Clinical Trials /

Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers

NCT02992964

Description:

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.

Related Conditions:
  • Cancer
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers
  • Official Title: Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers

Clinical Trial IDs

  • ORG STUDY ID: OZM-075
  • NCT ID: NCT02992964

Conditions

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

Interventions

DrugSynonymsArms
NivolumabOPDIVONivolumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimentalRegimen: 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)
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

        Part I

          1. 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.

          2. 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.

          3. Recurrent or relapse paediatric cancer patients suspected to be hypermutant, including
             those exhibiting evidence of one or more of the following:

               1. high microsatellite instability (MSI-H) in current or previous tumour;

               2. a mutation causing loss of mismatch repair gene (MLH1, MSH2, MSH6, PMS2, EPCAM or
                  MSH3) expression;

               3. hypermutation by local sequencing in current or previous tumour;

               4. a history of CMMRD, Lynch syndrome, xeroderma pigmentosum (XP), or other
                  established disorder affiliated with an elevated hypermutation rate;

               5. a functional mutation of polymerase genes (POLE or POLD1) in current or previous
                  tumour;

               6. a functionally impaired RRD pathway by other means;

               7. a temozolomide (TMZ) treated current or previous CNS tumour;

               8. a predisposing hypermutant cancer signature (i.e. dysregulation of an
                  apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)
                  cytidine deamination or UV-associated);

               9. other factors, which may predicate an elevated mutation burden at the discretion
                  of the Study Chair or Co-Chair.

          4. 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.

          5. 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

          1. 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.

          2. 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.

          3. 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.

          4. 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.

          5. 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.

          6. 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).

          7. 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.

          8. Previous treatment: patients must have fully recovered from the acute toxic effects of
             all prior anti-cancer therapy.

               1. Myelosuppressive chemotherapy: at least 21 days after the last dose of
                  myelosuppressive chemotherapy (42 days if prior nitrosourea).

               2. Hematopoietic growth factors: at least 14 days after the last dose of a
                  long-acting growth factor (e.g. Neulasta) 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. The duration of this interval must be discussed with
                  the Study Chair or Co-Chair.

               3. 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. The duration of this interval must be
                  discussed with the Study Chair or Co-Chair.

               4. Monoclonal antibodies: at least three (3) half-lives of the antibody after the
                  last dose of a monoclonal antibody.

               5. 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.

               6. 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. Organ Function Requirements:

             a. Adequate BM Function Defined as i. Peripheral absolute neutrophil count (ANC) ≥0.75
             x 109/L or 750/mm3. ii. Platelet count ≥75 x 109/L or 75,000/mm3 (transfusion
             independent, defined as not receiving platelet transfusions for at least 7 days prior
             to enrollment.

             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. These patients may receive transfusions (e.g. to achieve
             platelet threshold) provided they are not known to be refractory to platelet
             transfusions but will not be evaluable for hematologic toxicity.

             b. Adequate Renal Function Defined as: A serum creatinine based on age/gender as
             provided in Table 3 (see Section 4.2.2) c. Adequate Liver Function Defined as: i.
             Bilirubin (sum of conjugated + unconjugated or total bilirubin) ≤1.5x institutional
             upper limit of normal (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 Defined as: No
        history of chronic pulmonary disease (such as Cystic Fibrosis) and no evidence of dyspnea
        at rest, no exercise intolerance due to pulmonary insufficiency and a pulse oximetry > 92%
        on room air.

        e. Adequate Pancreatic Function Defined as: Serum lipase ≤ ULN. Patients with glucose
        intolerance should be on a stable regiment and be monitored.

        10. For patients with brain tumors, debulking surgery prior to treatment with nivolumab
        should be considered when appropriate to reduce the risk of pseudoprogression-associated
        toxicities. Such debulking surgery is not mandatory for trial enrollment. Patients should
        be recovered from surgery and wait at least 7 days from surgery before first dose.

        Exclusion Criteria:

        Part II Only

          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 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.

          2. Concomitant Medications

               1. 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.

               2. Investigational Drugs: Patients who are currently receiving another
                  investigational drug are not eligible.

               3. 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 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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with refractory hypermutated malignancies
Time Frame:5 years (60 months) from date of enrollment
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:The progression free survival (PFS) of pediatric patients with progressive or recurrent hypermutated malignancies including bMMRD patients treated with Nivolumab.
Time Frame:5 years (60 months) from date of enrollment
Safety Issue:
Description:
Measure:Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
Time Frame:5 years (60 months) from date of enrollment
Safety Issue:
Description:These will be assessed by abnormal findings in physical assessments, lab values, disease assessments and adverse events.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:The Hospital for Sick Children

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