Abstract CT004: European pediatric precision medicine program in recurrent tumors: first results from MAPPYACTS molecular profiling trial towards AcSe-ESMART proof-of-concept study

Geoerger, Birgit; Schleiermacher, Gudrun; Lacroix, Ludovic; Deloger, Marc; Bessoltane, Nadia; Harttrampf, Anne C.; Michiels, Stefan; Scoazec, Jean Yves; Fréneaux, Paul; Paolettí, Xavier; Delattre, Olivier; Hoog-Labouret, Natalie; Vassal, Gilles

doi:10.1158/1538-7445.am2017-ct004

Cited by 9 publications

(6 citation statements)

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“…We have therefore developed a multiarm, proof-of-concept trial (AcS e-ESMART, NCT02813135), which currently covers the most frequently detected altered pathways. This trial aims to determine through an enrichment strategy if theoretically "actionable" alterations in the targeted pathways may bring a clinical benefit to the patient (44). However, translating biological findings into clinical benefit should be the most challenging part in the current precision medicine approach.…”

Section: Discussionmentioning

confidence: 99%

Molecular Screening for Cancer Treatment Optimization (MOSCATO-01) in Pediatric Patients: A Single-Institutional Prospective Molecular Stratification Trial

Harttrampf

Lacroix

Deloger

et al. 2017

Clinical Cancer Research

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103

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This single-institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients to select a targeted therapy. Following treatment failure, patients with signed consent and ages above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next-generation sequencing for 75 target genes, whole-exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board. From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor, and 63.0% had an extra-cranial solid tumor. Median tumor cell content was 70% (range, 0%-100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy-number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment before inclusion. Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART. .

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Section: Discussionmentioning

confidence: 99%

Molecular Screening for Cancer Treatment Optimization (MOSCATO-01) in Pediatric Patients: A Single-Institutional Prospective Molecular Stratification Trial

Harttrampf

Lacroix

Deloger

et al. 2017

Clinical Cancer Research

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103

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“…On average, from 40% to 92% of patients were treated at a correct dose (15-26 for DE-EC, 16-27 for DE-ECext and 14-36 for EffTox). The number of observed toxicities was nearly the same (5)(6)(7)(8). The impact of the proportion of patients nonevaluable for toxicity is given in Table 3.…”

Section: Simulations Methodsmentioning

confidence: 82%

“…As a motivating example, we used the platform trial AcSe´-ESMART (NCT02813135) (European proof of concept of therapeutic Stratification trial of Molecular Anomalies in Relapsed or Refractory Tumours in children) of 10 Phase I/II parallel arms on children with malignancies that were recurrent or refractory to standard therapy. 8 Each arm is designed with a dose-finding part based on toxicity evaluation assuming that the activity increases with increasing doses, followed by an expansion cohort to evaluate the chance of activity.…”

Section: Introductionmentioning

confidence: 99%

Sequential or combined designs for Phase I/II clinical trials? A simulation study

et al. 2019

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Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy–toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. Methods: In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy–toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. Results: For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy–toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Conclusion: As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.

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“…AcS é-ESMART (Access Secured-European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors) is a proof-ofconcept, phase I or II, platform trial, designed to explore the targeting of cancer survival pathways in a molecularly enriched pediatric patient population (NCT02813135). 4 The cell cycle is tightly regulated by cyclin-dependent kinases (CDKs) that are activated by intermittently expressed cyclins. 5 CDK4 and CDK6 phosphorylate the retinoblastoma gene product (Rb), leading to the subsequent release of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial

Bautista

Paolettí

Rubino

et al. 2021

JCO

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PURPOSE AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) and ribociclib 175 mg/m2 once a day and everolimus 2.5 mg/m2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.

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Abstract CT004: European pediatric precision medicine program in recurrent tumors: first results from MAPPYACTS molecular profiling trial towards AcSe-ESMART proof-of-concept study

Cited by 9 publications

References 0 publications

Molecular Screening for Cancer Treatment Optimization (MOSCATO-01) in Pediatric Patients: A Single-Institutional Prospective Molecular Stratification Trial

Molecular Screening for Cancer Treatment Optimization (MOSCATO-01) in Pediatric Patients: A Single-Institutional Prospective Molecular Stratification Trial

Sequential or combined designs for Phase I/II clinical trials? A simulation study

Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial

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