A Phase I/IIa Trial With BMS-986158, a Small Molecule Inhibitor of the Bromodomain and;Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors

Patients with relapsed or refractory solid tumours have a very poor prognosis.
Despite advances in multimodal therapy, increases in overall survival in these
patient populations have been limited. The unmet need resides in the lack of
effective treatments to achieve long term survival, hence the need to test
compounds that have novel mechanisms of action, such as BET inhibitors, in
clinical studies.
Therapies that target the immune system to activate antitumour immune responses
have become an intense area of clinical and preclinical oncology research.
Several immunotherapeutic drugs have come to the market in recent years
including ipilimumab, pembrolizumab and nivolumab. Optimal combination partners
for these agents that will allow maximal antitumour effects will be critical to
realise the full potential of both immunotherapeutics and targeted anticancer
agents such as BMS-986158.
Acetylation of lysine residues is a widespread protein post-translational
modification (PTM), and extensively relevant to modulation of cellular
processes, including protein conformation and interaction. Histone lysine
acetylation was historically proposed to be a hallmark of transcriptionally
active genes. Therefore, deregulation of histone acetylation patterns often
drives the abnormal expression of oncogenes resulting in proliferation and
tumorigenesis. Bromodomain (BRD) proteins have been identified to regulate
lysine acetylation. Their interaction with acetylated chromatin influence gene
transcription.
Bromodomain and extra-terminal (BET) proteins belong to human BRD proteins
family, comprised of 4 members (BRD2, BRD3, BRD4, and BRDT). BET proteins have
been identified in oncogenic rearrangements, leading to highly oncogenic fusion
proteins, and thus play key roles in development of several types of cancer.
For example, BRD4 was found to form fully functional fusion gene with the NUT
(nuclear protein in testis) gene in NUT midline carcinoma, an aggressive
squamous cell carcinoma. BRD4 gene amplification and overexpression has been
correlated with adverse prognosis in many solid tumours.

Two early BET inhibitors, called JQ1 and I-BET, demonstrated therapeutic
effects in multiple tumour models of hematologic malignancies including
multiple myeloma (MM), as well as in solid tumours. The therapeutic activity of
BET inhibitors in hematologic malignancies correlates with transcriptional
suppression of key proto-oncogenes, including MYC and BCL2. c-MYC is the most
frequently amplified oncogene and is deregulated in 40% to 70% of all cancers;
in particular, amplification or over-expression of MYC is frequently observed
in lung cancer, ovarian cancer and breast cancer
Efforts to inhibit MYC have not been successful to date. Due to their mechanism
of action, BET inhibitors have the potential to effectively target the MYC
oncogene mediated tumour development.
Examination of BRD4 interaction with genes whose transcription is highly
sensitive to BET inhibitor JQ1, led to the observation that BRD4 (and
potentially other BET family members) localises to the promoter regions of many
oncogenes. Additionally, BRD4 is enriched in enhancer regions, leading to high
expression levels of many growth promoting genes, in addition to MYC oncogene.
In particular, the level of BRD4 presence in the so called super-enhancer
regions has been found to be remarkable. Super-enhancers are considerably
larger than typical gene enhancer regions and are densely populated by
transcription factors, leading to strong activation of gene transcription.
Super-enhancers are present in the many key oncogenes. As BRD4 is particularly
enriched in these critical control regions, it is suggested that inhibition of
the bromodomain activity of BRD4 will lead to transcriptional repression of
these key oncogenes. The close relationship between super-enhancers and BRD4
may explain why cancer cells are specifically sensitive to BRD4 inhibition,
despite ubiquitous BRD4 expression in a wide range of cells. Because tumour
cells are frequently highly reliant on high oncogene expression for survival,
selective disruption of super-enhancers by a BET inhibitor may represent an
effective strategy for the treatment of multiple tumour types with an
acceptable safety profile.

