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Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers

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ClinicalTrials.gov Identifier: NCT02992964
Recruitment Status : Recruiting
First Posted : December 14, 2016
Last Update Posted : December 4, 2018
Sponsor:
Information provided by (Responsible Party):
Daniel Morgenstern, The Hospital for Sick Children

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Refractory or Recurrent Hypermutated Malignancies Biallelic Mismatch Repair Deficiency (bMMRD) Positive Patients Drug: Nivolumab Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers
Actual Study Start Date : May 15, 2017
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab

Regimen: 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)

Drug: Nivolumab
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor.
Other Name: OPDIVO




Primary Outcome Measures :
  1. 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 ]
    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.

  2. To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with recurrent hypermutated malignancies. [ Time Frame: 5 years (60 months) from date of enrollment ]
    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.

  3. Estimating the feasibility of using Nivolumab as a treatment in bMMRD positive, pediatric patients with refractory or recurrent hypermutated malignancies. [ Time Frame: 5 years (60 months) from date of enrollment ]
    Feasibility of treatment will be measured using a patient's disease response assessment. This means using standard RECIST criteria for solid tumours, iRANO/RANO criteria for CNS malignancies and the revised AML International Working Group (IWG) Criteria for haematological malignancies; modified RECIST criteria for immune response may be considered during the time of study.


Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
    These will be assessed by abnormal findings in physical assessments, lab values, disease assessments and adverse events.



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Ages Eligible for Study:   12 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02992964


Contacts
Contact: Kristine Van Sickle 416-813-7654 ext 202886 kristine.vansickle@sickkids.ca
Contact: Ruben Machado 416-813-7654 ext 203204 ruben.machado@sickkids.ca

Locations
United States, Pennsylvania
Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Michael Fisher, MD       fisherm@email.chop.edu   
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Daniel Morgenstern, MD PhD    416-813-7654 ext 227565    daniel.morgenstern@sickkids.ca   
Contact: Ruben Machado, CCRP    416-813-7654 ext 203204    ruben.machado@sickkids.ca   
Sub-Investigator: Uri Tabori, MD         
Sub-Investigator: Vijay Ramaswamy, MD         
Sub-Investigator: Annie Huang, MD         
Principal Investigator: Daniel Morgenstern, MD PhD         
France
Institut Gustave Roussy Not yet recruiting
Villejuif, France, 94800
Contact: Jacques Grill, MD    33142114211      
Principal Investigator: Jacques Grill, MD         
Israel
Tel Aviv Sourasky Medical Centre Not yet recruiting
Tel Aviv, Israel, 64239
Contact: Rina Dvir, MD    97236973494    rinad@tlvmc.gov.il   
Principal Investigator: Rina Dvir, MD         
Sponsors and Collaborators
The Hospital for Sick Children
Investigators
Principal Investigator: Daniel A Morgenstern, MB BChir PhD The Hospital for Sick Children

Responsible Party: Daniel Morgenstern, Staff Oncologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT02992964     History of Changes
Other Study ID Numbers: OZM-075
First Posted: December 14, 2016    Key Record Dates
Last Update Posted: December 4, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Brain Neoplasms
Neoplastic Syndromes, Hereditary
Colorectal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs