A Randomized, Open-label Phase 2 Clinical Trial of BMS-986012 in Combination with Carboplatin, Etoposide, and Nivolumab as First-line Therapy in Extensive-stage Small Cell Lung Cancer

CA001-050 is a multicentre, phase 2, open-label study Involving patients with
extensive-stage small cell lung cancer (ES-SCLC). Approximately 120 patients
will take part in this study, approximately 15 will be from the Netherlands.

ES-SCLC has an impact on mortality and quality of life. The management and
treatment of the disease has placed a huge demand on various healthcare
services.

The standard treatment for decades is currently platinum-etoposide combination
chemotherapy. Although initial response rates to platinum-etoposide
chemotherapy are up to 78% most patients relapse within 6 months, and median
overall survival is approximately 10 months. In recent years immunotherapy
targeting immune checkpoint pathways, have shown anti-tumour response and
improved overall survival for patients, across multiple cancer types, including
ES-SCLC.

2 immunotherapy treatments atezolizumab and durvalumab have been approved for
use, in combination with chemotherapy. These treatment combinations have shown
an improvement in overall survival timelines in phase 2 and phase 3 studies.

In a recent phase 2 study conducted in the United States, patients were treated
with carboplatin or cisplatin and etoposide alone or in combination with
nivolumab, an anti-PD1 monoclonal Antibody, as first-line therapy for ES-SCLC.
Nivolumab in combination with platinum-etoposide significantly improved
progression free survival (PFS) compared to platinum-etoposide alone. Overall
survival was also improved in the nivolumab with platinum-etoposide arm. The
data from this study shows comparable efficacy with current approved therapies.

Although the addition of new immune targeting therapies have shown some
benefit, it has been limited. Innovative treatment combinations are needed to
treat this disease.

BMS-986012 is a monoclonal antibody that binds to a specific protein of the
cell membrane called fucosyl-monosialoganglioside-1 (fucosyl-GM1).
Immunohistochemistry (IHC) analysis of tumour tissues samples has shown
fucosyl-GM1 to be present in approximately 50 to 70% of SCLC tumours.
BMS-986012 shows a high-binding affinity and dose dependent binding to
fucosyl-GM1. The Fc receptor of the anitbody binds to natural Killer cells
(NK), macrophages or complement resulting in tumour cell death by
antibody-dependent cellular cytoxicity, antibody-dependent cellular
phagocytosis or complement dependent cytoxicity, respectively.

A first in human study has shown clinical support for the combination of
BMS-986012 with nivolumab. This was a phase 1/2 multicenter study in patients
with relapsed / refractory SCLC. 29 participants were treated, the majority of
which were in the second line setting. As 08-May-2020, clinical benefit has
been observed in 13 of 29 participants across both dose levels in dose
escalation and expansion, including 9 partial responses (PRs), 1 complete
response (CR), and 3 stable disease (SD) responses. 1 subject achieved a PR
after treatment beyond progression. Efficacy data are preliminary and subject
to change. In general, pruritus was the main adverse event (AE) observed,
generally Grade 1 or 2 in severity and considered an on-target treatment effect
of BMS-986012. Other AEs were similar to those seen in nivolumab, again the
majority of which were Grade 1 or 2 in severity. Based on the preliminary data,

BMS-986012, either administered as monotherapy or in combination with
nivolumab, appears to be well tolerated with an acceptable safety profile.
BMS-986012 has shown to have a tolerable safety profile both as a monotherapy
and in combination with chemotherapy or nivolumab.

Given the fact that anti-PD-(L)1 therapy in combination with standard-of-care
chemotherapy has led to improved survival rates in patients with ES-SCLC in the
first-line setting and the potential areas of synergy between BMS-986012 and
nivolumab, the addition of targeted therapy seems a logical approach to treat
patients.

This randomized study is designed to demonstrate that treatment with BMS-986012
in combination with carboplatin, etoposide, and nivolumab will have acceptable
safety and tolerability and will improve PFS compared with carboplatin,
etoposide, and nivolumab alone, in newly diagnosed participants with ES-SCLC.

