Risk-based, response-adapted, Phase II open-label trial of nivolumab + brentuximab vedotin (N + Bv) for children, adolescents, and young adults with relapsed/refractory (R/R) CD30 + classic Hodgkin lymphoma (cHL) after failure of first-line therapy, followed by brentuximab + bendamustine (Bv + B) for participants with a suboptimal response.

While the treatment of classic Hodgkin Lymphoma has improved dramatically over
the past 20 years, with 5 year event free survival rates close to 90%, there is
still a group of patients who either relapse or in whom first-line treatment
fails. These patients currently have a poor outcome and there is currently an
unmet need to improve the prognosis of this group of patients.

This is a study of nivolumab and brentuximab vedotin for children, adolescent
and young adults with classic Hodgkin Lymphoma who have failed previous
therapy, followed by brentuximab and bendamustine for those who did not receive
an optimal response.

Approximately 100 patients will take part globally, 4 of these will be in the
Netherlands. The study is sponsored by Bristol-Myers Squibb. The purpose of the
study is to evaluate the safety and anti-tumour activity of combination therapy
with nivolumab and brentuximab vedotin in a population of patients who have
failed standard frontline chemotherapy.

Following a screening period, eligible patients will be given nivolumab and
brentuximab vedotin every 3 weeks and depending on the patient*s response to
treatment they may later be given brentuximab vedotin and bendamustine.
Treatment will be given every three weeks and will be given 4 to 8 times in
total. They may receive further treatments such as involved field radiation
therapy and high dose chemotherapy followed by autologous stem cell transplant
thereafter. Patients will be followed up for 3 years after they stop study
treatment.

There are two treatment groups in this study: one with participants at low risk
of deterioration and one with participants at standard risk of deterioration.
The primary objective for each group is described below.

-Low Risk group: To describe the proportion of patients who remain free of
certain cancer related complications, events and death at 3 years. This will be
assessed by an independent blinded review group.

-Standard Risk group: To describe the proportion of patients who achieve a
complete metabolic response (measured by medical imaging) before receiving
high-dose chemotherapy followed by autologous stem cell transplant. This will
be assessed by an independent blinded review group.

This is a risk-based, response-adapted phase II open label trial in children,
adolescents and young adults with relapsed/refractory CD30+ classic Hodgkin
Lymphoma (cHL) after failure of first line therapy.

There are three periods to the study: screening, treatment and follow-up.

SCREENING PERIOD
The screening period of the study can take up to 28 days to complete. Tests
are to determine the patient*s eligibility to take part in the trial.
The screening tests/procedures include:
• Medical history and physical examination
• Vital signs measurement
• An assessment of how day to day activities are performed
• Blood and urine tests
• Pregnancy testing for women of child bearing potential (urine or blood sample)
•Request original samples of a tumour biopsy or undergo a biopsy procedure
•Tumour assessment by PET-CT
•Brain MRI may be performed if required

TREATMENT PERIOD
If it is safe and suitable for the patient to take part in the study as
determined by the results of the screening tests/procedures mentioned above
they will return to the hospital to receive treatment.

Patients will initially receive nivolumab at a dose of 3 mg/kg and brentuximab
vedotin at 1.8 mg/kg every three weeks. Depending on the patient*s response to
treatment they may later be given brentuximab vedotin (1.8 mg/kg) and
bendamustine (90 mg/m2) every three weeks. Treatment will be given for 4 to 8
doses in total. Thereafter patients may receive further treatments such as
involved field radiation therapy and high-dose chemotherapy followed by
autologous stem cell transplant.

A number of tests and procedures will be carried out during this period:
• Physical examination
• Vital signs measurement
• Review of any medications taken and any side effects experienced
• An assessment of how day to day activities are performed
• An assessment of the symptoms of disease
• Blood and urine tests
• Pregnancy testing for women of child bearing potential (urine or blood sample)
•Tumour assessment by PET-CT

FOLLOW-UP PERIOD
When patients stop or complete study treatment they will begin the last part of
the study, the follow-up period. During this period the investigator will
continue to assess the patient*s health condition.

Once treatment ends patients will be asked to come back to the hospital two
more times, once about a month after they stop study treatment and the second
time about two months after the first visit. During these visits some of the
study procedures may be repeated including collection of blood and scans.

After the last two visits to the hospital, visits may be conducted over the
phone. These will be conducted at 6, 12, 18, 24 and 36 months after they stop
study treatment. Patients may need to go back to the hospital for scans for
these visits.

A Data Monitoring Committee (DMC) will be established and meet regularly during
the study to ensure that subject safety is carefully monitored and to provide
oversight regarding safety and efficacy considerations.

Nivolumab, brentuximab vedotin, and bendamustine in this study are considered
investigational products.

Patients will initially receive nivolumab at a dose of 3 mg/kg and brentuximab
vedotin at 1.8 mg/kg every three weeks. Depending on the patient*s response to
treatment they may later be given brentuximab vedotin (1.8 mg/kg) and
bendamustine (90 mg/m2) every three weeks. Treatment will be given for 4 to 8
doses in total. Thereafter patients may receive further treatments such as
involved field radiation therapy and high-dose chemotherapy/autologous stem
cell transplant.

As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, urine testing, pregnancy testing (for
females of child bearing potential) and monitoring for adverse events. Patients
will be asked to complete questionnaires about their quality of life. Blood
will also be collected at certain visits for research purposes. There will be
tumour imaging performed in the form of PET-CT and MRI. If there is no archive
tumour tissue available or the sample was taken too long ago (more than 3
months), patients will be required to have a biopsy in order to participate.
Patients may also receive involved field radiation therapy or high dose
chemotherapy followed by autologous stem cell transplant.

The frequency of visits and number of procedures carried out during this trial
would typically be considered over and above standard of care. The procedures
are carried out by trained medical professionals and every effort will be made
to minimise any risks or discomfort to the patient.

Treatment for cancer often has side effects, including some that are life
threatening. To assure an ongoing favourable risk/benefit assessment for
participants enrolled onto the study, an independent Data Monitoring Committee
(DMC) will be established to provide oversight of safety and efficacy
considerations. Additionally, the DMC will provide advice to the sponsor
regarding actions the committee deems necessary for the continuing protection
of participants enrolled in the study.

New Immune system targeted therapy (immunotherapies) such as nivolumab could
potentially provide clinical benefit and improvements in the outcomes for
patients with this disease (improvement in progression free and overall
survival). However, with all experimental drugs and clinical trials, there are
known and unknown risks. Study medication and procedure related risks are
outlined in the patient information sheet in detail to ensure the patients are
fully informed before agreeing to take part in the study.