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Phase I Study of 131-I mIBG Followed by Nivolumab & Dinutuximab Beta Antibodies in Children With Relapsed/Refractory Neuroblastoma (MiniVan)

Primary Purpose

Neuroblastoma

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Nivolumab
Ch14.18/CHO
Sponsored by
University Hospital Southampton NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroblastoma focused on measuring 131-I-mIBG therapy, ch14.18/CHO, Nivolumab, MiniVan

Eligibility Criteria

1 Year - 99 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • At study entry patients must be > 1 year
  • Relapsed or refractory high risk neuroblastoma (as defined by International Neuroblastoma Risk Group (INRG) criteria)
  • MIBG avid disease on imaging within 4 weeks to study entry.
  • ≥ 3 months since any myeloablative chemotherapy / stem cell rescue
  • ≥ 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half lives since last dose of any monoclonal antibody therapy.
  • Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky)
  • Estimated life expectancy ≥ 12 weeks
  • Adequate bone marrow function: Absolute Neutrophil Count (ANC) >1.0 x 10/L, platelets, 20 x 10/L and haemoglobin > 8.0 g/dL.
  • Adequate renal function: serum creatinine <1.5 mg/dL or a estimated creatinine clearance or radioisotope Glomerular Filtration Rate Study (GFR) of > 60 mL/minute/1.73m2.
  • Adequate cardiac function: shortening fraction of 28 % by echocardiogram.
  • Adequate hepatic function: Alanine transaminase (ALT) or Aspartate transaminase (AST) < 5 x ULN and a total bilirubin < 1.5 x Upper Limit of Normal (ULN)
  • Adequate lung function: Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) >60% of the predicted by pulmonary function tests. Children unable to do Pulmonary Function Tests (PFTs) should have no dyspnea at rest and a pulse oximetry >94% on room air.
  • Adequate pancreatic function: serum lipase < 1.5 x upper limit normal
  • Patients may have had prior Central Nervous System (CNS) metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable prior for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema.
  • Patients must consent to the placement of a central venous line, if one has not already been placed.
  • Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery.
  • Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
  • Patients with seizure disorders may be enrolled if seizures are well controlled.
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional and national requirements for clinical trials must be met.
  • Expression of PD-L1 by tumour is not a pre-requisite
  • Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration.
  • Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy

Exclusion Criteria

  • Patients who have previously received ch14.18 (CHO or SP2/0) will not be excluded unless they have had severe or life threatening toxicity necessitating withdrawal of treatment previously or if they have a strong/neutralizing Human Antichimeric Antibody (HACA) (≥ 10 μg/ml)
  • Patients who have had previous 131-I mIBG therapy will not be excluded
  • Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study
  • Previous allogeneic stem cell transplant or solid organ transplant
  • Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • Patients receiving systemic corticosteroids (other than physiological replacement) or other immunosuppressive agents within 14 days prior to study entry
  • Unable to maintain platelets ≥ 50 x 109/l without transfusion
  • HIV or Hepatitis B or C infection
  • Patients with significant intercurrent illnesses and/or any of the following:

    • Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance.
    • Patients with significant psychiatric disabilities or uncontrolled seizure disorders.
    • Patients with active infections.
    • Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade >2) are ineligible.
    • Patients with clinically significant, symptomatic, pleural effusions.
    • Patients who require, or are likely to require, corticosteroid or other immunosuppressive drugs.

Sites / Locations

  • University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics; American Family Children's HospitalRecruiting
  • University Hospital Southampton NHS Foundation TrustRecruiting
  • University College London HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

The dose and schedule of 131-I mIBG will be constant, and the doses of ch14.18/ CHO and Nivolumab determined by cohort: Cohort I: 3 mg/kg Nivolumab (100% adult dose). No ch14.18/CHO. (3-6 patients) Cohort II: 50mg/m2/cycle ch14.18/CHO (50% established Long Term Intervention (LTI) dose) and 3 mg/kg Nivolumab (100% adult dose) (3-6 patients) Cohort III: 100mg/m2/cycle ch14.18/CHO (100% established LTI dose) and 3 mg/kg Nivolumab (100% adult dose) (initial 3-6 patients, expanded to 15 patient cohort if tolerated)

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients
• To determine the safety and tolerability of the novel combination of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients, assessed by nature, frequency, severity and timing of adverse events, including serious adverse events and immune related adverse events during administration of ch14.18/CHO

Secondary Outcome Measures

Anti-tumour response in patients with measureable disease as measured by immunocytology, MIBG, CT and/or MRI in patients receiving 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma
To document any evidence of efficacy of 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma (time to progression)
Anti-tumour response in patients with measureable disease as measured by immunocytology, MIBG, CT and/or MRI in patients receiving 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma
To document any evidence of efficacy of 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma (objective response rate)
KIR/KIR-Ligand genotype, FcγR genotype
To provide descriptive analysis of any associations between KIR/KIR-Ligand genotype, FcγR genotype and response

