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

Phase 1

• Conditions: HYPERMUTANT CANCERS; MedDRA version: 20.0 Level: PT Classification code 10078672 Term: DNA mismatch repair protein gene mutation System Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0 Level: PT Classification code 10038111 Term: Recurrent cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0 Level: PT Classification code 10070308 Term: Refractory cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

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

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-05-15
• Last Update Posted: 10 December 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• 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, wh

Exclusion Criteria

1. 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 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.
? Women who are surgically sterile, as well as azoospermic men do not require contraception.
*Women of childbearing potential” is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
** List of contraception methods is provided in the Appendix II
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 anti-cancer 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

Study & Design

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