scholarly journals Multicentric phase II trial of TI‐CE high‐dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors

2021 ◽  
Author(s):  
Christine Chevreau ◽  
Christophe Massard ◽  
Aude Flechon ◽  
Rémy Delva ◽  
Gwenaëlle Gravis ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Germ Cell ◽  
Phase Ii ◽  
Drug Monitoring ◽  
Phase Ii Trial ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
Therapeutic Drug ◽  
High Dose

Individualization of high dose carboplatin based on therapeutic drug monitoring (TDM) for the treatment of testicular germ cell tumors (TICE protocol): Results of a multicenter phase II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4554-4554 ◽  
Author(s):  
Fabienne Thomas ◽  
Sotheara Moeung ◽  
Sophie Broutin ◽  
Jerome Guitton ◽  
Michele Boisdron-Celle ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Germ Cell ◽  
Phase Ii ◽  
Drug Monitoring ◽  
Germ Cell Tumors ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
High Dose ◽  
Clearance Prediction ◽  
New Equation

4554 Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5th and 95thpercentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.

Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study

2017 ◽  
Vol 23 (23) ◽  
pp. 7171-7179 ◽  
Author(s):  
Sotheara Moeung ◽  
Christine Chevreau ◽  
Sophie Broutin ◽  
Jérôme Guitton ◽  
Bénédicte Lelièvre ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Germ Cell ◽  
Phase Ii ◽  
Multicenter Study ◽  
Drug Monitoring ◽  
Germ Cell Tumors ◽  
Therapeutic Drug ◽  
High Dose

Olaparib as salvage treatment for advanced germ cell tumors after chemotherapy failure: Results of the open-label, single-arm, IGG-02 phase II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5058-5058
Author(s):  
Ugo De Giorgi ◽  
Giuseppe Schepisi ◽  
Giorgia Gurioli ◽  
Carmela Pisano ◽  
Umberto Basso ◽  
...  
Keyword(s):  
Dna Repair ◽  
Germ Cell ◽  
Phase Ii ◽  
Survival Probability ◽  
Phase Ii Trial ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Open Label

5058 Background: Therapeutic options for patients with advanced germ cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. We aimed to evaluate olaparib activity in patients with refractory GCT. Methods: In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ cell cancer IGG-02 study (NCT02533765), patient eligibility included failure after high-dose chemotherapy or after at least 2 different cisplatin-based regimens. Measurements of serum tumor markers and computed tomography were carried out at baseline and every 6 weeks of olaparib treatment. The study primary endpoint was the overall response rate, the study planned to recruit initially 18 patients and not continue further recruitment until one or more responses were observed. Results: Between September 2015 and February 2019, 18 patients, median age 39 years (range, 22-61) were enrolled. The number of prior chemotherapy regimens was: 2 for 3 patients (16.7%), 3 for 5 patients (27.8%), >3 for 10 patients (55.6%). Sixteen cases (89.9%) received prior high-dose chemotherapy with support of hematopoietic progenitor cells. Grade 3-4 adverse events were observed in 5 patients (27.7%). There were no partial responses, 5 cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 7+ months and 13 (72.2%) progressive disease. The 12-week progression-free survival probability was 27.8% [95% confidence interval (CI): 10.1%-48.9%]. The 12-month overall survival probability was 27.8% (95% CI: 10.1%-48.9%). A germline DNA repair profile panel showed only a BRCA1 mutated case associated with a SD lasted 4 months. Conclusions: Olaparib as a single agent has marginal activity in heavily pretreated GCT patients, however, an anecdotic 4-month SD in the only BRCA mutated patient has been reported. Plans for future studies with olaparib are suggested in combination or following salvage chemotherapy in less pretreated and more selected GCT patients. The Study has been conducted with AstraZeneca contribution. Clinical trial information: NCT02533765 .

Phase II trial of TI-CE high dose chemotherapy (HDCT) with drug monitoring for individual carboplatin dosing in patients with relapsed advanced germ cell tumors: A multicentric prospective GETUG trial.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 401-401 ◽  
Author(s):  
Christine Chevreau ◽  
Christophe Massard ◽  
Aude Flechon ◽  
Remy Delva ◽  
Gwenaelle Gravis ◽  
...  
Keyword(s):  
Phase Ii ◽  
Drug Monitoring ◽  
Phase Ii Trial ◽  
Germ Cell Tumors ◽  
Area Under The Curve ◽  
Therapeutic Drug ◽  
High Dose ◽  
Dose Individualization ◽  
Carboplatin Dose ◽  
Very High

