards improved EFS and a one-third reduction in the risk of death from osteosarcoma. Mifamurtide has been approved in Europe for the treatment of newly diagnosed osteosarcoma in combination with chemotherapy.