A Phase 1/2 Multicenter Study of BMS-986012 in Subjects with Relapsed / Refractory Small Cell Lung Cancer (CA001-030)

Lung cancer has been the most common cancer in the world. It is also the most
common cause of death from cancer. Approximately 57% of patients have
metastatic disease at diagnosis, and in these patients the prognosis is poor;
with a 5-year survival less than 4%. These statistics include small cell lung
cancer (SCLC), which has an even poorer prognosis. Patients with SCLC rarely
survive more than a few months without treatment. However, SCLC is highly
responsive to multiple chemotherapeutic drugs, and chemotherapy dramatically
prolongs survival compared to best supportive care. Management of SCLC depends
on the stage of the disease at diagnosis. About 70-90% of newly-diagnosed
patients will respond to first-line therapy chemotherapy. Regimens containing a
platinum and etoposide are often chosen as first-line treatment in patients
with good performance status. However, median survival is 9-11 months and
long-term survival is rare. Fewer than 5% of patients with extensive disease
live beyond 2 years, even with multi-agent, intensive treatment with multiple
lines of therapy.

Few new agents with activity in SCLC have been identified, and none have been
successful thus far in Phase 3 studies. Fucosyl-GM1 (fuc-GM1) offers a cell
surface target known to be expressed in 70% of SCLC tumors by IHC. Fuc-GM1 has
been implicated in promoting cell proliferation, angiogenesis and immune tumor
cell evasion. Antibodies to fuc-GM1 have been shown to inhibit tumor growth and
to induce apoptosis of antigen
positive cells. BMS-986012 is a first-in-class fully human immunoglobulin G 1
monoclonal antibody that specifically binds to the fuc-GM1. In vivo
results in mice demonstrate that BMS-986012, as a single agent, is a potent
inhibitor of human SCLC tumor growth and can improve outcomes when combined
with chemotherapy. This first-in-human study will evaluate safety,
tolerability, and preliminary efficacy of this study drug in the SCLC
population.

Primary Objective
The primary objectives are to determine the multidose safety, tolerability,
dose limiting toxicities (DLTs), and the maximally tolerated dose (MTD) of
BMS-986012 administered as monotherapy in subjects with relapsed/refractory
SCLC.

Secondary Objectives
- To characterize the pharmacokinetics (PK) of BMS-986012.
- To investigate the preliminary antitumor activity of BMS-986012 as
monotherapy as measured by objective response rate (ORR), duration of response,
and progression-free survival (PFS).
- To characterize the immunogenicity of BMS-986012.
- To assess the effect of BMS-986012 on the QT interval.

Exploratory Objectives
- To explore associations between shed fucosyl-GM1 (fuc-GM1) at baseline and
antitumor activity.
- To explore associations between baseline fuc-GM1 positive circulating tumor
cells (CTCs) and anti-tumor activity.
- To explore associations of baseline NK-cell numbers, phenotype (by FACS) and
complement levels with pharmacodynamic changes and anti-tumor activity.
- To explore fuc-GM1-related biomarkers such as, but not limited to, markers of
neuroendocrine differentiation as potential prognostic markers of anti-tumor
activity.
- To explore associations between Fc gamma receptor (Fc*R) polymorphisms with
anti-tumor
activity.
- To explore the PK-PD relationship(s) of BMS-986012.
- To assess overall survival (OS).

This is an open-label ascending multiple dose study of BMS-986012 administered
once every 21 days (one cycle) as a single agent and will be conducted in two
parts. Dose escalation (Part 1) is to identify a potential MTD, (or maximum
administered dose (MAAD) if no MTD is determined). In Part 2, additional
subjects with SCLC will be enrolled at two doses at or below the MTD or MAAD to
confirm safety and evaluate efficacy at
these doses. The site in the Netherlands will only participate in part 2.

Subjects will complete up to 4 periods in the study: Screening (within 28 days
prior to administration of study medication), Treatment (until meeting
protocol-specified discontinuation criteria), Clinical Follow-up (approximately
100 days, see Table 5.1-3) and Survival Follow-up (up to approximately 3 years
following end of treatment).

The medicinal intervention includes BMS-986012 therapy. Study drug will be
supplied by the sponsor.

Part 2 will evaluate toxicity and preliminary efficacy of BMS-986012 as
second-line monotherapy in subjects who have relapsed following first-line
chemotherapy as follows: Cohort A: <= 3m response duration (refractory) at the
MTD/MAAD, Cohort B: <= 3m response duration (refractory) at a dose level below
the MTD/MAAD, Cohort C: > 3m response duration (sensitive) at the MTD/MAAD, and
Cohort D: > 3m response duration(sensitive) at a dose level below the MTD/MAAD.
The response duration referenced above is relative to the prior first-line
therapy.

Each treatment cycle consists of an IV infusion of BMS-986012 every 21 days.

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. In addition, every 6 weeks, patients will undergo radiographic
assessment of their tumours (by CT or MRI) until disease progression or
treatment discontinuation whichever occurs later.
Subjects may have pre-treatment biopsies performed or archival material, if
available, will be requested. Blood will also be collected at certain visits
for research purposes (PK, PD, immunogenicity and biomarker studies).
The frequency of visits and number of procedures carried out during this trial
would typically be considered over and above standard of care. These
procedures are conducted by medically trained 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.
Patients will be instructed when to contact their treating physicians if side
effects occur and are given a patient card with detailed information.