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European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART)

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ClinicalTrials.gov Identifier: NCT02813135
Recruitment Status : Recruiting
First Posted : June 24, 2016
Last Update Posted : February 24, 2021
National Cancer Institute, France
Information provided by (Responsible Party):
Gustave Roussy, Cancer Campus, Grand Paris

Brief Summary:

The first molecular profiling protocols have been launched in Europe (MOSCATO-01 (Geoerger 2014), MAPPYACTS, INFORM, iTHER, SM-PAEDS, etc.) determining multiple actionable alterations in pediatric recurrent cancers. Increasingly, stratified approaches are being implemented to enrich clinical trials of molecularly targeted agents and possibly improve outcomes in specific populations i.e. a molecularly enriched/predictive biomarker-driven approach. The diversity and heterogeneity of the detected molecular alterations and the low number of pediatric patients mandate an adapted, innovative trial design for the attributed treatment options in order to satisfy the current unmet medical need.

This basket trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe.

Condition or disease Intervention/treatment Phase
Children, Adolescents and Young Adults With Refractory or Recurrent Malignancies Drug: Ribociclib Drug: Topotecan Drug: Temozolomide Drug: AZD1775 Drug: Carboplatin Drug: Olaparib Drug: Irinotecan Drug: Nivolumab Drug: Enasidenib Drug: Lirilumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 397 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
Actual Study Start Date : August 3, 2016
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Arm Intervention/treatment
Experimental: ARM A. Ribociclib + Topotecan and Temozolomide
Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Ribociclib capsules or oral solution orally QD from Day 6 to 20 of a 28 day cycle.
Drug: Ribociclib
Drug: Topotecan
Drug: Temozolomide
Experimental: ARM C. AZD1775 + Carboplatin
AZD1775 capsules orally BID 3 days on / 4 days off in week 1; Carboplatin iv QD AUC 5 on Day 1 of a 21 day cycle.
Drug: AZD1775
Drug: Carboplatin
Experimental: ARM D. Olaparib + Irinotecan
Olaparib tablets orally BID on Day 1-10 of a 21 day cycle; Irinotecan iv QD Day 4-8 of a 21 day cycle.
Drug: Olaparib
Drug: Irinotecan
Experimental: Arm I. Enasidenib
Enasidenib orally on a continuous dosing once daily (QD) per 28 day cycle.
Drug: Enasidenib
Experimental: Arm J. Lirilumab + Nivolumab
Nivolumab iv QD every 2 weeks of a 28 day cycle (Days 1 and 15); Lirilumab iv QD every 4 weeks of a 28 day cycle (Day 1)
Drug: Nivolumab
Drug: Lirilumab

Primary Outcome Measures :
  1. Objective tumor response [ Time Frame: Objective tumor response will be measured according to RECIST 1.1 , RANO for HGG and INRC for NB after 56 day ]
  2. Time to progression [ Time Frame: Time to progression will be measured according to RECIST 1.1 , RANO for HGG and INRC for NB after after 56 days ]

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients must be diagnosed with a haematologic or solid tumor malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists.
  2. Age < 18 years at inclusion; patients 18 years and older may be included after discussion with the sponsor if they have a pediatric recurrent/refractory malignancy.
  3. Patient must have had advanced molecular profiling (i.e. WES/WGS +/- RNAseq) of their recurrent or refractory tumor i.e. at the time of disease progression/relapse; exceptionally patients with advanced molecular profiling at diagnosis may be allowed.
  4. Evaluable or measurable disease as defined by standard imaging criteria for the patient's tumor type (RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, Leukemia criteria, etc.).
  5. Patients with relapsed or refractory leukemia are eligible for this study.
  6. Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  7. Life expectancy ≥ 3 months
  8. Adequate organ function:

    Hematologic criteria (Leukemia patients are excluded from hematological criteria):

    • Peripheral absolute neutrophil count (ANC) ≥ 1000/μL(unsupported)
    • Platelet count ≥ 100,000/μL (unsupported)
    • Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)

    Cardiac function:

    • Shortening fraction (SF) >29% (>35% for children < 3 years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy).
    • Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrial arrhythmia.

