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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02992964


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT02992964
Ethics application status
Date submitted
2/12/2016
Date registered
14/12/2016
Date last updated
5/02/2020

Titles & IDs
Public title
Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers
Scientific title
Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers
Secondary ID [1] 0 0
OZM-075
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory or Recurrent Hypermutated Malignancies 0 0
Biallelic Mismatch Repair Deficiency (bMMRD) Positive Patients 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Nivolumab

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)


Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with refractory hypermutated malignancies - 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.
Timepoint [1] 0 0
5 years (60 months) from date of enrollment
Primary outcome [2] 0 0
To evaluate the objective response rate to Nivolumab in bMMRD positive pediatric patients with recurrent hypermutated malignancies. - 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.
Timepoint [2] 0 0
5 years (60 months) from date of enrollment
Primary outcome [3] 0 0
Estimating the feasibility of using Nivolumab as a treatment in bMMRD positive, pediatric patients with refractory or recurrent hypermutated malignancies. - 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.
Timepoint [3] 0 0
5 years (60 months) from date of enrollment
Secondary outcome [1] 0 0
The progression free survival (PFS) of pediatric patients with progressive or recurrent hypermutated malignancies including bMMRD patients treated with Nivolumab.
Timepoint [1] 0 0
5 years (60 months) from date of enrollment
Secondary outcome [2] 0 0
Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment - These will be assessed by abnormal findings in physical assessments, lab values, disease assessments and adverse events.
Timepoint [2] 0 0
5 years (60 months) from date of enrollment

Eligibility
Key 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.
Minimum age
12 Months
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA
Recruitment hospital [1] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Women's and Children's Hospital - North Adelaide
Recruitment postcode(s) [1] 0 0
- Westmead
Recruitment postcode(s) [2] 0 0
- South Brisbane
Recruitment postcode(s) [3] 0 0
- North Adelaide
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
Pennsylvania
Country [3] 0 0
Canada
State/province [3] 0 0
British Columbia
Country [4] 0 0
Canada
State/province [4] 0 0
Ontario
Country [5] 0 0
France
State/province [5] 0 0
Lyon
Country [6] 0 0
France
State/province [6] 0 0
Villejuif
Country [7] 0 0
Israel
State/province [7] 0 0
Tel Aviv-Yafo

Funding & Sponsors
Primary sponsor type
Other
Name
The Hospital for Sick Children
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Bristol-Myers Squibb
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02992964
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Daniel A Morgenstern, MB BChir PhD
Address 0 0
The Hospital for Sick Children
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Emily L Taylor
Address 0 0
Country 0 0
Phone 0 0
4168131500
Fax 0 0
Email 0 0
emilyl.taylor@sickkids.ca
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02992964

Additional trial details provided through ANZCTR
Accrual to date
1
Recruiting in Australia
Recruitment state(s)
QLD,SA
Funding & Sponsors
Primary sponsor
Primary sponsor name
Primary sponsor address
Primary sponsor country
Secondary sponsor category [1] 25
Other Collaborative groups
Name [1] 25
ANZCHOG
Address [1] 25
27-31 Wright Street, Clayton VIC 3168
Country [1] 25
Australia
Ethics approval
Ethics application status
 
Public notes
Women's and Children's Hospital
Queensland Children's Hospital

Contacts
Principal investigator
Title 129 0
A/Prof
Name 129 0
David Zeigler
Address 129 0
Country 129 0
Phone 129 0
Fax 129 0
Email 129 0
d.ziegler@unsw.edu.au
Contact person for public queries
Title 130 0
Mrs
Name 130 0
Robyn Strong
Address 130 0
27-31 Wright Street, Clayton VIC 3168
Country 130 0
Australia
Phone 130 0
+613 8572 2684
Fax 130 0
+613 9902 4810
Email 130 0
Robyn.Strong@hudson.org.au
Contact person for scientific queries
Title 131 0
A/Prof
Name 131 0
David Zeigler
Address 131 0
Country 131 0
Phone 131 0
Fax 131 0
Email 131 0
d.ziegler@unsw.edu.au