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

  • STATUS
    Recruiting
  • End date
    Jan 14, 2028
  • participants needed
    102
  • sponsor
    Centre Oscar Lambret
Updated on 14 June 2022

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

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

Details
Condition Childhood Solid Tumor
Treatment Capecitabine, cyclophosphamide, Nivolumab, Vinblastine
Clinical Study IdentifierNCT03585465
SponsorCentre Oscar Lambret
Last Modified on14 June 2022

Eligibility

Yes No Not Sure

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)
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)
Male and female subjects > 4 to < 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
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
Adequate organ function
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
Hematologic criteria - Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3
(unsupported)
Total bilirubin < 1.5 x ULN
White blood cells count ≥ 2500/mm3
Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 3 x ULN
Platelet count ≥ 100,000/mm3 (unsupported)
Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)
Able to comply with scheduled follow-up and with management of toxicity
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)
Patient able to comfortably swallow capsules
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
aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT < 3 x
ULN
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
months or PR or CR was obtained

Exclusion Criteria

For patients with CNS tumor
Leukemia
Active autoimmune disease requiring immunosuppressive treatment
Known congenital immunodeficiency
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
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
o Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan
History of organ transplant
o Participants with bulky tumor on imaging are ineligible; bulky tumor is defined as
Severe infections requiring parenteral antibiotic therapy
i) Tumor with any evidence of uncal herniation or severe midline shift ii) Tumor with
Active tuberculosis
diameter of > 6 cm in one dimension on contrast-enhanced MRI iii) Tumor that in the
History of interstitial lung disease
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
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
Vaccination with live, attenuated vaccines within 4 weeks of the first dose of the
study drugs except inactivated vaccines
Known absence of dihydro-pyrimidine-deshydrogenase (DPD) activity; although a DPD
deficiency can't be precisely defined, 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 and should not be 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
INCLUSION CRITERIA FOR TRANS-METROPD1
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
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