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

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ClinicalTrials.gov Identifier: NCT03585465
Recruitment Status : Recruiting
First Posted : July 13, 2018
Last Update Posted : May 11, 2021
Sponsor:
Collaborators:
Anticancer Fund, Belgium
Bristol-Myers Squibb
CTD-CNO
Information provided by (Responsible Party):
Centre Oscar Lambret

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.


Condition or disease Intervention/treatment Phase
Childhood Solid Tumor Drug: Vinblastine Drug: Cyclophosphamide Drug: Capecitabine Drug: Nivolumab Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Metro-PD1: a Phase I/II Trial Evaluating Anti-PD1 (Nivolumab) in Combination With Metronomic Chemotherapy in Children and Teenagers With Refractory / Relapsing Solid Tumors
Actual Study Start Date : March 26, 2019
Estimated Primary Completion Date : May 2025
Estimated Study Completion Date : January 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: A: Cyclophosphamide Vinblastine Nivolumab
This arm was applicable to first stage, and is closed
Drug: 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

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

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

Experimental: B: Capecitabine Nivolumab
This arm was applicable to first stage, and is closed
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

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

Experimental: C: Cyclophosphamide Vinblastine Capecitabine
This arm was applicable to first stage, and is closed
Drug: 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

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

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

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

Experimental: "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

Drug: 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

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

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

Experimental: "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

Drug: 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

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

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

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




Primary Outcome Measures :
  1. Dose Limiting Toxicities according to the NCI-CTCAE V5 [ Time Frame: Over the first chemotherapy cycle (28 days) ]
    First Stage Primary Outcome 3 metronomic CT are : A:Cyclophosphamide + Vinblastine B:Capecitabin C:Cyclophosphamide + Vinblastine + Capecitabin

  2. Progression-free survival according appropriate criteria (RANO, RAPNO, WHO, INRC, RECIST v1.1). [ Time Frame: up to 2 years ]
    Second Stage Primary Outcome Metronomic chemotherapy is the same as regimen selected at the end of the first stage


Secondary Outcome Measures :
  1. Adverse events according to the NCI-CTCAE V5. [ Time Frame: up to 2 years ]
    First Stage Secondary Outcome 1 & Second Stage Secondary Outcome 1

  2. Tumor response in terms of complete/partial response or stable/progressive disease (using RANO, RAPNO, WHO, INRC, or RECIST v1.1) and overall survival [ Time Frame: up to 2 years ]
    Second Stage Secondary Outcome 2

  3. Dose-intensity for each drug (ratio between the computed dose-intensity, and the protocol dose-intensity) [ Time Frame: up to 2 years ]
    First Stage Secondary Outcome 2 & Second Stage Secondary Outcome 3



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03585465


Contacts
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Contact: Alicia PROBST +33320295918 promotion@o-lambret.fr

Locations
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Belgium
Cliniques Universitaires Saint-Luc (CUSL) Active, not recruiting
Brussel, Belgium
University Hospital Ghent Active, not recruiting
Gent, Belgium
University Hospital Leuven Active, not recruiting
Leuven, Belgium
France
Centre Oscar Lambret Recruiting
Lille, France
Contact: Anne-Sophie DEFACHELLES         
Centre Léon Bérard (IHOPe) Recruiting
Lyon, France
Contact: Pierre LEBLOND         
Hôpital La Timone, AP-HM Recruiting
Marseille, France
Contact: Nicolas ANDRE         
Hôpital d'Enfants - CHRU Nancy Active, not recruiting
Nancy, France
Hôpital Mère-Enfant, CHU Nantes Active, not recruiting
Nantes, France
Institut Curie Recruiting
Paris, France
Contact: Isabelle AERTS         
Hôpital de Hautepierre, CHRU Strasbourg Recruiting
Strasbourg, France
Contact: Natacha ENTZ-WERLE         
Hôpital des Enfants - CHU Toulouse Active, not recruiting
Toulouse, France
Sponsors and Collaborators
Centre Oscar Lambret
Anticancer Fund, Belgium
Bristol-Myers Squibb
CTD-CNO
Investigators
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Study Director: Pierre LEBLOND, MD Centre Oscar Lambret
Study Director: Nicolas ANDRE, MD CHU La Timone
Study Director: Leen WILLEMS, MD University Hospital, Ghent
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Responsible Party: Centre Oscar Lambret
ClinicalTrials.gov Identifier: NCT03585465    
Other Study ID Numbers: Metro-PD1-1708
First Posted: July 13, 2018    Key Record Dates
Last Update Posted: May 11, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Cyclophosphamide
Capecitabine
Nivolumab
Vinblastine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents, Immunological
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators