Nivolumab in Combination With Metronomic Chemotherapy in Paediatrics Refractory / Relapsing Solid Tumors

NCT03585465 | Active Not Recruiting Phase 1 DMC

• 3 other identifiers: Metro-PD1-17082024-513470-22-002018-000096-32
• Study Type: interventional
• Target: 63
• Locations: 2 countries
• Sites: 11

Brief Summary

The study is a two-stage trial:

1. 1.First stage (closed - 16 patients recruited in France):
2. 2.Second stage (opened - 86 patients expected in France and Belgium):
3. 3."Trans-MetroPD1" ancillary sub-study is partially implemented since April 2022, and proposed to patients participating to second stage

Conditions

Childhood Solid Tumor

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicities according to the NCI-CTCAE V5

  First Stage Primary Outcome 3 metronomic CT are : A:Cyclophosphamide + Vinblastine B:Capecitabin C:Cyclophosphamide + Vinblastine + Capecitabin

  Over the first chemotherapy cycle (28 days)

• Progression-free survival according appropriate criteria (RANO, RAPNO, WHO, INRC, RECIST v1.1).

  Second Stage Primary Outcome Metronomic chemotherapy is the same as regimen selected at the end of the first stage

  up to 2 years

Secondary Outcomes (7)

• Adverse events according to the NCI-CTCAE V5.

  up to 2 years

• Tumor response in terms of complete/partial response or stable/progressive disease (using RANO, RAPNO, WHO, INRC, or RECIST v1.1) and overall survival

  up to 2 years

• Dose-intensity for each drug (ratio between the computed dose-intensity, and the protocol dose-intensity)

  up to 2 years

• Description of molecular profile (number of genetic alterations) on individual tumor ; the data will be collected from large-scale analysis programs performed in Europe (Mappyacts, France Genomic 2025) in agreement with the Sponsors

  At study entrance

• Health Related Quality of Life using the age-appropriate KINDL-R questionnaire (self- and proxy-assessment)

  from date of randomization until the date of first documented progression or date corresponding to the end of treatment, assessed up to 24 months

Study Arms (5)

A: Cyclophosphamide Vinblastine Nivolumab

EXPERIMENTAL

This arm was applicable to first stage, and is closed

Drug: Vinblastine; Drug: Cyclophosphamide; Drug: Nivolumab

B: Capecitabine Nivolumab

EXPERIMENTAL

This arm was applicable to first stage, and is closed

Drug: Capecitabine; Drug: Nivolumab

C: Cyclophosphamide Vinblastine Capecitabine

EXPERIMENTAL

This arm was applicable to first stage, and is closed

Drug: Vinblastine; Drug: Cyclophosphamide; Drug: Capecitabine; Drug: Nivolumab

"Metronomic CT "

EXPERIMENTAL

metronomic chemotherapy selected at the end of first stage (C: Cyclophosphamide Vinblastine Capecitabine) This arm is applicable to second stage, and 43 patients are expected

Drug: Vinblastine; Drug: Cyclophosphamide; Drug: Capecitabine

"Metronomic CT + Nivolumab"

EXPERIMENTAL

metronomic chemotherapy selected at the end of first stage (C: Cyclophosphamide Vinblastine Capecitabine) + Nivolumab This arm is applicable to second stage, and 43 patients are expected

Drug: Vinblastine; Drug: Cyclophosphamide; Drug: Capecitabine; Drug: Nivolumab

Interventions

Vinblastine DRUG

* Experimentals Arm A or C (First stage): 2 mg/m2/day IV, weekly per cycle, 28 days cycle * Experimental Arms Metronomic or Metronomic+Nivolumab (second stage): see C

"Metronomic CT "; "Metronomic CT + Nivolumab"; A: Cyclophosphamide Vinblastine Nivolumab; C: Cyclophosphamide Vinblastine Capecitabine

Cyclophosphamide DRUG

* Arm A (First stage): 30 mg/m2/day PO, D1-4// D8-11// D15-18// D22-25 per cycle, 28 days cycle * Arm C (First stage): 30 mg/m2/day PO, D1-D4// D15-D18 per cycle, 28 days cycle * Metronomic or Metronomic+Nivolumab Arm (second stage): see C

"Metronomic CT "; "Metronomic CT + Nivolumab"; A: Cyclophosphamide Vinblastine Nivolumab; C: Cyclophosphamide Vinblastine Capecitabine

Capecitabine DRUG

* Arm B (First stage): 400 to 600 mg/m2/day PO, all days per cycle, 28 days cycle * Arm C (First stage): 400 to 600 mg/m2/day PO, D8-D11// D22-D25 per cycle, 28 days cycle * Metronomic or Metronomic+Nivolumab Arm (second stage): see C

