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

ConditionPediatric Cancer

Trial statusRecruiting

Trial phasePhase 1, Phase 2

Trial typeInterventional

Biological sexAll

AgeUp to 18

SponsorGustave Roussy, Cancer Campus, Grand Paris

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.).

Disqualifiers

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.

Trial design

Design model

Parallel

Treatments tested in this trial

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
Drug
Avelumab
Drug
Peposertib
Drug
Capivasertib
Drug
Vinorelbine
Drug

Treatment groups

472 Participants

are divided into 18 treatment groups

Treatment groups

See each treatment group below.

Group A: Arm A. Ribociclib + Topotecan and TemozolomideExperimental treatment 3 interventions

Group B: Arm B. Ribociclib + EverolimusExperimental treatment 2 interventions

Group C: ARM C. Adavosertib + CarboplatinExperimental treatment 2 interventions

Group D: Arm D. Olaparib + IrinotecanExperimental treatment 2 interventions

Group E: Arm E. Vistusertib single agentExperimental treatment 1 intervention

Group F: Arm F. Vistusertib + Topotecan and TemozolomideExperimental treatment 3 interventions

Group G: Arm G. Nivolumab + Cyclophosphamide +/- RadiotherapyExperimental treatment 2 interventions

Group H: Arm H. Selumetinib + VistusertibExperimental treatment 2 interventions

Group I: Arm I. EnasidenibExperimental treatment 1 intervention

Group J: Arm J. Lirilumab + NivolumabExperimental treatment 2 interventions

Group K: Arm K. Fadraciclib (CYC065) + TemozolomideExperimental treatment 2 interventions

Group L: Arm L. Fadraciclib (CYC065) + CytarabineExperimental treatment 2 interventions

Group M: Arm M. Ribociclib + Everolimus +/- DexamethasoneExperimental treatment 3 interventions

Group N: Arm N. Ceralasertib (AZD6738) + OlaparibExperimental treatment 2 interventions

Group O: Arm O. Futibatinib (TAS-120)Experimental treatment 1 intervention

Group P: Arm P. Capmatinib (INC280) + EverolimusExperimental treatment 2 interventions

Group Q: Arm Q. Peposertib + Avelumab and Metronomic TemozolomideExperimental treatment 3 interventions

Group R: Arm R. Capivasertib + metronomic VinorelbineExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

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)

Time frame

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)

Time frame

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.

Time frame

During treatment period

Secondary outcomes

Pharmacokinetics (PK)

To characterize single or multiple-dose PK of the agent(s)

Time frame

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.

Time frame

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.

Time frame

Between the first document response and the time of first documented progression