Full Information

First Posted
August 25, 2016
Last Updated
August 1, 2023
Sponsor
University Hospital Southampton NHS Foundation Trust
Collaborators
University College London Hospitals, University of Wisconsin, Madison, University Hospital Greifswald, Solving Kids' Cancer US/EU, Joining Against Cancer in Kids, The Band of Parents
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1. Study Identification

Unique Protocol Identification Number
NCT02914405
Brief Title
Phase I Study of 131-I mIBG Followed by Nivolumab & Dinutuximab Beta Antibodies in Children With Relapsed/Refractory Neuroblastoma
Acronym
MiniVan
Official Title
A Phase I Study of 131-1 mIBG Followed by Nivolumab and Dinutuximab Beta in Children With Relapsed/Refractory Neuroblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 24, 2018 (Actual)
Primary Completion Date
November 2023 (Anticipated)
Study Completion Date
November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital Southampton NHS Foundation Trust
Collaborators
University College London Hospitals, University of Wisconsin, Madison, University Hospital Greifswald, Solving Kids' Cancer US/EU, Joining Against Cancer in Kids, The Band of Parents

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Neuroblastoma, the most common extra-cranial solid tumour in children, remains one of the major challenges in paediatric oncology. A promising way to further improve outcome in this disease appears to be the development of adjuvant therapeutic strategies. In this research the anti-GD2 antibody, which is a standard treatment, is to be combined with 131-l Metaiodobenzylguanidine (mlBG) and anti-Programmed Cell Death Protein 1 (anti-PD1) antibody Nivolumab - the investigated drugs - with the aim of generating sustained anti-neuroblastoma immunity. In particular it will be determined the safety and tolerability of the novel combination as well as documented any evidence of efficacy in paediatric patients with relapsed and refractory high risk neuroblastoma. This study is sponsored by the University Hospital Southampton and will take place in 4 hospitals in the United Kingdom, Germany and USA. The estimated duration of the study is 2 years, starting in December 2016. This is an "adaptive study". Such design uses accumulating of data from the ongoing trial to modify aspects of the study (e.g. duration, number of treatments) without undermining its validity or integrity. There will be 3 cohorts of patients. As safety of Nivolumab is well established, Cohort 1 will assess its safety and tolerability in combination with 131-l mlBG. Cohort 2 will then add anti-GD2 to the drug combination, assessing safety and tolerability. Cohort 3 will escalate all 3 agents to the full 100% dose level to assure safety for expanded analyses of clinical and laboratory data at that dose level. Patients will initially be recruited into Cohort 1. Patients must have completed at least 12 weeks of trial treatment without reaching a Dose Limiting Toxicity before a patient can be recruited to the next cohort. A minimum of 3 evaluable patients will be treated in cohorts 1-3. Assuming the full dose combination therapy (cohort) is tolerable, 15 evaluable patients will be treated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroblastoma
Keywords
131-I-mIBG therapy, ch14.18/CHO, Nivolumab, MiniVan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment
Arm Type
Experimental
Arm Description
The dose and schedule of 131-I mIBG will be constant, and the doses of ch14.18/ CHO and Nivolumab determined by cohort: Cohort I: 3 mg/kg Nivolumab (100% adult dose). No ch14.18/CHO. (3-6 patients) Cohort II: 50mg/m2/cycle ch14.18/CHO (50% established Long Term Intervention (LTI) dose) and 3 mg/kg Nivolumab (100% adult dose) (3-6 patients) Cohort III: 100mg/m2/cycle ch14.18/CHO (100% established LTI dose) and 3 mg/kg Nivolumab (100% adult dose) (initial 3-6 patients, expanded to 15 patient cohort if tolerated)
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, MDX1106, ONO-4538, anti-PD-1) NSC#748726, IND #124729
Intervention Description
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains consisting of 440 amino acids and 2 identical light chains. Molecular weight is 146,221 daltons.
Intervention Type
Drug
Intervention Name(s)
Ch14.18/CHO
Other Intervention Name(s)
Mouse-human chimeric monoclonal anti-GD2 Immunoglobulin G1 (IgG1) antibody
Intervention Description
APN311 (ch14.18/CHO) is manufactured in a Good Manufacturing Practice (GMP) compliant facility of Polymun Scientific, Austria according to a state of the art aseptic manufacturing process based on a characterized and stable Chinese Hamster Ovary (CHO) cell line. After propagation of the working cell bank (WCB) in small volume vessels/bioreactors, manufacture is carried out in a 2500 L stirred tank reactor utilizing components which are free of material of animal or human origin.
Primary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients
Description
• To determine the safety and tolerability of the novel combination of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients, assessed by nature, frequency, severity and timing of adverse events, including serious adverse events and immune related adverse events during administration of ch14.18/CHO
Time Frame
2 Years
Secondary Outcome Measure Information:
Title
Anti-tumour response in patients with measureable disease as measured by immunocytology, MIBG, CT and/or MRI in patients receiving 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma
Description
To document any evidence of efficacy of 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma (time to progression)
Time Frame
2 Years