    Renal and hepatic function:

    • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age
    • Total bilirubin ≤ 1.5 x ULN
    • Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 2,5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2,5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN.
  9. Able to comply with scheduled follow-up and with management of toxicity.
  10. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months (7 months for arm J) after the last study treatment administration. Acceptable contraception are defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials"
  11. For all oral medications patients must be able to comfortably swallow capsules (except for those for which an oral solution is available); nasogastric or gastrostomy feeding tube administration is allowed only if indicated.
  12. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
  13. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion Criteria:

  1. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease. Patients on stable doses of corticosteroids for at least 7 days prior to receiving study drug may be included.
  2. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
  3. Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable ischemia,congestive heart failure within 12 months of screening)
  4. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
  5. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
  6. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less.
  7. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose
  8. Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
  9. Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
  10. Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
  11. Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8).
  12. Currently taking medications that are mainly metabolized by CYP3A4/5, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 and have a low therapeutic index that cannot be discontinued at least 7 days or 5 x reported elimination half-life prior to start of treatment with any of the investigational drugs and for the duration of the study (Refer to Appendix 9).
  13. Known hypersensitivity to any study drug or component of the formulation.
  14. Pregnant or nursing (lactating) females.
  15. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02813135

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Contact: Birgit Geoerger, MD 1 42 11 4661 ext +33 birgit.geoerger@gustaveroussy.fr
Contact: Xavier Paoletti, MD 1 42 11 6564 ext +33 xavier.paoletti@gustaveroussy.fr

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Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Karsten Nyson, MD    35 45 08 09 ext +45    karsten.nysom@regionh.dk   
Gustave Roussy Recruiting
Villejuif, Val De Marne, France, 94805
Contact: Birgit Geoerger, MD    1 42 11 4661 ext +33    birgit.geoerger@gustaveroussy.fr   
Contact: Xavier Paoletti, MD    1 42 11 6564 ext +33    xavier.paoletti@gustaveroussy.fr   
Principal Investigator: Birgit Geoerger, MD         
University Children's Hospitalermany Not yet recruiting
Heidelberg, Germany
Contact: Olaf Witt, MD    6221 56 4555 ext +49    O.Witt@Dkfz-Heidelberg.de   
Fondazione IRCCS Istituto Nazionale dei Tumori Not yet recruiting
Milan, Italy
Contact: Michela Casanova, MD    02 23 90 25 94 ext +39    Michela.Casanova@istitutotumori.mi.it   
Erasmus MC, Sophia Children's Hospital Not yet recruiting
Rotterdam, Netherlands
Contact: Michel Zwaan, MD    10 703 6691 ext +31    c.m.zwaan@erasmusmc.nl   
Unidad de Oncología Pediátrica Hospital Niño Jesús Not yet recruiting
Madrid, Spain, 28009
Contact: Francisco Bautista, MD    915 035 900 ext +43    franciscojose.bautista@salud.madrid.org   
United Kingdom
Pediatric and Adolescent Oncology The Royal Marsden Hospital Not yet recruiting
Sutton, United Kingdom
Contact: Lynley Marshall, MD    208 661 3678 ext +44    Lynley.Marshall@icr.ac.uk   
Sponsors and Collaborators
Gustave Roussy, Cancer Campus, Grand Paris
National Cancer Institute, France
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Study Chair: Birgit Geoerger, MD Gustave Roussy, Cancer Campus, Grand Paris
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Gustave Roussy, Cancer Campus, Grand Paris
ClinicalTrials.gov Identifier: NCT02813135    
Other Study ID Numbers: 2016-000133-40
2016/2396 ( Other Identifier: CSET Number )
First Posted: June 24, 2016    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Congenital Abnormalities
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Poly(ADP-ribose) Polymerase Inhibitors