A Phase 3 Randomized Clinical Trial of Nivolumab alone, Nivolumab in
Combination with Ipilimumab, or an Investigator's Choice Chemotherapy in
Participants with Microsatellite Instability High (MSI-H) or Mismatch
Repair Deficient (dMMR) Metastatic Colorectal Cancer

Colorectal cancer is one of the leading causes of cancer-related death
worldwide with a 5-year survival rate of approximately 14% in patients with
metastatic disease (mCRC).
The current Standard of Care (SOC) for the patients with dMMR/MSI-H mCRC who
haven*t received any prior systemic therapy (1L) or who have received one prior
line of systemic therapy (2L) consists of combination of cytotoxic agents that
are frequently used together with anti-VEGF or - anti-EGFR antibodies. These
combinations are referred as chemotherapy.
Patients with metastatic dMMR/MSI-H CRC have a worse outcome when treated with
this standard of care, yet they may have potential durable benefit if treated
with checkpoint inhibitors.

The purpose of this study is to assess the effectiveness (how well the drug
works), safety, and how well the patient can tolerate one of the following
three treatment regimens:
• A - nivolumab
• B - nivolumab plus ipilimumab
• C - chemotherapy (SOC)
Nivolumab and Ipilimumab are antibodies (a type of human protein) that are
being tested to see if it will stimulate the body*s immune system to work
against tumour cells. Nivolumab is approved to treat certain cancer types in
many countries (including countries in the EU and the US). Nivolumab is
approved in the US for treatment of mCRC (Aug-2017).

In this trial, patients will undergo screening tests to check that it is safe
for them to take part in the trial. Those patients who are suitable will be
randomly allocated to receive one of the treatment regimens.

Patients will undergo the following procedures during the study: tumour tissue
biopsy (possible), CT/MRI scans, physical exams, blood, urine and stool
sampling for routine safety testing and study specific testing.

974 participants are expected to be treated in the study, with approximately 28
participants treated in the NLD. The study is sponsored by Bristol Myers Squibb

This study has been transitioned to CTIS with ID 2023-503956-29-00 check the CTIS register for the current data.

Primary Objective:
All lines
1) To compare the BICR-assessed PFS of participants with centrally confirmed
dMMR/MSI-H mCRC and randomized to nivolumab plus ipilimumab combination therapy
arm or nivolumab monotherapy arm

1L
1) To compare the BICR-assessed PFS of participants with centrally confirmed
dMMR/MSI-H mCRC who have not received prior treatment for metastatic disease
and randomized to nivolumab plus Ipilimumab combination therapy arm or
chemotherapy arm


Secondary Objectives:

All lines
1) To compare the BICR-assessed ORR of participants with centrally confirmed
dMMR/MSI-H mCRC and randomized to nivolumab plus ipilimumab combination therapy
arm or nivolumab monotherapy arm.

2) To compare the OS of participants with centrally confirmed dMMR/MSI-H mCRC
and randomized to nivolumab plus ipilimumab combination therapy arm or
nivolumab monotherapy arm.

3) To estimate the Investigator-assessed PFS of participants with centrally
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus ipilimumab
combination therapy arm or nivolumab monotherapy arm.

4) To estimate the BICR-assessed PFS of participants with dMMR/MSI-H mCRC per
local testing who were randomized to nivolumab plus ipilimumab combination
therapy arm or nivolumab monotherapy arm

1L:
1)To compare the BICR-assessed PFS of participants with centrally confirmed
dMMR/MSI-H mCRC who have not received prior treatment for metastatic disease
and randomized to nivolumab plus Ipilimumab combination therapy arm or
nivolumab monotherapy arm.

2) To compare the BICR-assessed ORR of participants with centrally confirmed
dMMR/MSI-H mCRC who have not received prior treatment for metastatic disease
and randomized to nivolumab plus Ipilimumab combination therapy arm or
chemotherapy arm.

3) To compare the BICR -assessed ORR of participants with centrally confirmed
dMMR/MSI-H mCRC who have not received prior treatment for metastatic disease
and randomized to nivolumab plus Ipilimumab combination therapy arm or
nivolumab monotherapy arm.

