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

Study Overview
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Brief Summary
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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: 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 To explore first signals of activity in a molecularly enriched study population.

Detailed Description
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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.

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

Conditions
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Pediatric Cancer

Intervention / Treatment
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* Drug: Ribociclib
* Drug: Topotecan
* Drug: Temozolomide
* Drug: Everolimus
* Drug: Adavosertib
* Drug: Carboplatin
* Drug: Olaparib
* Drug: Irinotecan
* Drug: Vistusertib
* Drug: Nivolumab
* Drug: Cyclophosphamide
* Drug: Selumetinib
* Drug: Enasidenib
* Drug: Lirilumab
* Drug: Fadraciclib
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Ceralasertib
* Drug: Futibatinib
* Drug: Capmatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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. 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.). Patients with relapsed or refractory leukemia are eligible for this study. 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. Life expectancy ≥ 3 months 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. Able to comply with scheduled follow-up and with management of toxicity. 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 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. 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. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements. Exclusion Criteria: 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. 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). 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) Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose 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. 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). 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. Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8). 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). Known hypersensitivity to any study drug or component of the formulation. Pregnant or nursing (lactating) females. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A. Ribociclib + Topotecan and Temozolomide<br>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<br> <br> * Other names: LEE011;Drug: Topotecan<br> <br> * Other names: Hycamtin;Drug: Temozolomide<br> <br> * Other names: Temodar;|
| Experimental: Arm B. Ribociclib + Everolimus<br>Ribociclib capsules or oral solution orally QD for 21 days of each 28 day cycle; Everolimus orodispersible tablets orally QD for 28 days. | Drug: Ribociclib<br> <br> * Other names: LEE011;Drug: Everolimus<br> <br> * Other names: Afinitor;|
| Experimental: ARM C. Adavosertib + Carboplatin<br>Adavosertib 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: Adavosertib<br> <br> * Other names: AZD1775;Drug: Carboplatin<br> <br> * Other names: Paraplatin;|
| Experimental: Arm D. Olaparib + Irinotecan<br>Olaparib tablets orally BID on Day 1-10 of a 21 day cycle Irinotecan iv QD on Day 4-8 of a 21 day cycle. | Drug: Olaparib<br> <br> * Other names: Lynparza;Drug: Irinotecan<br> <br> * Other names: CPT-11;|
| Experimental: Arm E. Vistusertib single agent<br>Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle. | Drug: Vistusertib<br> <br> * Other names: AZD2014;|
| Experimental: Arm F. Vistusertib + Topotecan and Temozolomide<br>Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Vistusertib tablets orally BID 3 days on/4 days off per week of a 28 day cycle. | Drug: Topotecan<br> <br> * Other names: Hycamtin;Drug: Temozolomide<br> <br> * Other names: Temodar;Drug: Vistusertib<br> <br> * Other names: AZD2014;|
| Experimental: Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy<br>Nivolumab iv QD every 2 weeks of a 28 day cycle (Days 1 and 15); Cyclophosphamide tablets or oral solution orally BID, 1 week on/1 week off; Palliative irradiation/radiofrequency/cryotherapy starting 2 weeks after the first nivolumab injection. | Drug: Nivolumab<br> <br> * Other names: Opdivo;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;|
| Experimental: Arm H. Selumetinib + Vistusertib<br>Selumetinib capsules twice daily on a continous administration. Vistusertib orally twice daily on an intermittent schedule : 2 days on / 5 days off per week of a 28 day cycle. | Drug: Vistusertib<br> <br> * Other names: AZD2014;Drug: Selumetinib<br> <br> * Other names: Koselugo;|
| Experimental: Arm I. Enasidenib<br>Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle. | Drug: Enasidenib<br> <br> * Other names: Idhifa;|
| Experimental: Arm J. Lirilumab + Nivolumab<br>Nivolumab iv QD on Day 1 and 15 of a 28 day cycle; Lirilumab iv QD on Day 1 of a 28 day cycle | Drug: Nivolumab<br> <br> * Other names: Opdivo;Drug: Lirilumab<br> <br> * Other names: BMS-986015;|
| Experimental: Arm K. Fadraciclib (CYC065) + Temozolomide<br>Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Temozolomide capsules orally QD on Day 1-5 of a 28 day cycle | Drug: Temozolomide<br> <br> * Other names: Temodar;Drug: Fadraciclib<br> <br> * Other names: CYC065;|
| Experimental: Arm L. Fadraciclib (CYC065) + Cytarabine<br>Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Cytarabine iv or sc on Day 2-5 and Day 8-11 of a 28 day cycle | Drug: Fadraciclib<br> <br> * Other names: CYC065;Drug: Cytarabine<br> <br> * Other names: Cytosar-U;|
| Experimental: Arm M. Ribociclib + Everolimus +/- Dexamethasone<br>Ribociclib capsules or tablets orally QD on Day 1-21 of a 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle. For patients with leukemia and lymphoma: Dexamethasone orally or iv on Day 1-7 of each 28 day cycle. For patients with ALL, AML and Non-Hodgkin Lymphoma (NHL), Intrathecal chemotherapy will be administered additionally as per standard practice depending on CNS status. | Drug: Ribociclib<br> <br> * Other names: LEE011;Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Dexamethasone<br> <br> * Other names: Maxidex;|
| Experimental: Arm N. Ceralasertib (AZD6738) + Olaparib<br>Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle | Drug: Olaparib<br> <br> * Other names: Lynparza;Drug: Ceralasertib<br> <br> * Other names: AZD6738;|
| Experimental: Arm O. Futibatinib (TAS-120)<br>Futibatinib tablets orally on a continuous dosing QD per 28 day cycle | Drug: Futibatinib<br> <br> * Other names: Tas-120;|
| Experimental: Arm P. Capmatinib (INC280) + Everolimus<br>Capmatinib tablets orally on a continuous dosing BID per 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle. | Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Capmatinib<br> <br> * Other names: INC280;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) | To characterize single or multiple-dose PK of the agent(s) | Depending on the treatment arm | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, Adolescents, Young adults, Recurrent malignancies, Refractory malignancies