"Metronomic CT "; "Metronomic CT + Nivolumab"; B: Capecitabine Nivolumab; C: Cyclophosphamide Vinblastine Capecitabine

Nivolumab DRUG

* Arm A, B or C (First stage): 3 mg/kg IV, D1 \& D15 per cycle, 28 days cycle * Metronomic+Nivolumab Arm (second stage): 3 mg/kg IV, D1 \& D15 per cycle, 28 days cycle

"Metronomic CT + Nivolumab"; A: Cyclophosphamide Vinblastine Nivolumab; B: Capecitabine Nivolumab; C: Cyclophosphamide Vinblastine Capecitabine

Eligibility Criteria

• Age: 0 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Histologically proven diagnosis of solid malignant tumor. Confirmed progressive or refractory disease despite standard therapy or for which no effective standard therapy exists
• Histologically proven diagnosis of: embryonal brain tumor ; ependymoma ; low-grade glioma (LGG) ; high-grade glioma (HGG) except diffuse Intrinsic Pontine glioma (DIPG) Supratentorial Diffuse Midline Glioma K27M mutated are eligible ; rhabdomyosarcoma ; neuroblastoma ; Ewing sarcoma ; and other solid tumors and after approval from coordinators (except DIPG, osteosarcoma, lymphoma), and confirmed progressive or refractory disease despite standard therapy or for which no effective standard therapy exists (this criterion is applicable to stage 2 only)
• Evaluable or measurable disease as defined by adequate standard imaging criteria for each patient's tumor type (see corresponding appendices for definition of evaluable and/or measurable lesions):
• RANO criteria for patients with high grade glioma (HGG), who are eligible at stage 1 only
• RAPNO criteria for patients with low grade glioma
• WHO for other cerebral tumors
• INRC criteria for patients with neuroblastoma (NB),
• RECIST v1.1 for tumors other than cerebral tumors and neuroblastoma
• 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
• Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3 (unsupported)
• White blood cells count ≥ 2500/mm3
• Platelet count ≥ 100,000/mm3 (unsupported)

You may not qualify if:

• Leukemia
• Diagnosis of lymphoma, diffuse intrinsic pontine glioma or osteosarcoma (for stage 2 only)
• 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 requiring high doses of corticosteroids \>0.25mg/kg prednisolone or equivalent) or increasing doses of corticosteroids during the 7 days prior to receiving study drug.
• For patients with CNS tumor:
• o Evidence of \> Grade 1 recent CNS hemorrhage on the baseline MRI scan.
• o Participants with bulky tumor on imaging are ineligible; bulky tumor is defined as: i) Tumor with any evidence of uncal herniation or severe midline shift ii) Tumor with diameter of \> 6 cm in one dimension on contrast-enhanced MRI iii) Tumor that in the opinion of the investigator, shows significant mass effect
• 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 within 12 months of screening)
• Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Active autoimmune disease requiring immunosuppressive treatment
• Known congenital immunodeficiency
• Presence of any NCI-CTCAE v5 grade ≥ 2 treatment-related extra-hematological 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, 6 weeks in case of nitrosourea.
• No clinical benefit with previous antiPD1 or antiPDL1 treatment (SD during a period inferior to 6 months, or PD).

Sponsors & Collaborators

• Centre Oscar Lambret: lead
• Anticancer Fund, Belgium: collaborator
• Bristol-Myers Squibb: collaborator
• CTD-CNO: collaborator
• ECS-Progastrin SA: collaborator

Study Sites (11)

Cliniques Universitaires Saint-Luc (CUSL)

Brussels, Belgium

Location

University Hospital Ghent

Ghent, Belgium

Location

University Hospital Leuven

Leuven, Belgium

Location

Centre Oscar Lambret

Lille, France

Location

Centre Léon Bérard (IHOPe)

Lyon, France

Location

Hôpital La Timone, AP-HM

Marseille, France

Location

Hôpital d'Enfants - CHRU Nancy

Nancy, France

Location

Hôpital Mère-Enfant, CHU Nantes

Nantes, France

Location

Institut Curie

Paris, France

Location

Hôpital de Hautepierre, CHRU Strasbourg

Strasbourg, France

Location

Hôpital des Enfants - CHU Toulouse

Toulouse, France

Location

MeSH Terms

Interventions

Vinblastine; Cyclophosphamide; Capecitabine; Nivolumab

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Pierre LEBLOND, MD

  Centre Oscar Lambret

  STUDY DIRECTOR

• Nicolas ANDRE, MD

  CHU La Timone

  STUDY DIRECTOR

• Leen WILLEMS, MD

  University Hospital, Ghent

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2018
• First Posted: July 13, 2018
• Study Start: March 26, 2019
• Primary Completion: December 31, 2025
• Study Completion (Estimated): January 1, 2027
• Last Updated: March 18, 2026

Record last verified: 2026-03

Locations

FR (8); BE (3)