4) To compare the OS of participants with centrally confirmed dMMR/MSI-H mCRC
who have not received prior therapy and randomized to nivolumab plus ipilimumab
combination therapy arm or nivolumab monotherapy arm.

5) To estimate the BICR-assessed PFS of participants with centrally confirmed
dMMR/MSI-H mCRC who have not received prior treatment for metastatic disease
and randomized to nivolumab monotherapy arm or chemotherapy arm.

6) To estimate the OS of participants with centrally confirmed dMMR/MSI-H mCRC
who have not received prior therapy and randomized to nivolumab plus ipilimumab
combination therapy arm or chemotherapy arm.

7) To estimate the BICR-assessed ORR of participants with centrally confirmed
dMMR/MSI-H mCRC who have not received prior treatment for metastatic disease
and randomized to nivolumab monotherapy arm or chemotherapy arm.

8) To estimate the BICR-assessed PFS of participants with dMMR/MSI-H mCRC per
local testing who have not received prior treatment and randomized to nivolumab
plus ipilimumab combination therapy arm or chemotherapy arm.

9) To estimate the BICR-assessed PFS of participants with dMMR/MSI-H mCRC per
local testing who have not received prior treatment and randomized to nivolumab
plus ipilimumab combination therapy arm or nivolumab monotherapy arm.

Companion Diagnostics (CDx) (all lines and 1L):
1) To estimate the BICR-assessed PFS of participants with confirmed dMMR/MSI-H
status by each central test who have not received prior therapy and randomized
to nivolumab plus ipilimumab combination therapy arm or chemotherapy arm.

2) To estimate the BICR-assessed PFS of participants with confirmed dMMR/MSI-H
status by each central test and randomized to nivolumab plus ipilimumab
combination therapy arm or nivolumab monotherapy arm.


Crossover cohort:
1) To estimate the BICR-assessed PFS of participants with centrally confirmed
dMMR/MSI-H mCRC treated in the crossover cohort.

2) To estimate the BICR-assessed ORR of participants with centrally confirmed
dMMR/MSI-H mCRC treated in the crossover cohort

This is a Phase 3, randomised, open-label 3-arm study of nivolumab monotherapy
(Arm A), nivolumab plus ipilimumab combination therapy (Arm B) or an
investigator*s choice chemotherapy (Arm C) for the treatment of participants
with recurrent or metastatic dMMR/MSIH CRC. The study will enroll participants
across all lines of therapy, however randomisation to Arm C will be restricted
to participants who have received no more than 1 prior line of systemic therapy
(0 or 1). Study specific definition of the line of therapy (number of prior
systemic treatments for metastatic disease) is provided in Appendix 10 of the
protocol. Participants will receive treatment until progression, toxicity,
discontinuation for other reasons, or reaching maximum treatment duration.
Study participants from all three arms that discontinue study treatment will
enter the Follow Up phase (first treatment Follow Up) and will follow the
assessment schedules outlined in Table 2-5 of the protocol. Participants
assigned to Arm C that experience documented progression of disease (PD) per
RECIST 1.1 by Blinded Independent Central Review (BICR) will have an option to
crossover to nivolumab plus ipilimumab therapy (Crossover Cohort) provided that
they complete at least Follow Up Visit 1 within the Follow Up phase and meet
all other crossover criteria outlined in the protocol Section 6.2.1. Crossover
Cohort participants will receive treatment until progression, toxicity,
discontinuation for other reasons, or reaching maximum treatment duration.
After study treatment discontinuation, they will also enter the Follow Up phase
(second treatment Follow Up) and will follow the assessment schedules outlined
in Table 2-5 of the protocol

