Non-Comparative, Open-Label, Multiple Cohort Phase 1/2 Study of Nivolumab and Nivolumab plus Ipilimumab in Subjects with Virus-Positive and Virus-Negative Solid Tumors

CA209-358 is a multicentre, phase 1/2 study involving an investigational drug
called Nivolumab given alone in patients with neoadjuvant Squamous Cell
Carcinoma of Head and Neck (SCCHN), or neoadjuvant Cervical, Vaginal, Vulvar
carcinoma (GYN) or Merkel cell carcinoma (MCC); or patients with viral positive
metastatic SCCHN, gastric cancer (GC), GYN, MCC or Nasopharyngeal carcinoma
(NPC).
For patients with metastatic disease treatment options are limited. For gastric
carcinoma there is a poor survival prognosis for Stage II-III tumors and
advanced and metastatic gastric cancer with current treatment options.
For nasopharyngeal carcinoma there is poor overall survival and no established
standard of care for patients who progress after first line of chemotherapy in
the recurrent or metastatic setting.
For SCC head and neck there is no effective standard of care that provides
survival benefits beyond 4 - 6 months in second line platinum refractory
recurrent or metastatic SCCHN.
For the GYN carcinomas after first line chemotherapy, there is no standard of
care that has demonstrated improved benefit over best supportive care.
For metastatic MCC the disease is incurable with chemotherapy with very poor
overall survival (<10%).

Therefore, for all these cancers there is classed to be an unmet medical need.

It has been established that virus associated tumors express PD-1 ligands. The
hypothesis of this study is that these tumor types may be more likely to
respond to nivolumab which blocks the interaction of PDL-1/PD-L2 and PD-1, in
two settings, a neoadjuvant or window of opportunity cohort in patients with
resectable disease and a cohort of patients with metastatic disease who have
progressed after one line of therapy or refused standard of care.

Nivolumab and ipilimumab has been shown to have survival benefit in patients
across a number of tumor types.

Approximately 84 neoadjuvant and 400 metastatic patients will take part
globally.

In patients with neoadjuvant disease the purpose of the study is to define the
safety and tolerability of the drug. In patients with metastatic disease the
purpose is to determine if treatment with Nivolumab or Nivolumab and ipilimumab
will lead to clinical benefit in patients in those tumour types.

This is an Non-Comparative, Open-Label, Multiple Cohort Phase 1/2 Study of
Nivolumab and Nivolumab plus Ipilimumab in Subjects with Virus-Positive and
Virus-Negative Solid Tumors
The first cohort, a neoadjuvant treatment regimen of 84 subjects in 3 tumor
types, has the following major goal:
Investigate the safety and tolerability of neoadjuvant nivolumab
administration, which is the primary objective of this cohort;

Enrollment for each tumor type in the neoadjuvant cohort will pause after the
first 10 subjects are enrolled to assess safety and determine the number of
subjects with chemotherapy/radiation (GYN patients where appropriate) or
surgical (SCCHN, MCC, and GYN patients) delays beyond 4 weeks from the planned
date. If * 3 of the first 10 subjects for a single tumor type have delays
beyond 4 weeks from the planned surgery date or planned start date for
chemoradiation due to a nivolumab immune-related adverse event(s) specified in
the label, that specific tumor cohort will close. The remaining tumor types in
the neoadjuvant cohort will not close enrollment should a tumor type(s) close
due to a delay in surgery due to nivolumab. If the first 8 patients for a
single tumor type experience no delay, a pause in enrollment will not be
required.
The Neoadjuvant Cohort will enroll 3 tumor types: HPV positive and negative
SCCHN, HPV-positive cervical/vaginal/vulvar cancers, and
polyomavirus-associated Merkel Cell carcinoma. The SCCHN tumor types will
require virus testing prior to study drug assignment. Twenty-one virus positive
and 21 virus negative SCCHN subjects will be enrolled. The other tumor types
will not require prospective virus testing for entry, given the high (> 85%)
infection rate. The virus negative group will serve as a control group for the
biological analysis. Subjects will have an initial biopsy, receive 2 doses of
nivolumab, followed by a surgical resection or chemotherapy/radiation. No other
pre-surgical therapy is allowed.

The second cohort, a treatment regimen of 400 subjects in the
recurrent/metastatic setting in 5 tumor types, has the following major goal:
Evaluate the investigator-assessed objective response rate (ORR) of nivolumab
monotherapy or nivolumab/ipilimumab combination, which is the primary objective
of this cohort

The Metastatic Cohort will enroll subjects in the metastatic or recurrent
setting with their disease. This cohort will be comprised of the 5 following
tumor types: EBV-related Gastric, EBV-related nasopharyngeal, HPV-positive
SCCHN, HPV-positive cervical/vulvar/vaginal, and polyomavirus-associated Merkel
Cell carcinoma. The SCCHN and gastric tumor types will require virus testing to
ensure positivity prior to treatment. Nivolumab will be administered until
unacceptable toxicity or disease progression as defined by RECIST 1.1.

The investigational product is: nivolumab (BMS-936558) and ipilimumab
(BMS-734016).

Neoadjuvant Cohort subjects will receive two doses of nivolumab administered at
240 mg IV on Day 1 and on Day 15.

Metastatic Cohort subjects will receive treatment depending on study arm (see
protocol).

Subjects who complete the neoadjuvant portion of the study and complete
standard of care treatment who develop unresectable recurrent or metastatic
disease within 1 year of surgical resection or completion of standard of care
(whichever is later) may receive treatment with nivolumab on Day 1 of a
treatment cycle every 2 weeks (14 days), if eligible.

As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements
including oxygen saturation levels, blood tests for safety assessment,
pregnancy testing (for females of child bearing potential) and monitoring for
adverse events. For patients in the neoadjuvant cohort they will be required to
provide a biopsy after nivolumab dosing though this may form part of their
surgical resection. For patients in the metastatic cohort, every 8 weeks (from
week 9 onwards) patients will undergo radiographic assessment of their
tumour(s) (by Spiral CT or MRI) through the first year, then every 12 weeks
until disease progression or treatment discontinuation whichever occurs later.
An additional PET scan would be required to confirm complete response.

Blood samples will be collected at certain visits for research purposes (PK and
immunogenicity) including Biomarker samples. The frequency of visits and number
of procedures carried out during this trial would typically be considered over
and above standard over care. These procedures are carried out by trained
medical professionals and every effort will be made to minimize any risks or
discomfort to the patient. Treatment for cancer often have side effects,
including some that are life-threatening. Because of the potential for
clinically meaningful nivolumab related AEs requiring early recognition and
prompt intervention, management algorithms have been developed for suspected
pulmonary toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity,
neurological toxicity and nephrotoxicity.

The clinical benefit of nivolumab, as measured by independent radiologic review
committee (IRRC)
assessed objective response rate (ORR) will be utilized.