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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

Studienbeginn:
August 2016

Letztes Update:
30.05.2023

Wirkstoff:
Ribociclib, Topotecan, Temozolomide, Everolimus, Adavosertib, Carboplatin, Olaparib, Irinotecan, Vistusertib, Nivolumab, Cyclophosphamide, Selumetinib, Enasidenib, Lirilumab, Fadraciclib, Cytarabine, Dexamethasone, Ceralasertib, Futibatinib, Capmatinib

Indikation (Clinical Trials):
Congenital Abnormalities

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Gustave Roussy, Cancer Campus, Grand Paris

Collaborator:
National Cancer Institute, France

Studienleiter

Birgit Geoerger, MD
Study Chair
Gustave Roussy, Cancer Campus, Grand Paris

Kontakt

Birgit Geoerger, MD
Kontakt:
Phone: +33 (0)1 42 11 46 61
E-Mail: birgit.geoerger@gustaveroussy.fr» Kontaktdaten anzeigen

Jonathan Rubino, MS
Kontakt:
Phone: +33 (0)1 42 11 58 87
E-Mail: jonathan.rubino@gustaveroussy.fr» Kontaktdaten anzeigen

Studienlocations
(3 von 7)

University Children's Hospitalermany
Heidelberg
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Olaf Witt, MD
Phone: +49 6221 56 4555
E-Mail: O.Witt@Dkfz-Heidelberg.de» Ansprechpartner anzeigen

Rigshospitalet
2100 Copenhagen
DenmarkNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Karsten Nyson, MD
Phone: +45 35 45 08 09
E-Mail: karsten.nysom@regionh.dk» Ansprechpartner anzeigen

Gustave Roussy
94805 Villejuif
FranceRekrutierend» Google-Maps
Ansprechpartner:
Birgit Geoerger, MD
Phone: +33 (0)1 42 11 46 61
E-Mail: birgit.geoerger@gustaveroussy.fr

Jonathan Rubino, MS
Phone: +33 (0)1 42 11 58 87
E-Mail: jonathan.rubino@gustaveroussy.fr» Ansprechpartner anzeigen

Fondazione IRCCS Istituto Nazionale dei Tumori
Milan
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Michela Casanova, MD
Phone: +39 02 23 90 25 94
E-Mail: Michela.Casanova@istitutotumori.mi.it» Ansprechpartner anzeigen

Erasmus MC, Sophia Children's Hospital
Rotterdam
NetherlandsAktiv, nicht rekrutierend» Google-Maps

Unidad de Oncología Pediátrica Hospital Niño Jesús
28009 Madrid
SpainRekrutierend» Google-Maps
Ansprechpartner:
Alba Rubio, MD
Phone: +43 915 03 59 00
E-Mail: franciscojose.bautista@salud.madrid.org» Ansprechpartner anzeigen

Pediatric and Adolescent Oncology The Royal Marsden Hospital
Sutton
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Lynley Marshall, MD
Phone: +44 208 661 3678
E-Mail: Lynley.Marshall@icr.ac.uk» Ansprechpartner anzeigen

Alle anzeigen

Studien-Informationen

Detailed 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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Recommended phase II dose (RP2D) (Time Frame - During the first cycle):
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)

2. Maximum Tolerated Dose (MTD) (Time Frame - During the first cycle):
The MTD will be defined as the dose associated with or closest to 25% of Dose Limiting Toxicities (DLTs)

3. Objective Response Rate (ORR) (Time Frame - During treatment period):
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.

Secondary outcome:

1. Pharmacokinetics (PK) (Time Frame - Depending on the treatment arm):
To characterize single or multiple-dose PK of the agent(s)

2. Progression Free Survival (PFS) (Time Frame - From treatment initiation until the date of first documented progression or death):
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.

3. Evaluation of duration of response (DoR) (Time Frame - Between the first document response and the time of first documented progression):
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.

Studien-Arme

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.
Experimental: Arm B. Ribociclib + Everolimus
Ribociclib capsules or oral solution orally QD for 21 days of each 28 day cycle; Everolimus orodispersible tablets orally QD for 28 days.
Experimental: ARM C. Adavosertib + Carboplatin
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.
Experimental: Arm D. Olaparib + Irinotecan
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.
Experimental: Arm E. Vistusertib single agent
Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle.
Experimental: Arm F. Vistusertib + Topotecan and Temozolomide
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.
Experimental: Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy
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.
Experimental: Arm H. Selumetinib + Vistusertib
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.
Experimental: Arm I. Enasidenib
Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle.
Experimental: Arm J. Lirilumab + Nivolumab
Nivolumab iv QD on Day 1 and 15 of a 28 day cycle; Lirilumab iv QD on Day 1 of a 28 day cycle
Experimental: Arm K. Fadraciclib (CYC065) + Temozolomide
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
Experimental: Arm L. Fadraciclib (CYC065) + Cytarabine
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
Experimental: Arm M. Ribociclib + Everolimus +/- Dexamethasone
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.
Experimental: Arm N. Ceralasertib (AZD6738) + Olaparib
Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle
Experimental: Arm O. Futibatinib (TAS-120)
Futibatinib tablets orally on a continuous dosing QD per 28 day cycle
Experimental: Arm P. Capmatinib (INC280) + Everolimus
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.

Geprüfte Regime

Ribociclib (Kisqali / LEE011 / )
Topotecan (Hycamtin)
Temozolomide (Temodar)
Everolimus (Afinitor)
Adavosertib (AZD1775)
Carboplatin (Paraplatin)
Olaparib (Lynparza)
Irinotecan (Camptosar / CPT-11 / )
Vistusertib (AZD2014)
Nivolumab (Opdivo)
Cyclophosphamide (Cytoxan)
Selumetinib (Koselugo)
Enasidenib (Idhifa)
Lirilumab (BMS-986015)
Fadraciclib (CYC065)
Cytarabine (Arabinosylcytosine / Cytosar-U / )
Dexamethasone (Decadron / Dexasone / Diodex / Hexadrol / Maxidex / )
Ceralasertib (AZD6738)
Futibatinib (Tas-120)
Capmatinib (Tabrecta / INC280 / )

Quelle: ClinicalTrials.gov

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