PET-CT Sub study:
Although fucosyl-GM1 protein receptors are known to be expressed on the
majority of SCLC tumours the receptor is most often lost from the biopsied
tissue sample, during the process of creating a paraffin-embedded tumour block
of tissue for analysis.

Therefore alternative methods for obtaining and handling tissues samples are
needed.

The purpose of this study is to test the investigational imaging tracer,
BMS-986279. The tracer is a slightly modified version of the main study
treatment drug BMS-986012, called a tracer. The tracer attaches to a specific
protein of the cell membrane called fucosyl-GM1. It is designed to be an
imaging biomarker to detect fucosyl-GM1 expression.

This study has been transitioned to CTIS with ID 2024-510700-36-00 check the CTIS register for the current data.

Study CA001-050 is a Phase 2 randomized, open label, multicenter clinical study
designed to assess the safety and tolerability, of treatment with MS-986012 in
combination with chemotherapy (carboplatin and etoposide) and nivolumab when
administered to patients with small cell lung cancer. The study will also
assess the effectiveness of this treatment combination in comparison to
treatment with chemotherapy and nivolumab alone.

PET-CT Sub study:
There are no primary or secondary objectives and endpoints.

1. Assess safety of [89Zr] fuc-GM1 PET tracer BMS-986279.
2. Examine any correlation between BMS-986279 tracer uptake of the tumor lesion
with fuc-GM1 expression levels measured by
Immunohistochemistry (IHC) and/or liquid chromatography-mass
spectroscopy (LC-MS) at baseline.
3. Review variations in baseline BMS- 986279 tracer uptake in tumor lesions.
4. Explore any associations between uptake of the tracer BMS-986279 to the
tumor lesion and anti-tumor response to BMS-986012 treatment.

Approximately 120 subjects will participate in the study. In the Netherlands it
is expected that 15 subjects will take part

The study is divided into a screening period, 2 treatment periods and a
follow-up period. During the first treatment period (an induction period)
patients will receive chemotherapy (carboplatin and etoposide) in combination
with Nivolumab and/or BMS-986012. In the second treatment period (the
maintenance period) patients will receive Nivolumab in combination with
BMS-986012 or Nivolumab alone. The effectiveness of the study treatment will be
compared to the standard of care treatment. Patients will be assigned by chance
to one of two treatment groups.

• Arm A: BMS-986012, chemotherapy and nivolumab for the first 4 cycles
followed by BMS-986012 and nivolumab from cycle 5 onwards.
• Arm B: Chemotherapy and nivolumab for the first 4 cycles followed by
nivolumab from cycle 5 onwards.

During the induction treatment period (cycle 1 to 4), each cycle is 3 weeks
long.
During the maintenance treatment period (cycle 5 onwards), each cycle is 4
weeks long. The treatment period may continue for up to 2 years after the first
dose of the study treatment.

If subjects are eligible to participate in the study after completing the
screening assessments, they will be randomised. Randomisation will be done by
an automated sorting process through IVRS (a telephone based computer system).
This maintains the integrity of the randomisation itself. To be eligible for
randomisation patients must meet the inclusion criteria and must not meet any
of the exclusion criteria.

Randomisation will be stratified based on the presence of liver metastases and
ECOG performance score (PS) 0 or 1. There is an 50% chance the patient will be
assigned to treatment Arm A and a 50% chance that the patient will be assigned
to Arm B

Patients will be treated until disease progression or unacceptable toxicity.

VISITS AND ASSESSMENTS
The screening period may consist of one or more visits to the hospital.
Patients who consent to participate in the study will undergo a physical exam,
vital signs tests, ECG, and blood and urine sample rests to determine their
eligibility. Patients will need to provide a tissue sample from their tumour.
The status of the patient's cancer will be assessed to establish a baseline.
This will be achieved by using Computer Tomography (CT) scans at screening of
the chest, abdomen, pelvis and any known suspected areas of disease. Patients
will also receive an MRI of the brain. Patients will be asked to complete
questionnaires to assess signs and symptoms of their disease and how it might
be affecting their daily activities (PGIS and LCSS).