BMS-986158 has been tested against a wide-array of cancer cell lines in vitro
and has demonstrated potent cytotoxicity against multiple haematologic and
solid tumours. Many of the most sensitive cancer types are driven by c-MYC
including multiple myeloma (MM), acute myeloid leukemia (AML) and small cell
lung carcinoma (SCLC). In particular, BMS-986158 demonstrated potent and
selective cytotoxic activity in multiple SCLC cell lines.
BMS-986158 was evaluated in vivo in a panel of patient-derived xenografts (PDX)
in mice. In an ovarian cancer PDX model that was determined to have
amplification of the BRD4 gene, tumour regression was observed during the
BMS-986158 dosing period suggesting that tumours with BRD4 amplification may be
particularly sensitive to BET inhibition. Analyses of the human cancer genome
atlas (TCGA) data show that approximately 27% of ovarian tumours of serous
histology, that are BRCA 1/2 wildtype, also have BRD4 amplification.
Moreover, therapeutic effects of BET inhibitors were also observed in xenograft
models of breast cancer.
In the pivotal 1-month oral toxicity studies, the highest non-severely toxic
dose (HNSTD) in dogs was 0.15 mg/kg. The dog was considered the most
appropriate species for calculation of the maximum recommended starting dose
(MRSD) in human trials because a non-tolerated dose was attained in dog (i.e.
the more sensitive species) but not rat. The starting dose of 0.75 mg/day was
selected based upon the human equivalent dose (HED; scaled by body-surface
area) of the HNSTD in dogs. Projections of the human minimum efficacious dose
are 4 to 11 mg/day. For further details please refer to Protocol section 1.4
and Investigator Brochure.
The nonclinical toxicity profile of BMS-986158 has been well characterised and
it supports first-in-human dosing in cancer patients, currently ongoing in the
Escalation part of the study. As mentioned previously, patients in the
Netherlands will only participate to the subsequent cohort Expansion part of
the study.

To assess the safety and tolerability and to define the dose limiting
toxicities (DLT) and maximum tolerated dose (MTD) of BMS-986158 as for subjects
with selected advanced solid tumors.

Study Phase: Phase I/IIa
Part 1A (monotherapy, ovarian, triple negative breast [TNBC] and small cell
lung cancer [SCLC]), dose
escalation with Arms A, B, and C enrolling at different dosing schedules (See
Figure 3.1-1). Arm A will enroll
first. Each subject in Arm A, B and C will be administered a single dose of
BMS-986158 on Cycle 1 Day 1 and no
additional doses will be administered until Cycle 2 Day 1. For subjects in Arm
A on Cycle 2 Day 1, which must be
within 7 days of the Cycle 1 Day 1 dose administration, and on each subsequent
cycle, subjects will receive once
daily dosing for 5 consecutive days of each week, followed by a 2-day rest
period, on a 28-day cycle. For subjects in
Arm B on Cycle 2 Day 1, which must be within approximately 7 days of the Cycle
1 Day 1 dose administration, and
on each subsequent cycle, subjects will receive once daily dosing for 14
consecutive days, followed by a 7-day rest
period, on a 21-day cycle. For subjects in Arm C on Cycle 2 Day 1, which must
be within approximately 7 days of
the Cycle 1 Day 1 dose administration, and on each subsequent cycle, subjects
will receive once daily dosing for 7
consecutive days, followed by a 14-day rest period, on a 21-day cycle.
Depending on the accumulated safety and
pharmacokinetics (PK) of Treatment Arm A in Part 1A, at the Sponsor*s
discretion, a decision will be made to
select, initially, either Treatment Arm B or C for enrollment. The starting
dose levels of Arms B or C will depend
on the safety and tolerability of the dose levels in Arm A, but will be no
greater than the maximum dose tolerated in
Arm A. Subjects may continue to receive treatment until disease progression,
unacceptable adverse events (AEs) or
withdrawal of consent, or as defined in Section 3.5.
Part 2A (monotherapy) expansion. Cohort expansions will be carried out at the
doses selected from dose
escalation, and may represent the maximum tolerated dose (MTD), maximum
administered dose, or an alternative
dose selected from dose escalation.
Part 1 consists of the dose escalation phase with BMS-986158 administered as
monotherapy (Part 1A). To
minimize risks to subjects from unanticipated acute toxicities, a waiting
period of at least 5 days will occur between
dose administrations for the first, second, and third subjects. This waiting
period is mandatory only in the first
Cohort of Treatment Arm A of Part 1A.
Part 2 consists of cohort expansions in solid tumors (monotherapy). Treatment
in Part 2 will be initiated when the
MTD (or maximum administered dose level if no MTD is determined) and dose
schedule for Part 1 has been
determined. The doses selected for Part 2 will not exceed the Part 1A MTD or
maximum administered dose level.

Study Drug: includes Investigational [Medicinal] Products (IP/IMP) as listed:
BMS-986158 is formulated as a hard gelatin capsule partially filled with a
white to off-white waxy, semi-solid to
solid dispersion to be administered by oral route.
Study Drug for BMS-986158
Medication Potency:
BMS- 986158 0.25 mg and 2 mg

The potential side effects and risks of BMS-986158 are based on what we have
learned from studies in animals and in limited human trials with compounds
similar to BMS-986158.

Based on what we have learned from ongoing small clinical studies with similar
compounds (<100 patients total) and from animal studies with BMS-986158 the
following side effects and risks may be experienced.

