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

NCT ID: NCT03585465

Last Updated: 2026-01-23

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 63 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-26
• Study Completion Date: 2027-01-31

Brief Summary

The study is a two-stage trial:

1. First stage (closed - 16 patients recruited in France):

Phase I feasibility trial to evaluate the safety of the combination of Nivolumab + metronomic chemotherapy considering three possible metronomic chemotherapy regimens

2. Second stage (opened - 86 patients expected in France and Belgium):

Phase II randomized controlled balanced 1:1 open-label trial comparing the efficacy of the metronomic chemotherapy regimen selected at the end of the previous stage (arm C: cyclophosphamide, capecitabine, vinblastine), with or without nivolumab.

3. "Trans-MetroPD1" ancillary sub-study is partially implemented since April 2022, and proposed to patients participating to second stage

Detailed Description

1. First stage (closed):

• Arm A: Nivolumab + Cyclophosphamide-Vinblastine
• Arm B: Nivolumab + Capecitabin
• Arm C: Nivolumab + Cyclophosphamide-Vinblastine + Capecitabin

Arm A and Arm B have been allocated sequentially (A/B/A/B/A/B). Arm C has been opened, since arm A and Arm B were deemed safe.

In each arm, the second patient was not recruited before the first patient has been observed for a 28-day duration.

2. Second stage (opened):

Following the analysis of safety data from first stage, and according to IDMC's recommendations on December 2020, the metronomic chemotherapy selected for second stage was arm C: cyclophosphamide, capecitabine, vinblastine

Randomization will be balanced 1:1, controlling for:

• histological type: embryonal brain tumor, ependymoma, low-grade glioma, rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and other solid tumors after approval from coordinators,
• and treating center, using a dynamic allocation of treatment (minimization program) with a random factor set at 0.8.

3. Trans-MetroPD1 is divided into 3 axes:

• to evaluate the health-related quality of life
• to measure the kinectis of progastrin/hPG80, a biomarker over-expressed in a wide range of cancers
• to determine the distribution of immune cells within blood tissue

Conditions

Childhood Solid Tumor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A: Cyclophosphamide Vinblastine Nivolumab

This arm was applicable to first stage, and is closed

Group Type: EXPERIMENTAL

Vinblastine

Intervention Type: 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

Cyclophosphamide

Intervention Type: 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

Nivolumab

Intervention Type: 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

B: Capecitabine Nivolumab

This arm was applicable to first stage, and is closed

Group Type: EXPERIMENTAL

Capecitabine

Intervention Type: 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

Nivolumab

Intervention Type: 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

C: Cyclophosphamide Vinblastine Capecitabine

This arm was applicable to first stage, and is closed

Group Type: EXPERIMENTAL

Vinblastine

Intervention Type: 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

Cyclophosphamide

Intervention Type: 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

Capecitabine

Intervention Type: 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

Nivolumab

Intervention Type: 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 "

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

Group Type: EXPERIMENTAL

Vinblastine

Intervention Type: 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

Cyclophosphamide

Intervention Type: 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

Capecitabine

Intervention Type: 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 + Nivolumab"

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

Group Type: EXPERIMENTAL

Vinblastine

Intervention Type: 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

Cyclophosphamide

Intervention Type: 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

Capecitabine

Intervention Type: 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

Nivolumab

Intervention Type: 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

Interventions

Vinblastine

• 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

Intervention Type: DRUG

Cyclophosphamide

• 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

Intervention Type: DRUG

Capecitabine

• 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

Intervention Type: DRUG

Nivolumab

• 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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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)
• Male and female subjects < 18 years of age at inclusion; patients of 18 years and older may be included after discussion with the sponsor if they had a pediatric recurrent/refractory malignancy diagnosed before the age of 18.
• 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)
• 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) < 3 x ULN;
• aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT < 3 x ULN
• Able to comply with scheduled follow-up and with management of toxicity.
• Females of child bearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment.
• Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for 6 months after stopping the study drug for young men, and for 12 months after stopping the study drug for young women
• Patients on stable doses of corticosteroids (≤0.25 mg/kg prednisolone or equivalent) for at least 7 days prior to receiving study drug may be included.
• 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.
• Patients can have received prior treatment with antiPD1 or antiPDL1 if at least SD for 6 months or PR or CR was obtained.
• Patients with a known partial deficiency of dihydro-pyrimidine-deshydrogenase (DPD) activity are eligible, and must have an uracilemia value ≥16ng/ml and <150ng/ml
• Adult patient (or parents/legal representatives if patient is minor) understand the preparation process of soluble capecitabine, and are able to reconstitute oral solution of capecitabine at home

• Patient or parents/legal representative has/have given written informed consent to participate to all or part of Trans-MetroPD1 study
• If patient or parents/legal representative agrees to participate to the dosage of circulating progastrin only, patient body weight must be ≥ 8 kg to allow sample collection while respecting blood volume limits in paediatric population
• If patient or parents/legal representative agrees to participate to immune cells count only, or both immune cells count and dosage of circulating progastrin, patient body weight must be ≥ 54 kg to allow sample collection while respecting blood volume limits in paediatric population

Exclusion Criteria

• 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).
• 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.
• Known hypersensitivity to any study drug or component of the formulation.
• Absence of effective contraception in patients of childbearing age
• Pregnant or nursing (lactating) females.
• Vaccination with live, attenuated vaccines within 4 weeks of the first dose of the study drugs except inactivated vaccines.
• Patient with a known complete absence of DPD activity; it is known that patients carrying some homozygous or heterozygous mutations of DPYD responsible for the complete or almost complete absence of enzymatic activity of DPD, are exposed to a maximum risk of life-threatening or fatal toxicity ; patients with a complete deficiency of DPD activity (uracilemia ≥150ng/ml) should not be included in the trial neither treated with capecitabine
• Patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases)
• Acute urinary tract infection, pre-existing hemorrhagic cystitis; obstruction of the urinary tract
• History of organ transplant
• Severe infections requiring parenteral antibiotic therapy
• Active tuberculosis
• History of interstitial lung disease

• Minimum Eligible Age: 0 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Anticancer Fund, Belgium

OTHER

Sponsor Role: collaborator

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

CTD-CNO

UNKNOWN

Sponsor Role: collaborator

ECS-Progastrin SA

INDUSTRY

Sponsor Role: collaborator

Centre Oscar Lambret

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pierre LEBLOND, MD

Role: STUDY_DIRECTOR

Centre Oscar Lambret

Nicolas ANDRE, MD

Role: STUDY_DIRECTOR

CHU La Timone

Leen WILLEMS, MD

Role: STUDY_DIRECTOR

University Hospital, Ghent

Locations

Cliniques Universitaires Saint-Luc (CUSL)

Brussels, , Belgium

University Hospital Ghent

Ghent, , Belgium

University Hospital Leuven

Leuven, , Belgium

Centre Oscar Lambret

Lille, , France

Centre Léon Bérard (IHOPe)

Lyon, , France

Hôpital La Timone, AP-HM

Marseille, , France

Hôpital d'Enfants - CHRU Nancy

Nancy, , France

Hôpital Mère-Enfant, CHU Nantes

Nantes, , France

Institut Curie

Paris, , France

Hôpital de Hautepierre, CHRU Strasbourg

Strasbourg, , France

Hôpital des Enfants - CHU Toulouse

Toulouse, , France

Countries

Belgium; France

Other Identifiers

2024-513470-22-00

Identifier Type: CTIS

Identifier Source: secondary_id

Metro-PD1-1708

Identifier Type: -

Identifier Source: org_study_id