During the treatment period patients will undergo many of the same tests and
procedures conducted during the screening period. In addition, patients will be
asked to complete the following questionnaires to assess signs and symptoms of
their disease and how it might be affecting their daily activities: PGIS, PGIC,
LCSS and FACIT GP5 up to cycle 28 Day 1. Patient-reported outcome (PROs)
collection has been limited to cycle 28 during treatment period
(approximatively 2 years of treatment). Follow-up collection remains unchanged.

Exploratory blood samples (study drug blood levels and biomarkers [taken to
measure substances in the blood such as cells, DNA and other markers]) will be
collected from all patients at certain visits throughout the study. Study drug
blood levels will be measured to assess study drug plasma concentration at
various points. Routine blood assessments will be collected for safety tests
prior to dosing.

After patients have completed the treatment period or for those who permanently
discontinue the study drug before the end of the treatment period, they will
enter a post treatment follow-up period. During this period, the study doctor
will continue to assess their health condition. Patients will visit the
hospital 3 times in the first 4 months. During the follow-up period patients
will undergo a physical examination and vital signs assessment. Patients will
be asked to complete questionnaires about their disease. Blood samples will
also be collected for routine safety checks. The remaining follow-up visits
can take place on the phone or at the hospital. These contacts will take place
about every 3 months or more often.


PET-CT SUB STUDY
Patients participating in the PET-CT sub study
Approximately 15 subjects will take part in the Netherlands.

BMS-986279 PET will be performed at select, qualified site(s) in the
Netherlands, participating in the main CA001-050 study.

Subjects will be asked to provide a separate consent from the main study
consent, to participate in this stub-study. Screening safety blood and urine
laboratory tests will be completed. The values must meet the inclusion and
exclusion criteria, as defined in section 6.2 of the main study CA001-050
protocol.

If a subject is eligible, within 3 days after providing a tissue sample
(biopsy) from the tumour (ideally on the same day) they will receive 1 tracer
injection. The tumour tissue sample will be collected during the screening
period of the main study.

Subjects will receive either 1 or 4 PET-CT scans depending on whether they are
participating in the part of the imaging study in which the optimal tracer dose
and imaging time point is being evaluated (dosimetry part).

The first 4 participants will enter the dosimetry part of the study. They will
have 4 PET-CT scans on Day 1, Day 6, Day 8 and Day 14 after receiving the
tracer injection.

In case the first 4 dosimetry subjects are not able to complete all scheduled
scans or if the dosimetry data is not sufficient to guarantee image quality, up
to 4 additional subjects from the remaining 11 will be participate in the
dosimetry.

Subjects not participating in the dosimetry part of the study will only have 1
PET-CT scan, typically between Day 5 and Day 8 after receiving the tracer
injection.

For patients participating in dosimetry:
A blood sample will be collected before or after each PET-CT scan, to evaluate
the pharmacokinetics (PK) of BMS-986279.

Subjects will undergo screening tests and assessments to determine eligibility,
and those eligible for the study will be randomised to a treatment arm in the
following ratio: 1:1 Arm A: Induction period (cycle 1 - 4) Carboplatin &
Etoposide (chemotherapy) Q3W (Intravenous administration) + BMS-986012 420 mg
Q3W (Intravenous administration over 60 mins) + Niolvumab 360mg Q3W
(Intravenous administration over 30 mins) Etoposide will also be given on Day 2
and Day 3 of each treatment cycle (cycle 1-4 only) Maintenance period (cycle 5
onwards) BMS-986012 560 mg Q4W (Intravenous administration over 60 mins) +
Niolvumab 480mg Q4W (Intravenous administration over 30 min Arm B: Induction
period (cycle 1 - 4) Carboplatin & Etoposide (chemotherapy) Q3W (Intravenous
administration) + Nivolumab 360 mg Q3W (Intravenous administration over 30
mins) Etoposide will also be given on Day 2 and Day 3 of each treatment cycle
(cycle 1-4 only) Maintenance period (cycle 5 onwards) Nivolumab 480 mg Q4W
(Intravenous administration over 30 mins) The dose of carboplatin and etoposide
will be based on respective product labels for the treatment of SCLC PET-CT SUB
STUDY There is no intervention. The sub-study is being conducted for
exploratory purposes only. Subjects will receive one intravenous injection of
the radiolabelled agent or tracer BMS-986279, after a tissue sample (biopsy) is
provided at screening. Approximately 37 MBq of the tracer will be injected.
This is a limited dose of radioactivity.

Several sources of clinical and preclinical research suggest that a combination
of BMS-986012 with nivolumab or chemotherapy show a statistically significant
improvement in antitumour activity when compared to chemotherapy alone, which
may be beneficial to patients with Extensive Stage Small Cell Lung Cancer
(ES-SCLC).

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. Based on the nonclinical safety profile of
BMS-986012 and the lack of unexpected toxicity observed in the program to date,
the potential safety risks are expected to be minimal. BMS-986012 has been
tested previously in various clinical trials where patients were treated with
either BMS-986012 alone, in combination with nivolumab or in combination with
chemotherapy. Given the experience with BMS-986012, a favourable benefit-risk
relationship has been established, which supports further investigation of the
compound. An urgent need exists for new therapies for participants with SCLC.

Therefore the study has been designed to closely monitor patients safety
throughout, to assess toxicity and safety data points. Safety monitoring will
occur at study sites, by the Sponsor, and also by an external, independent Data
Monitoring Committee (DMC). Due to the combination of the 4 drugs, there will
be additional monitoring conducted by the DMC. The DMC will assess whether the
established threshold for the safety evaluable population has been met and make
a benefit-risk recommendation to the study team. Evaluable patients are defined
as those who have completed 8 weeks of treatment or those who have discontinued
due to study drug toxicity prior to completing the evaluation period.

Medical Monitoring by the Sponsor (Safety Medical Team)
Patient safety will be monitored by the Sponsor continuously. The Sponsor will
review patient-level data entered in the clinical database as well as
aggregated safety data across studies. This approach facilitates close
monitoring of individual safety events as well as surveillance for potential
safety signals. The SMT will consist of Medical safety assessment physician,
single-case review physician, the study medical monitor(s), biostatistician and
epidemiologist, at minimum.

As part of the study, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
biopsy, ECG, blood and urine tests for safety assessment, pregnancy testing
(for females of child bearing potential) and monitoring for adverse events.

Blood will also be collected at certain visits for research purposes (PK, and
biomarker studies).

Patients will be asked to complete to complete questionnaires about their
disease and quality of life and various points throughout the study.

Women of child-bearing potential must agree to follow instructions for methods
of contraception for the duration of treatment with the study treatment.

Smoking can have an influence on the severity of lung cancer disease symptoms.
Consequently, use of tobacco products will be assessed at each study visit. Use
of a nicotine patch should be recorded as a concomitant medication.

Patients participating in the PET-CT Sub study will be required to fast for a
minimum of 4 hours before the PET-CT Scans. Although this is the first study of
BMS-986279 in humans, there are no known adverse effects from the
administration of BMS-986279.

Patients will be asked to attend the hospital for the study procedures to be
performed. Timings of these visits will be based on the protocol schedule but
will be mutually agreed with both the hospital staff and the patient to avoid
patient and/or staff attending hospital at unsocial hours, and to minimise any
inconvenience to the patient. Patients will be reimbursed for reasonable travel
expenses incurred for attending study visits.

PET-CT SUB STUDY
Patients participating in the PET-CT Sub study will be required to fast for a
minimum of 4 hours before the PET-CT Scans. Although this is the first study of
BMS-986279 in humans, there are no known adverse effects from the
administration of BMS-986279.

The amount of BMS-986279 tracer used for the PET scan is far below the
therapeutic dose of BMS-986012 that is used in clinical studies; therefore, a
pharmacological effect or an impact on normal body processes is not anticipated.

The amount of radiation exposure from BMS-986279 PET is expected to be
approximately 25 mSv and will be further assessed in the human dosimetry of
this study.

The low-dose computed tomography (CT) scan will give an additional ~3 mSv per
scan. Therefore, the total dose per participant is expected to be ~37 mSv for
dosimetry (4 low-dose CTs) and ~28 mSv (1 low-dose CT) for others.

An initial radiation dose of 37 MBq will be used based on results from prior
administrations of the tracer given to participants without any adverse events.