Title
Anti-tumour response in patients with measureable disease as measured by immunocytology, MIBG, CT and/or MRI in patients receiving 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma
Description
To document any evidence of efficacy of 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma (objective response rate)
Time Frame
2 Years
Title
KIR/KIR-Ligand genotype, FcγR genotype
Description
To provide descriptive analysis of any associations between KIR/KIR-Ligand genotype, FcγR genotype and response
Time Frame
2 Years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: At study entry patients must be > 1 year Relapsed or refractory high risk neuroblastoma (as defined by International Neuroblastoma Risk Group (INRG) criteria) MIBG avid disease on imaging within 4 weeks to study entry. ≥ 3 months since any myeloablative chemotherapy / stem cell rescue ≥ 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half lives since last dose of any monoclonal antibody therapy. Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky) Estimated life expectancy ≥ 12 weeks Adequate bone marrow function: Absolute Neutrophil Count (ANC) >1.0 x 10/L, platelets, 20 x 10/L and haemoglobin > 8.0 g/dL. Adequate renal function: serum creatinine <1.5 mg/dL or a estimated creatinine clearance or radioisotope Glomerular Filtration Rate Study (GFR) of > 60 mL/minute/1.73m2. Adequate cardiac function: shortening fraction of 28 % by echocardiogram. Adequate hepatic function: Alanine transaminase (ALT) or Aspartate transaminase (AST) < 5 x ULN and a total bilirubin < 1.5 x Upper Limit of Normal (ULN) Adequate lung function: Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) >60% of the predicted by pulmonary function tests. Children unable to do Pulmonary Function Tests (PFTs) should have no dyspnea at rest and a pulse oximetry >94% on room air. Adequate pancreatic function: serum lipase < 1.5 x upper limit normal Patients may have had prior Central Nervous System (CNS) metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable prior for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema. Patients must consent to the placement of a central venous line, if one has not already been placed. Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery. Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding. Patients with seizure disorders may be enrolled if seizures are well controlled. All patients and/or their parents or legal guardians must sign a written informed consent All institutional and national requirements for clinical trials must be met. Expression of PD-L1 by tumour is not a pre-requisite Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration. Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy Exclusion Criteria Patients who have previously received ch14.18 (CHO or SP2/0) will not be excluded unless they have had severe or life threatening toxicity necessitating withdrawal of treatment previously or if they have a strong/neutralizing Human Antichimeric Antibody (HACA) (≥ 10 μg/ml) Patients who have had previous 131-I mIBG therapy will not be excluded Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study Previous allogeneic stem cell transplant or solid organ transplant Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger Patients receiving systemic corticosteroids (other than physiological replacement) or other immunosuppressive agents within 14 days prior to study entry Unable to maintain platelets ≥ 50 x 109/l without transfusion HIV or Hepatitis B or C infection Patients with significant intercurrent illnesses and/or any of the following: Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance. Patients with significant psychiatric disabilities or uncontrolled seizure disorders. Patients with active infections. Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade >2) are ineligible. Patients with clinically significant, symptomatic, pleural effusions. Patients who require, or are likely to require, corticosteroid or other immunosuppressive drugs.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Danny Pratt
Phone
+44(0)2381204989
Ext
3943
Email
danny.pratt@uhs.nhs.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juliet Gray
Organizational Affiliation
Consultant Paediatric Oncologist
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics; American Family Children's Hospital
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jenny L Weiland
Phone
608-890-8070
Email
pedshemoncresearch@g-groups.wisc.edu
First Name & Middle Initial & Last Name & Degree
Celeste Matsushima
Phone
608-890-8069
Email
pedshemoncresearch@g-groups.wisc.edu
First Name & Middle Initial & Last Name & Degree
Kenneth B DeSantes, MD
Facility Name
University Hospital Southampton NHS Foundation Trust
City
Southampton
State/Province
Hampshire
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Danny B Pratt
Phone
023 8120 4989
Ext
3943
Email
danny.pratt@uhs.nhs.uk
First Name & Middle Initial & Last Name & Degree
Tom Bower
Phone
023 8120 4989
Ext
3853
Email
thomas.bower@uhs.nhs.uk
First Name & Middle Initial & Last Name & Degree
Juliet C Gray
Facility Name
University College London Hospital
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pamela Niem
Phone
023 447 7135
Email
Pamela.Niem@nhs.net
First Name & Middle Initial & Last Name & Degree
Sarah Taylor
Phone
07890 60 9229
Email
sarah.taylor83@nhs.net
First Name & Middle Initial & Last Name & Degree
Mark Gaze

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Phase I Study of 131-I mIBG Followed by Nivolumab & Dinutuximab Beta Antibodies in Children With Relapsed/Refractory Neuroblastoma

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