Patients will be randomly assigned to one of three treatment Arms:
Arm A (Nivolumab monotherapy): Nivolumab 240 mg administered every 2 weeks
(Q2W) for up to 6 doses (2 cycles), followed by nivolumab 480 mg administered
every 4 weeks (Q4W) until disease progression, unacceptable toxicity,
withdrawal of consent, or until reaching maximum treatment duration.
Arm B (Nivolumab plus ipilimumab): Nivolumab 240 mg plus ipilimumab 1 mg/kg
both administered every 3 weeks (Q3W) for up to 4 doses (2 cycles), followed by
nivolumab 480 mg administered every 4 weeks (Q4W) until disease progression,
unacceptable toxicity, withdrawal of consent, or until reaching maximum
treatment duration.
Arm C (Investigator*s Choice Chemotherapy): One of 6 Investigator*s choice
chemotherapy regimens (FOLFOX; FOLFOX + bevacizumab; FOLFOX + cetuximab;
FOLFIRI; FOLFIRI + bevacizumab; FOLFIRI + cetuximab) administered every 2 weeks
(Q2W) until disease progression, unacceptable toxicity, withdrawal of consent,
or until reaching maximum treatment duration.
Details of Arm C treatment are listed below:
FOLFOX- oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 400 mg/m2
bolus followed by fluorouracil 2400 mg/m2 in continuous infusion administered
over 46 hours IV on Day 1, Day 15 and Day 29 during Cycles 1 and 2. Starting
from Cycle 3 the drugs will be administered on Day 1 and Day 15 of each cycle.
FOLFOX +Bevacizumab - Bevacizumab 5 mg/kg administration will then be followed
by oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 and
fluorouracil 2400 mg/m2 in continuous infusion administered over 46 hours IV on
Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter on Day 1 and Day
15 for all subsequent cycles.
FOLFOX + Cetuximab - Cetuximab 500 mg/m2 administration will then be followed
by oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 and
fluorouracil 2400 mg/m2 in continuous infusion administered over 46 hours IV on
Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter on Day 1 and Day
15 for all subsequent cycles
FOLFIRI - irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400
mg/m2 and fluorouracil 2400 mg/m2 in continuous infusion administered over 46
hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles. Starting from
Cycle 3 the drugs will be administered on Day 1 and Day 15 of each cycle.
FOLFIRI + Bevacizumab - Bevacizumab 5 mg/kg administration will then be
followed by irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400
mg/m2 and fluorouracil 2400 mg/m2 in continuous infusion administered over 46
hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter on
Day 1 and Day 15 for all subsequent cycles.
FOLFIRI + Cetuximab - Cetuximab 500 mg/m2 administration will then be followed
by irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 and
fluorouracil 2400 mg/m2 in continuous infusion administered over 46 hours IV on
Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter on Day 1 and Day
15 for all subsequent cycles

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, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events & serious adverse events.
Stool samples will be collected at screening and once during treatment.
Patients will be asked to complete questionnaires (EQ-5D-3L, EORTC QLQ-C30 and
QLQ-CR29) about their quality of life. Blood will also be collected at certain
visits for research purposes (PK, immunogenicity and biomarker studies). If
there is no archival tumour tissue available or the sample was taken too long
ago (>= 3 months), patients will be required to have a biopsy in order to
participate. Surgery will be performed on patients post completion of
neo-adjuvant therapy. A tumour biopsy will also be performed at disease
progression. Patients will undergo radiographic assessment of their tumours by
CT or MRI at screening and brain MRI if clinically indicated. Subsequent
imaging assessments will be performed every 6 weeks for the first 24 weeks,
then every 8 weeks until disease recurrence or progression (confirmed by
blinded independent central review). The frequency of visits and number of
procedures carried out during this trial would be typically 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. A Data monitoring committee will not be used for
this study and a rationale for this has been provided by BMS and enclosed
within this application. BMS will conduct rigorous safety monitoring to ensure
patients* safety by regularly and systematically reviewing safety data; the
reported safety events will be closely followed-up; sites and study
investigators will receive training on the implementation of nivolumab toxicity
management strategies. New immune system targeted therapy (immunotherapies)
such as nivolumab could potentially provide clinical benefit and improvements
in the outcomes for patients with this disease. 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.