401 Background: HDCT is a valid option of treatment for relapsed advanced GCTs pts. The results of the TICE regimen as salvage therapy in poor risk pts demonstrated a 50% complete response (CR) but with very high variability of measured carboplatin area under the curve (AUC) (between 10.9-36.7 for target AUC = 24 mg.min/mL). We initiated a phase II trial of TICE with therapeutic drug monitoring (TDM) for individual carboplatin dosing in order to target the 3-day AUC to 24 mg/min/mL. Methods: Were included pts with unfavorable relapsed GCTs , secondarily classified according to the International Prognostic Factors Study Group. Pts were treated according the TICE regimen with two cycles combining paclitaxel and ifosfamide followed by three cycles HDCT: carboplatin plus etoposide with stem cell support. Carboplatin dose was adapted on day 3 based on carboplatin clearance (Cl) at day 1, in order to reach the target AUC. The primary endpoint was the CR rate (cCR sCR pCR). A Simon Minimax design was performed using the following hypothesis: p0 = 50%, p1 = 65 α = 5%, β = 10%. Results: Between 03/2009 and 11/2015 101 pts were accrued, 60 pts were treated in first relapse (34 classified as high and very high-risk) and 41 in 2ndor more relapse. 72 pts (71%) received the whole treatment, 12 pts (10%) did not receive any cycle of HDCT. 29pts (26%) stopped treatment earlier, 8 for toxicity. Three pts died on treatment. 35/79 (44.3%) evaluable pts achieved a CR. 19 pts (24%) presented a PRm-. The mean observed carboplatin AUC was 24.5 mg.min/mL (between 18.9 and 28.8) at C1.Following TDM, the modification of the total carboplatin dose during C1 was comprised between -33% and +44%, showing the benefit of TDM in comparison with individual dosing based only on carboplatin Cl predicted according to patient’s renal characteristics. Conclusions: The CR rate observed in this very poor prognosis population was 44.3% and 69.6% CR + PRm-. Carboplatin dose individualization based on TDM allowed to reach more accurately the target AUC compared to previous reports. Clinical trial information: NCT00864318.

Validation of a Therapeutic Drug Monitoring Strategy for Thiotepa in a High-Dose Chemotherapy Regimen

2001 ◽  
Vol 23 (6) ◽  
pp. 650-657 ◽  
Author(s):  
Alwin D. R. Huitema ◽  
Ron A. A. Mathôt ◽  
Matthijs M. Tibben ◽  
Sjoerd Rodenhuis ◽  
Jos H. Beijnen
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Chemotherapy Regimen ◽  
High Dose Chemotherapy ◽  
Therapeutic Drug ◽  
High Dose ◽  
Monitoring Strategy

scholarly journals Perspectives and Expertise in Establishing a Therapeutic Drug Monitoring Programme for Challenging Childhood Cancer Patient Populations

2022 ◽  
Vol 11 ◽  
Author(s):  
Shelby Barnett ◽  
Victoria Holden ◽  
Quentin Campbell-Hewson ◽  
Gareth J. Veal
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Cancer Patient ◽  
Childhood Cancer ◽  
Drug Monitoring ◽  
Clinical Information ◽  
High Dose Chemotherapy ◽  
Paediatric Oncology ◽  
Therapeutic Drug ◽  
High Dose ◽  
Patient Groups

The utility of Therapeutic Drug Monitoring (TDM) in the setting of childhood cancer is a largely underused tool, despite the common use of cytotoxic chemotherapeutics. While it is encouraging that modern advances in chemotherapy have transformed outcomes for children diagnosed with cancer, this has come at the cost of an elevated risk of life-changing long-term morbidity and late effects. This concern can limit the intensity at which these drugs are used. Widely used chemotherapeutics exhibit marked inter-patient variability in drug exposures following standard dosing, with fine margins between exposures resulting in toxicity and those resulting in potentially suboptimal efficacy, thereby fulfilling criteria widely accepted as fundamental for TDM approaches. Over the past decade in the UK, the paediatric oncology community has increasingly embraced the potential benefits of utilising TDM for particularly challenging patient groups, including infants, anephric patients and those receiving high dose chemotherapy. This has been driven by a desire from paediatric oncologists to have access to clinical pharmacology information to support dosing decisions being made. This provides the potential to modify doses between treatment cycles based on a comprehensive set of clinical information, with individual patient drug exposures being used alongside clinical response and tolerability data to inform dosing for subsequent cycles. The current article provides an overview of recent experiences of conducting TDM in a childhood cancer setting, from the perspectives of the clinicians, scientists and pharmacists implementing TDM-based dosing recommendations. The ongoing programme of work has facilitated investigations into the validity of current approaches to dosing for some of the most challenging childhood cancer patient groups, with TDM approaches now being expanded from well-established cytotoxic drugs through to newer targeted treatments.

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