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

• Status: Recruiting
• Trial end date: 2028-01-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centre Oscar Lambret
• Collaborators: Anticancer Fund, Belgium; Bristol-Myers Squibb; CTD-CNO
• Treatments: Antibodies, Monoclonal; Capecitabine; Cyclophosphamide; Nivolumab; Vinblastine

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 (this criterion is applicable to stage 1 only)

• Histologically proven diagnosis of: embryonal brain tumor, ependymoma, low-grade glioma (LGG), rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and other solid tumors and after approval from coordinators (except high grade glioma, 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 > 4 to < 18 years of age at inclusion; patients 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.

• Patient able to comfortably swallow capsules.

• 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.

EXCLUSION CRITERIA:

• Leukemia

• Diagnosis of lymphoma, high grade glioma (HGG) including 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.

• 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

• History of organ transplant

• Severe infections requiring parenteral antibiotic therapy

• Active tuberculosis

• History of interstitial lung disease