• Common (>20%): nausea, vomiting, diarrhea, low platelet counts
• Less common (<20%): low red blood cell counts, low white blood cell counts,
high sugar levels, low amounts of some blood clotting proteins, sores in mouth,
stomach pain/sores
• Rare, but may be serious: bleeding from the stool, low sperm counts,
sensitivity to the sun, increased susceptibility to infections

In particular, the following will be closely monitored during the study:

o Stomach and intestines: patients will be instructed to report to the study
team any changes in stool frequency or consistency and also any abdominal
symptoms such as pain or nausea. Diarrhoea can cause dehydration, and in
severe cases, can lead to kidney impairment (decreased kidney function).
Patients will be provided with medication and instructions how to treat
diarrhoea.
o Blood sugar levels (metabolism). Because of potential changes in the blood
sugar levels, patients will be asked to fast (not eat or drink for at least 8
hours) before their blood samples are drawn and study medication taken on cycle
1 day 1 and cycle 3 day 1 and on additional days if clinically indicated.
o Immune system: blood cell counts and in particular white blood cell counts
will be evaluated frequently throughout the study. Patients will also be
examined for signs of infection (such as fever, aches, and chills).
o Bone marrow: blood cell counts will be evaluated frequently throughout the
study and patients will also be examined for signs of anaemia, fatigue and
bleeding.
o Proteins that regulate blood clotting (coagulation). Patients* blood will be
tested for any abnormalities concerning these proteins during Cycle 1 and
beyond, if clinically indicated.
o Reproductive organs: shrinkage in size and other changes to the reproductive
organs have been observed in male animals treated with multiple doses of
BMS-986158. If appropriate, the Investigator will discuss the potential risks
to patients* reproductive organs and the option of sperm and egg banking.
o Skin: BMS-986158 may make one*s skin more sensitive to sunlight. Patients
will be instructed to wear sunscreen and protective clothing when outside.

The risks will be further minimised by using of pre-medications (as permitted),
frequently monitoring the safety of the participants during and after
treatment, and providing a list of prohibited medications to the subjects, and
their GPs to prevent possible drug to drug interactions.

Risks for men/women of childbearing potential (known and unknown) will be
minimised through regular pregnancy testing, and by informing female subjects
that they must use contraception during the study and for 30 days following
treatment with BMS-986158 and that they must not breastfeed while receiving
BMS-986158 and up to 30 days from the last dose of BMS-986158. Male subjects
with female partners of childbearing potential must also use contraception
during the study and for 90 days after treatment with BMS-986158.


Other side effects
Blood draws or use of an IV catheter may cause infection, bruising, redness,
discomfort, or bleeding at the needle puncture site.

In rare cases, patients have allergic reactions (itching or rash) to the dyes
used in different types of imaging assessments. If severe, patients may have
difficulty breathing and dangerous lowering of blood pressure. If subjects are
aware of an allergy to a contrast dye, or to iodine or shellfish, they will be
advised to notify their study doctor and radiologist.

For subjects who undergo a tumour tissue biopsy, a fine needle aspiration or
core biopsy may cause pain, swelling or bruising at the insertion site. A
surgical biopsy may cause pain or bruising at the incision site, a possible
reaction to the anaesthesia or numbing agents, irritation from stitches or
staples, and the possibility of infection. For biopsies, risk will be minimised
by controlling the pain using medication, if necessary. If the biopsy is CT
guided this will involve exposure to ionising radiation. These tests and
procedures will be conducted by trained medical professionals.
CT, MUGA and bone scans are also associated with exposure to ionising
radiation. Please refer to Part B section 3 for further details.

Risks from taking prohibited medications will be minimised, as the study team
will frequently review all concomitant medication being taken by subjects.

Subjects will be required to attend the research unit on a regular basis whilst
they are on the study, thus involving an increase in travel. Reasonable travel
expenses will be reimbursed. Subjects may have to alter any pre-existing
plans/appointments to fit in with the required visits, as laid out in the
protocol. These visits are necessary to monitor the subjects* safety and
well-being.

As a subject in this study, risks may be associated with loss of patient
confidentiality if identifiable genetic or health information were disclosed to
unauthorised persons. There is possible discrimination by employers or
insurance providers, if this information were to be disclosed. Bristol-Myers
Squibb (study sponsor) believes that the risks of such improper disclosure are
very small because they have adopted strict privacy and confidentiality
procedures.

Occasionally during the course of a study, subjects may be found to have a
previously undiagnosed medical condition. In this situation, their study doctor
will take the necessary steps to ensure they receive appropriate treatment.

If during the course of this study, new information becomes available about
BMS-986158, it will be discussed with patients and they will be asked if they
would like to continue in the study. As a consequence of this new information,
and to ensure patient safety, it may be necessary to make modifications to the
study design which could include changing the timing of dosing, changing the
number of tests being performed or perhaps even stopping the study. In any
event, the subject and investigator will be fully informed and the subject will
be given every opportunity to consider their continued participation in the
study.