Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers

NCT02992964 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: OZM-075
• Study Type: interventional
• Target: 11
• Locations: 5 countries
• Sites: 10

Brief Summary

This is an open-label, single arm, multi-center, pilot study of Nivolumab in pediatric patients with recurrent or refractory hypermutant malignancies aged 12 months to 18 years of age. This study is to assess clinical and radiological benefits of treatment with Nivolumab in children with hypermutated cancers, including those with bMMRD syndrome. It is our expectation that patients with bMMRD syndrome will account for the majority of patients enrolled on this study.

Conditions

Refractory or Recurrent Hypermutated Malignancies; Biallelic Mismatch Repair Deficiency (bMMRD) Positive Patients

Outcome Measures

Primary Outcomes (3)

• To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with refractory hypermutated malignancies

  Objective response rate will assessed by physical assessments, lab values, disease assessments and adverse events that are related to treatment. Scheduled time-points and the above assessments are detailed further in section "9.1 Study Calendar" of the protocol.

  5 years (60 months) from date of enrollment

• To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with recurrent hypermutated malignancies.

  Objective response rate will assessed by physical assessments, lab values, disease assessments and adverse events that are related to treatment. Scheduled time-points and the above assessments are detailed further in section "9.1 Study Calendar" of the protocol.

  5 years (60 months) from date of enrollment

• Estimating the feasibility of using Nivolumab as a treatment in bMMRD positive, pediatric patients with refractory or recurrent hypermutated malignancies.

  Feasibility of treatment will be measured using a patient's disease response assessment. This means using standard RECIST criteria for solid tumours, iRANO/RANO criteria for CNS malignancies and the revised AML International Working Group (IWG) Criteria for haematological malignancies; modified RECIST criteria for immune response may be considered during the time of study.

  5 years (60 months) from date of enrollment

Secondary Outcomes (2)

• The progression free survival (PFS) of pediatric patients with progressive or recurrent hypermutated malignancies including bMMRD patients treated with Nivolumab.

  5 years (60 months) from date of enrollment

• Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

  5 years (60 months) from date of enrollment

Study Arms (1)

Nivolumab

EXPERIMENTAL

Regimen: Nivolumab will be administered every 14 days until disease progression or treatment discontinuation due to unacceptable toxicities. Treatment may extend up to 2 years in patients who show clinical and radiological benefit. Dose: 3 mg/kg intravenously as a continuous infusion over 60 min (+/-10 min window)

Drug: Nivolumab

Interventions

Nivolumab DRUG

Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody (HuMAb; immunoglobulin G4 \[IgG4\]-S228P) that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor.

Also known as: OPDIVO

Nivolumab

Eligibility Criteria

• Age: 12 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Part I
• Consent/ Assent: Patient and/or Legally Acceptable Representative (LAR; such as a parent or guardian, as applicable) must be willing and able to provide written informed consent/assent for the trial as per local requirements.
• Age: patients must be ≥ 12 months and \<25 years of age at time of Part I enrollment. Local centres are only obligated to treat/ admit patients in accordance their age range capabilities.
• Recurrent or relapse paediatric cancer patients suspected to be hypermutant, including those exhibiting evidence of one or more of the following:
• high microsatellite instability (MSI-H) in current or previous tumour;
• a mutation causing loss of mismatch repair gene (MLH1, MSH2, MSH6, PMS2, EPCAM or MSH3) expression;
• hypermutation by local sequencing in current or previous tumour;
• a history of CMMRD, Lynch syndrome, xeroderma pigmentosum (XP), or other established disorder affiliated with an elevated hypermutation rate;
• a functional mutation of polymerase genes (POLE or POLD1) in current or previous tumour;
• a functionally impaired RRD pathway by other means;
• a temozolomide (TMZ) treated current or previous CNS tumour;
• a predisposing hypermutant cancer signature (i.e. dysregulation of an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deamination or UV-associated);
• other factors, which may predicate an elevated mutation burden at the discretion of the Study Chair or Co-Chair.
• Diagnosis: patients must have histologic or cytologic confirmation of malignancy at the time of initial diagnosis or relapse (as specified above). Patients with multiple concurrent and/or sequential neoplasms are eligible, including CNS and haematological malignancies.
• Specimen availability: patients must be able to provide specimen (archival or newly obtained biopsy) of a tumor lesion, appropriately obtained and preserved in a manner compatible for TMB analysis or applicable IHC staining for MMR gene protein expression, if applicable (as described in the Lab Manual). Only those with an already ascertained TMB level report from the laboratory specified in the Lab Manual or those with proof of RRD as outlined in the Lab Manual will be exempt from mandatory tissue submission.

