Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers

Stopped early · Phase 1/Phase 2

Conditions studied: Refractory or Recurrent Hypermutated Malignancies, Biallelic Mismatch Repair Deficiency (bMMRD) Positive Patients

In brief

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.

Key facts

Study ID

NCT02992964

Run by

The Hospital for Sick Children

People needed

11

Starts

2017-05-15

Expected to finish

2023-11-20

Last updated by the study team

2024-04-02

Who can join

Age: 1 and older, up to 18. Sex: any. Healthy volunteers: not accepted.

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.
• If tissue (including archival) is not available, a new tissue specimen may be obtained if deemed clinically appropriate. Any such biopsy will not be considered a trial-related procedure.
• Inclusion Criteria Part II
• Consent/ Assent: Patient and 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.
• Confirmation of hypermutation or Proof of RRD: patient must have completed and verified a sufficient TMB level or have proof of RRD diagnosed in the appropriate lab, as outlined in the Lab Manual.
• Age: patients must be ≥ 12 months and < 25 years of age at the time of Part II enrollment. Local centres are only obligated to treat/ admit patients in accordance their age range capabilities.
• Diagnosis: patients must have had histologic verification of malignancy at the time of initial diagnosis or at relapse (as specified above). Patients with multiple concurrent and/or sequential neoplasms are eligible, including CNS and haematological malignancies.
• Disease status: patients must have either measurable or evaluable disease in accordance with criteria as outlined in Section 10. Tumour lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Treatment options: patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life. Chemotherapy-naïve patients will be eligible in cases where first-line therapy does not include chemotherapy (e.g. surgery alone for management of ependymoma).
• Performance status: Karnofsky ≥ 50% for patients > 16 years of age or Lansky ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Previous treatment: patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.

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.
• Non-Compliance: Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Previous anti-PD-1 and/or anti-PD-L1 therapy: Patients who have received prior anti-PD-1 and/or anti-PD-L1 directed therapy (mAb or small molecule) are not eligible.
• Live vaccines: Patients who have received a live vaccine within 30 days of start of study treatment are not eligible.

Where it is running

• Dana-Farber Cancer Institute — Boston, Massachusetts, United States
• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States
• The Children's Hospital at Westmead — Westmead, New South Wales, Australia
• Queensland Children's Hospital — South Brisbane, Queensland, Australia
• Women's and Children's Hospital — North Adelaide, South Australia, Australia
• Children's & Women's Health Centre of British Columbia — Vancouver, British Columbia, Canada
• The Hospital for Sick Children — Toronto, Ontario, Canada
• Centre Leon Berard — Lyon, France
• Institut Gustave Roussy — Villejuif, France
• Tel Aviv Sourasky Medical Centre — Tel Aviv, Israel

Full record on ClinicalTrials.gov

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