HYPERMUTANT CANCERS MedDRA version: 22.0 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: 21.1 Level: PT Classification code 10070308 Term: Refractory cancer System Organ Class: 10029104
Conditions
Sponsors
Hospital for Sick Children
Eligibility
Sex/Gender
All
Inclusion criteria
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 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 ofactive 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. d. Adequate Pulmonary Function: No history of chronic pulmonary disease and no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency and a pulse ox
Exclusion criteria
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 CoChair. 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 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 no
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the objective response rate to Nivolumab in pediatric patients with refractory or recurrent hypermutated malignancies including patients with replication repair deficiencies (RRD), such as constitutional mismatch repair deficiency (CMMRD).;Secondary Objective: 1. To determine the PFS and OS of paediatric patients with progressive or recurrent hypermutated malignancies, including RRD patients such as CMMRD, treated with nivolumab. 2. To evaluate safety and tolerability of nivolumab administered as a single agent at the adult recommended dose of 3 mg/kg every 2 weeks. To define and describe the toxicities in paediatric patients with progressive or recurrent hypermutated malignancies including RRD patients, such as CMMRD. Companion Biomarker Exploratory Objectives: 1) To explore associations between tumour mutation burden (TMB) and response to nivolumab. 2) To discover biomarkers predicting response of hypermutant cancers undergoing PD-1 blockade. 3) To explore the use of minimally invasive methods to monitor and predict response to immune checkpoint inhibition in hypermutant cancers.;Primary end point(s): Tumour disease evaluation, includes objective response rate (ORR = complete response [CR] and partial response [PR]) as defined by iRECIST response criteria for solid tumours (revised for neuroblastoma using the revised INRC), iRANO response criteria for CNS malignancies, RECIL 2017 response criteria for lymphomas, revised criteria according to Creutzig, et al. (2012) for acute myeloid leukemia (AML), and response criteria as specified for acute lymphoblastic leukemia (ALL). Patients with response of 'stable disease' (SD) will also be reported as part of the final analysis of clinical benefit, but will not contribute to the primary efficacy outcome measure.;Timepoint(s) of evaluation of this end point: After enrollment of 10 subjects and at the end of the study. The end of the study is defined as the date when the last patient, last visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - PFS is defined as the time from the first dose of the study drug administration to the occurrence of disease progression or death from any cause during the study. - OS is defined as time from first dose of study drug to death from any cause. - A safety evaluation by the Safety Committee will be performed after Patient 1-Cycle 1, Patient 4-Cycle 1, Patient 7-Cycle 1, and Patient 10Cycle 1. Enrollment will be held after each time point until a safety evaluation of adverse events (AE) and serious adverse events (SAE) confirms it is safe to resume enrollment. - Toxicities will be described and defined in paediatric patients, focusing on SAEs, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Toxicities (drugrelated AEs) of any grade, plus all Grade = 3 AEs, all Grade = 3 laboratory toxicities and all SAEs will be collected for this study.;Timepoint(s) of evaluation of this end point: At the end of the study. The end of the study is defined as the date when the last patient, last visit (LPLV) occurs | — |
Countries
Canada, Denmark, France, Germany, Israel, Italy, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactAnuska Mohaboe
SMS-oncology
Outcome results
None listed