You may not qualify if:

• Part II Only
• Women who are pregnant or breastfeeding and men who are sexually active with women of childbearing potential (WOCBP)\* who are not willing to use effective contraception, or to practice abstinence if this is the usual lifestyle and preferred contraception for the patient. \*\*
• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as there is yet no available information regarding human fetal or teratogenic toxicities.
• WOCBP must have a negative serum pregnancy test every 4 weeks. and During Part II screening, WOCBP must have a negative serum pregnancy test. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab administration. WOCBP who are sexually active, must be willing to adhere to effective contraception during treatment and for 5 months after the last dose of nivolumab.
• Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 7 months after the last dose of nivolumab.
• Women who are surgically sterile, as well as azoospermic men do not require contraception.
• Concomitant Medications
• Corticosteroids: Patients requiring systemic steroid therapy or any other form of immunosuppressive therapy within seven (7) days prior to first dose of trial therapy or while on trial are not eligible. The use of physiologic doses of corticosteroids (up to 5mg/m2/day prednisone equivalent) is permitted following discussion with the Study Chair or Co-Chair.
• Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
• Patients with a History of Autoimmune Disease
• Patients with a history of autoimmune disorder that has required systemic treatment in the previous two (2) years are not eligible. Asymptomatic laboratory abnormalities (e.g. ANA, rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder. Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy) is not considered a form of systemic treatment.
• Infection: Patients who have an uncontrolled infection are not eligible.
• HIV and/or Hepatitis B/C patients: Patients with known HIV/AIDS or acute/chronic Hepatitis B or C are excluded.
• Transplant patients: Patients who have received prior allogeneic Bone Marrow (BM) transplants or prior solid organ transplantation are not eligible.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• Bristol-Myers Squibb: collaborator

Study Sites (10)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

The Children's Hospital at Westmead

Westmead, New South Wales, Australia

Location

Queensland Children's Hospital

South Brisbane, Queensland, Australia

Location

Women's and Children's Hospital

North Adelaide, South Australia, Australia

Location

Children's & Women's Health Centre of British Columbia

Vancouver, British Columbia, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Centre Leon Berard

Lyon, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Tel Aviv Sourasky Medical Centre

Tel Aviv, 64239, Israel

Location

Related Publications (3)

• Das A, Tabori U, Sambira Nahum LC, Collins NB, Deyell R, Dvir R, Faure-Conter C, Hassall TE, Minturn JE, Edwards M, Brookes E, Bianchi V, Levine A, Stone SC, Sudhaman S, Sanchez Ramirez S, Ercan AB, Stengs L, Chung J, Negm L, Getz G, Maruvka YE, Ertl-Wagner B, Ohashi PS, Pugh T, Hawkins C, Bouffet E, Morgenstern DA. Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency. Clin Cancer Res. 2023 Dec 1;29(23):4770-4783. doi: 10.1158/1078-0432.CCR-23-0411.

  PMID: 37126021 BACKGROUND

• Henderson JJ, Das A, Morgenstern DA, Sudhaman S, Bianchi V, Chung J, Negm L, Edwards M, Kram DE, Osborn M, Hawkins C, Bouffet E, Cho YJ, Tabori U. Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study. JCO Precis Oncol. 2022 Mar;6:e2100286. doi: 10.1200/PO.21.00286. No abstract available.

  PMID: 35235414 DERIVED

• Rittberg R, Harlos C, Rothenmund H, Das A, Tabori U, Sinha N, Singh H, Chodirker B, Kim CA. Immune Checkpoint Inhibition as Primary Adjuvant Therapy for an IDH1-Mutant Anaplastic Astrocytoma in a Patient with CMMRD: A Case Report-Usage of Immune Checkpoint Inhibition in CMMRD. Curr Oncol. 2021 Feb 1;28(1):757-766. doi: 10.3390/curroncol28010074.

  PMID: 33535600 DERIVED

MeSH Terms

Conditions

Turcot syndrome

Interventions

Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Daniel A Morgenstern, MB BChir PhD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Oncologist

Study Record Dates

• First Submitted: December 2, 2016
• First Posted: December 14, 2016
• Study Start: May 15, 2017
• Primary Completion: November 20, 2023
• Study Completion: November 20, 2023
• Last Updated: April 2, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); AU (3); FR (2); US (2); IL (1)