Early study to evaluate the effect of Nivolumab in children with cancersthat grow/arise due to lot of abnormal DNA.

Phase 1

• Conditions: Hypermutant cancers; MedDRA version: 22.0Level: PTClassification code 10078672Term: DNA mismatch repair protein gene mutationSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: PTClassification code 10038111Term: Recurrent cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10070308Term: Refractory cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-002054-37-GB
• Lead Sponsor: The Hospital for Sick Children

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2019-11-20
• Last Update Posted: 9 September 2024

Recruitment & Eligibility

• Status: A
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Patient and LAR must be willing and able to provide written informed
consent/assent for the trial as per local requirements
2. patient must have completed and verified a sufficient TMB level or
have proof of RRD diagnosed in the appropriate lab
3. patients must be = 12 months and < 25 years of age at the time of
Part I/II enrollment
3. Recurrent of relapse pediatric cancer patients suspected to be
hypermutant.
4. patients must have had histologic verification of malignancy at the
time of initial diagnosis or at relapse
5. patients must be able to provide specimen of a tumor lesion.
5. patients must have either measurable or evaluable disease in
accordance with criteria as outlined in Section 10
6. 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
7. Karnofsky = 50% for patients > 16 years of age or Lansky = 50 for
patients = 16 years of age
8. patients must have fully recovered from the acute toxic effects of all
prior anti-cancer therapy.
a. Myelosuppressive chemotherapy: at least 21 days after the last dose
(42 days if prior nitrosourea)
b. Hematopoietic growth factors: at least 14 days after the last dose of a
long-acting growth factor or 7 days for short-acting growth factor. For
agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during
which adverse events are known to occur.
c. Biologic (anti-neoplastic agent): at least 14 days after the last dose of
a biologic agent. For agents that have known adverse events occurring
beyond 14 days after administration, this period must be extended
beyond the time during which adverse events are known to occur.
d. Monoclonal antibodies: at least three (3) half-lives of the antibody
after the last dose of a monoclonal antibody.
e. Radiation Therapy (XRT): at least 14 days after local palliative XRT
(small port). At least 150 days must have elapsed if prior Total Body
Irradiation, craniospinal XRT or if = 50% radiation of pelvis. At least 42
days must have elapsed if other substantial BM radiation.
f. Stem Cell Infusion without Total Body Irradiation (TBI): no evidence of
active graft vs. host disease and at least 56 days must have elapsed
after transplant or stem cell infusion. Patients with prior allogeneic
transplants (including solid organ) are not eligible.
9. a. Adequate BM Function Defined as
i. Peripheral ANC =0.75 x 109/L or 750/mm3.
ii. Platelet count =75 x 109/L or 75,000/mm3.
iii. Hemoglobin = 90g/L (transfusion permitted).
iv. Patients with known BM metastatic disease or haematological
malignancies will be eligible for study provided they meet
haematological criteria.
b. Renal Function : serum creatinine based on age/gender as provided in
Table 3
c. Liver Function:
i. Bilirubin (sum of conjugated + unconjugated or total bilirubin) =1.5x
institutional ULN for age (except for patients with Gilbert's Syndrome,
when bilirubin of < 51 µmol/L or 3.0 mg/dL is permitted).
ii. ALT/AST:
1. = 2.5 x institutional ULN for patients without liver metastases.
2. = 5 x institutional ULN for patients with liver metastases.
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d. Adequate Pulmonary Function: No history of chronic pulmonary
disease and no evidence of dyspnea at rest, no exercise int

Exclusion Criteria

1. Women who are pregnant or breastfeeding and men who are sexually
active with women of childbearing potential 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 pregnancy test every 4 weeks. 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.
2. Concomitant Medications
a. 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.
Note: Use of topical, ocular, intra-articular, intra-nasal or inhaled
corticosteroids will not render a patient ineligible. A brief course of
corticosteroids for prophylaxis (e.g. contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g. delayed-type
hypersensitivity reaction caused by contact allergen) is permitted if
completed at least 7 days prior to initiation of therapy.
b. Investigational Drugs: Patients who are currently receiving another
investigational drug are not eligible.
c. Anti-cancer Agents: Patients who are currently receiving other anticancer
agents are not eligible.
3. 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.
4. Infection: Patients who have an uncontrolled infection are not eligible.
5. HIV and/or Hepatitis B/C patients: Patients with known HIV/AIDS or
acute/chronic Hepatitis B or C are excluded.
6. Transplant patients: Patients who have received prior allogeneic Bone
Marrow (BM) transplants or prior solid organ transplantation are not
eligible.
7. 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.
8. 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.
9. Live vaccines: Patients who have received a live vaccine within 30
days of start of study treatment are not eligible.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified