Phase 1/2a First-In-Human Study of BMS-986218 Monoclonal Antibody Alone & in
Combination with Nivolumab in Advanced Solid Tumors

This is a Phase 1/2a, first-in-human (FIH) study of BMS-986218, a
non-fucosylated (NF) variant of the anti-cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4) monoclonal antibody (mAb), alone and in combination with
nivolumab (anti-programmed cell death 1 [PD-1]), in humans with advanced solid
tumors.
Anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) are approved immunotherapies
that define the field of checkpoint blockade. Ipilimumab is the first
immunotherapy to show a survival advantage in late-stage metastatic melanoma
and has also demonstrated a significant 25% reduction in risk of recurrence or
death in the adjuvant treatment in melanoma. Blockade of CTLA-4 by ipilimumab
has demonstrated anti-tumor activity in other
malignancies, including lung, prostate cancer, and renal cell carcinoma (RCC).
However, no significant activity was observed in bladder, colorectal,
esophageal, pancreatic, gastric, hepatocellular, or breast cancer. Ipilimumab
is also currently in clinical development in combination with nivolumab. The
combination was associated with a greater benefit in melanoma compared to each
single agent. Benefit with the combination has also been observed in non-small
cell lung cancer (NSCLC) and RCC and is currently being evaluated in other
tumor types. The activation of a
pre-existing but attenuated immune response to cancer by checkpoint blockade is
associated with an adverse event (AE) profile that is inherent to immune
activation. Ipilimumab treatment-related AEs can involve multiple organ systems
(digestive, skin, and endocrine) that require cessation of drug and treatment
with steroids, which attenuate the AEs but do not maintain anti-tumor
responses. The combination regimen is associated with an increased incidence of
AEs compared to nivolumab monotherapy, but a similar overall AE profile.
Developing a new anti-CTLA-4 antibody
(Ab) with a more manageable AE profile and an increased depth and breadth of
response would provide a significant improvement to anti-CTLA-4 therapy.

BMS-986218 (CTLA-4.4g1fa-nf) is a human mAb against CTLA-4. The sequence is
derived from the original hybridoma 10D1. The amino acid sequence is exactly
the same as that of ipilimumab but differs solely in its glycosylation pattern.
The Ab is expressed in a fucosyltransferase-8 knockout Chinese hamster ovary
cell line.
Compared to ipilimumab, the glycans attached to the heavy chain Ab do not
contain fucose. As a consequence, the NF Ab harbors a higher affinity for Fc*
receptors and improves antibody-dependent cellular cytotoxicity (ADCC) in
addition to the CTLA-4 blocking activity of ipilimumab. T-regulatory cells
(Tregs) are highly infiltrating in tumors, where they play an important role in
impairing anti-tumor immune response by dampening effector cytolytic T-cell
function. Tregs in tumors express higher levels of CTLA-4, and some studies
have shown that part of the mechanism of action of ipilimumab is related to
Treg depletion triggered by ADCC mediation once ipilimumab binds to
CTLA-4-positive Tregs, but this aspect is controversial and ipilimumab may not
be a strong ADCC-mediating Ab.
Pre-clinical studies with anti-CTLA-4-NF show enhanced ADCC compared to
ipilimumab, correlating with more profound Treg depletion in the tumor (but not
the periphery). Therefore, it is expected that anti-CTLA-4-NF will result in a
more efficacious therapy by combining CTLA-4 blocking with the depletion of
Tregs expressing CTLA-4.
Based on this differentiated mechanism of action, this study will evaluate the
safety and preliminary efficacy of BMS-986218 alone and in combination with
nivolumab in tumors where ipilimumab did not demonstrate sufficient clinical
activity and in tumors where high Treg infiltration is correlated with worse
prognosis (eg, NSCLC, RCC, cutaneous melanoma), or in participants with
progressive or recurrent disease after prior immunotherapy with an anti-PD-1 or
anti-programmed death ligand 1 (PD-L1) containing regimen.

Primary Objectives:
- To characterize the safety, tolerability, and DLTs and to determine the
MTD/RP2D of BMS-986218 administered as monotherapy and in combination with
nivolumab in participants with advanced solid tumors
- To evaluate the efficacy and safety of BMS-986218 monotherapy relative to
ipilimumab in participants with advanced cutaneous melanoma previously treated
with anti-PD-1/PD-L1 immunotherapy (Part 2 A only)
- To evaluate the efficacy and safety of BMS-986218 alone and in combination
with nivolumab in NSCLC (Part 2B and Part 2C)
- To evaluate the efficacy and safety of BMS-986218 alone and in combination
with nivolumab in MSS CRC (Part 2D)

Secondary Objectives:
- To evaluate the preliminary efficacy of BMS-986218 alone and in combination
with nivolumab in advanced solid tumors (Part 1A and Part 1B)
- To characterize the PK and immunogenicity of BMS-986218 when administered
alone and in combination with nivolumab

Exploratory Objectives:
- To explore the potential associations between anti-tumor activity and select
biomarker measures in the tumor and peripheral blood prior to treatment and
following administration of BMS-986218 alone and in combination with nivolumab
- To explore the associations between BMS-986218 serum PK, safety, efficacy,
and clinical biomarkers
- To characterize cytokines, circulating immune subsets,TILs, gene expression
profile, proteomics, and Foxp3/CD8 receptor ratio and explore the association
between response and pharmacodynamic markers in the tumor and peripheral blood
- To measure Tregs, and assess Treg change over time and in association with
response
- To assess the preliminary efficacy of BMS-986218 alone and in combination
with nivolumab in advanced solid tumors using iRECIST
- To assess the OS in participants treated with BMS-986218 alone and in
combination with nivolumab
- To characterize the PK and immunogenicity of nivolumab when administered in
combination with BMS-986218
- To assess the potential effect of BMS-986218 when administered as monotherapy
on the QTc interval
- To evaluate TTD in QoL and physical functioning (Part 2A)
- To evaluate changes in QoL, health status and patient reported tolerability
(Part 2A, Part 2B, Part 2C,and Part 2D)

This is a Phase 1/2a, open-label study of BMS-986218, administered as a single
agent and in combination with nivolumab, in participants with advanced solid
tumors. The study is comprised of 2 parts: dose escalation and dose expansion.

Part 1: The Dose Escalation Phase, where the dose of BMS-986218, given alone or
in combination with nivolumab, is escalated to determine the maximum tolerated
dose/recommended Phase 2 dose (MTD/RP2D).
The Safety Evaluation of Combination Doses of BMS-986218 with Nivolumab (Part
1B) will evaluate the safety and tolerability of doses of BMS-986218 in
combination with nivolumab. The combination of BMS-986218 with nivolumab will
be evaluated using a BLRM employing the EWOC principle. Starting at least 1
dose level lower than the current monotherapy dose level of BMS-986218
demonstrating an acceptable safety
profile, BMS-986218 will be studied in combination with a 480 mg Q4W flat dose
of nivolumab.
Determination of the MTD for the Safety Evaluation of Combination Doses of
BMS-986218 with Nivolumab (Part 1B) will be guided by BLRM-copula.

Part 2: The Expansion Phase, where the cohort of participants is expanded to
gather additional safety, tolerability, preliminary efficacy, pharmacokinetic
(PK), and pharmacodynamic information in specific patient populations,
regarding BMS-986218 alone and in combination with nivolumab.
- The Randomized BMS-986218 Monotherapy Cohort Expansion in Cutaneous Melanoma
(Part 2A) will evaluate the preliminary efficacy of BMS-986218 monotherapy
relative to ipilimumab monotherapy in a cohort of cutaneous melanoma
participants who have received prior immunotherapy with an anti-PD-1 or
anti-PD-L1 containing regimen and must have progressive or recurrent disease
after prior PD-1/PD-L1 directed therapy. Three dose levels for BMS-986218 from
the Part 1A Q4W monotherapy escalation will be evaluated that have had at least
6 DLT evaluable participants and meet safety criteria: one at 7 mg Q4W, one at
20 mg Q4W, and one at 70 mg Q4W. Evaluating multiple different doses will aid
in selecting the regimen that will ultimately provide the optimal benefit-risk
ratio to future study participants. Participants must not have received prior
anti-CTLA-4 therapy in the advanced or metastatic setting.
- The Randomized BMS-986218 Monotherapy Cohort Expansion (Part 2B) will
evaluate the preliminary efficacy of BMS-986218 in tumor types in which a high
level of Treg infiltration correlates with poor prognosis. The tumor types to
be evaluated will include NSCLC; other tumor types may be explored in the
future. Participants should have received and then progressed on or
relapsed/recurrence after anti-PD-1/PD-L1 directed therapy in monotherapy or in
combination with chemotherapy. Prior anti-CTLA-4 therapy is allowed for no more
than 20% of participants. Participants who have been intolerant to prior
immunotherapy are excluded. Three dose levels or schedules for BMS-986218 from
the Part 1A Q4W monotherapy escalation will be evaluated that have had at least
6 DLT evaluable participants and meet safety criteria: one at 7 mg Q4W, one at
20 mg Q4W, and one at 70 mg Q4W. The rationale for evaluating multiple dose
levels is to optimize the benefit-risk ratio for the participant.
- In the BMS-986218 Combination Therapy Cohort Expansion (Part 2C) in NSCLC,
the preliminary efficacy and safety of BMS-986218 in combination with nivolumab
will be assessed in participants with NSCLC who have progressed or relapsed
after anti-PD-1/PD-L1 therapy. Participants must not have received prior
anti-CTLA-4 therapy in the advanced or metastatic setting. One or more doses to
be evaluated in Part 2C will be selected from the range of doses assessed as
tolerable in Part 1B, and which do not exceed the MTD or highest dose
administered that has cleared safety. These dose(s) will be selected based on
the totality of available safety, tolerability, efficacy, PK and PD data. The
evaluation of efficacy in Part 2C will initially occur at one or more dose
levels starting with up to 20 participants at each dose level. Additional
participants up to 40 at a dose level may be evaluated following initial signal
assessment. In Part 2C, participants will be treated Q4W for up to 2 calendar
years regardless of treatment delays.
- In the BMS-986218 Combination Therapy Cohort Expansion in MSS CRC (Part 2D),
the preliminary efficacy and safety of BMS-986218 in combination with nivolumab
will be assessed in participants with MSS CRC who have progressed or relapsed
on at least 1 prior standard therapy. Participants must not have received prior
anti-CTLA-4 therapy in the advanced or metastatic setting. The dose to be
evaluated in Part 2D will be selected from the range of doses assessed as
tolerable in Part 1B, and which do not exceed the MTD or highest dose
administered that has cleared safety. The dose will be selected based on the
totality of available safety, tolerability, efficacy, PK, and PD data.
Regardless of whether or not RAS mutation status is known, all participants
will be tested during screening for extended RAS (NRAS and KRAS) and BRAF
mutation status. Results from this testing at screening is not required prior
to receiving treatment on study. The RAS status evaluation will be conducted
with the goal of enrolling approximately 20 participants each with either
mutation or wild-type with respect to extended RAS status. The Sponsor may
elect to prioritize enrollment of participants based on mutation status. In
Part 2D, participants will be treated Q4W for up to 2 calendar years regardless
of treatment delays.

The duration of the study will be approximately 5 years.

All dosing will occur every three or four weeks as follows:
- Part 1B (BMS-986218 + Nivolumab), will be administered every 4 weeks on Day 1
of each 28 days cycle.
- Part 2A (BMS-986218 monotherapy for cutaneous melanoma subjects), will be
administered every 4 weeks on Day 1 of each 28 days cycle.
- Part 2A (Ipilimumab monotherapy for cutaneous melanoma subjects) will be
administered every 3 weeks on Day 1 of each 21 day cycle.
- Part 2B (BMS-986218 monotherapy for NSCLC- adenocarcinoma or squamous cell
subtypes), will be administered every 4 weeks on Day 1 of each 28 days cycle.
- Part 2C (NSCLC participants) (BMS-986218 + Nivolumab), will be administered
every 4 weeks on Day 1 of each 28 days cycle.
- Part 2D (MSS CRC participants) (BMS-986218 + Nivolumab), will be administered
every 4 weeks on Day 1 of each 28 days cycle.

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 women of child bearing potential), and monitoring for
adverse events.
In addition,patients will undergo radiographic assessment of their tumours (by
CT or MRI) as per follow:
Body Imaging
Part 2A : Tumour imaging assessment to be performed at 12 weeks from the first
dose, regardless of dose delays, if any (+/- 1 week), prior to initiating the
next cycle of treatment.
Part 2B, 2C and 2D : Tumour imaging assessment to be performed Q8W from the
first dose (+/- 1 week), prior to initiating next cycle of treatment.
After that, subsequent tumour imaging assessments to be performed Q8W (+/- 1
week), prior to initiating the next cycle of treatment.
Participants who remain free of subsequent therapy will undergo tumour imaging
assessment Q8W (+/- 1 week) until subsequent tumour-directed therapy is
initiated or until 48 weeks after discontinuation of trial treatment/EOT visit,
and then Q12W (+/- 2 weeks) for a total duration of 2 years.

Brain Imaging: Participants with history of brain metastasis will have MRI
performed as clinically indicated and at the discretion of the Investigator.