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

Pediatric Cancer Clinical Trial

— ESMART  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02813135
• Other study ID #: 2016-000133-40
• Secondary ID: 2016/2396
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 3, 2016
• Est. completion date: August 2027

Study information

• Verified date: May 2023
• Source: Gustave Roussy, Cancer Campus, Grand Paris
• Contact: Birgit Geoerger, MD
• Phone: +33 (0)1 42 11 46 61
• Email: birgit.geoerger[@]gustaveroussy.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This proof-of-concept platform trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe (Geoerger 2017; Geoerger 2019).

The aims of the trial are:

1. To determine the recommended phase II dose (RP2D) of a specific anticancer agent and/or a relevant combination in a pediatric population, to document its tolerability and

2. To explore first signals of activity in a molecularly enriched study population.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 460
• Est. completion date: August 2027
• Est. primary completion date: August 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Congenital Abnormalities
• Pediatric Cancer

Intervention

Drug:
• Ribociclib

• Topotecan

• Temozolomide

• Everolimus

• Adavosertib

• Carboplatin

• Olaparib

• Irinotecan

• Vistusertib

• Nivolumab

• Cyclophosphamide

• Selumetinib

• Enasidenib

• Lirilumab

• Fadraciclib

• Cytarabine

• Dexamethasone

• Ceralasertib

• Futibatinib

• Capmatinib

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen
France	Gustave Roussy	Villejuif	Val De Marne
Germany	University Children's Hospitalermany	Heidelberg
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan
Netherlands	Erasmus MC, Sophia Children's Hospital	Rotterdam
Spain	Unidad de Oncología Pediátrica Hospital Niño Jesús	Madrid
United Kingdom	Pediatric and Adolescent Oncology The Royal Marsden Hospital	Sutton

Sponsors (2)

Lead Sponsor	Collaborator
Gustave Roussy, Cancer Campus, Grand Paris	National Cancer Institute, France

Countries where clinical trial is conducted

Denmark,  France,  Germany,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recommended phase II dose (RP2D)	Defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and/or PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD)	During the first cycle
Primary	Maximum Tolerated Dose (MTD)	The MTD will be defined as the dose associated with or closest to 25% of Dose Limiting Toxicities (DLTs)	During the first cycle
Primary	Objective Response Rate (ORR)	Defined as the proportion of participants who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators.; In patients with leukemia, ORR is defined as the percentage of patients attaining CR, CRi or CRp.	During treatment period
Secondary	Pharmacokinetics (PK)	To characterize single or multiple-dose PK of the agent(s)	Depending on the treatment arm
Secondary	Progression Free Survival (PFS)	Defined as the time from treatment initiation until the date of first documented progression (clinically or radiologically) or death from any cause. Patients alive and free of progression at the cut-off date will be censored at the last assessment date.	From treatment initiation until the date of first documented progression or death
Secondary	Evaluation of duration of response (DoR)	Defined as the time period between the first documented response (complete response (CR) or partial response (PR)) and the time of progression, according to RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, etc.	Between the first document response and the time of first documented progression