Epacadostat (INCB24360) in Combination With Sirolimus in Advanced Malignancy

Indoleamine 2,3 dioxygenase-1 (IDO1) is a target of cancer immunotherapy. Epacadostat
(INCB24360) is an oral IDO1 inhibitor. IDO1 activation blocks T-cell activation, enhances
T-cell apoptosis and promotes the differentiation of naïve T cells to regulatory T cells
(Tregs). Preclinical findings suggest that IDO1 is critical for cancers to evade immune
surveillance and can be exploited for cancer immunotherapy.

Sirolimus is an oral Mammalian Target Of Rapamycin (mTOR) inhibitor. Protein Kinase B mTOR
pathway has been considered one of major signaling cascade downstream of receptor kinases in
human cells. Its activation in human cancer cells prompted scientists to develop its
inhibitors.

Preclinical findings found that sirolimus can enhance activity of anti-Programmed Death-1
(PD-1) antibody by suppressing Programmed Death Ligand-1 (PD-L1) expression in human lung
cancer models. Sirolimus is also known to suppress function of Tregs which contribute to
immune evasion in cancer.

Other research groups also reported that autophagy is essential for Thymus cell/lymphocyte
(T-cell) -mediated apoptosis which can be enhanced by AKT/mTOR/Phosphoinositide 3-kinase
(PI3K) inhibitors. These studies indicate that autophagy is essential for T-cell mediated
apoptosis signaling. Because autophagy is at least partially down-regulated by mTOR, mTOR
inhibitors such as sirolimus can be used to pharmacologically induce autophagy. Overall,
these findings suggest that activation of mTOR and resultant suppression of autophagy play a
critical role in resistance of IDO1 inhibitor.

There is a clear unmet need for patients with advanced NSCLC whose median survival is
approximately one year. Those who progressed on both standard first-line chemotherapy and
second line anti-PD-1 inhibitor do not have any standard therapeutic option. Novel
therapeutic strategy needs to develop for this population.

The IDO1 inhibitor epacadostat is currently being investigated in clinical trials in
combination with various agents. However, these existing studies do not consider that mTOR
and/or autophagy are key mechanisms of its resistance despite the abovementioned background
information. The purpose of this phase I study is to test the combination of sirolimus with
the IDO1 inhibitor in order to overcome potential resistance mechanisms associated with the
use of IDO1.

Inclusion Criteria:

Participants must meet all of the inclusion criteria to participate in this study.

- Ability to understand and the willingness to sign a written informed consent.

- Prior treatment with at least one line of systemic therapy.

- Dose escalation: subjects with advanced and unresectable solid tumor who progressed on
at least one line of systemic therapy, and no approved therapy or standard therapy
with demonstrated clinical benefit exists; and all subjects with T790M mutation
positive NSCLC have progressed on osimertinib.

*Note - Disease measurability is not required for dose escalation.

- Dose expansion: subjects with metastatic or recurrent NSCLC who progressed on at least
one line of systemic therapy for metastatic or recurrent disease, which must include
anti PD-1 or PD-L1 inhibitor, and must have measurable disease by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1 and accessible tumor for biopsy. Molecular
status of Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK)
must have been assessed for nonsquamous NSCLC. Those with activating EGFR mutation or
ALK gene arrangement must have progressed on at least one kinase inhibitor.

- Age ≥ 18 years.

- Eastern Cooperative Oncology Group (ECOG) Performance Status #0-2.

- Adequate organ and marrow function as defined below:

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/microliter (mcL)

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9 grams per deciliter (g/dL)

- Total bilirubin within normal institutional limits

- Aspartate Aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT) ≤
2.5 X institutional upper limit of normal (ULN)

- Alanine Aminotransferase (ALT) Serum Glutamic Pyruvic Transaminase (SPGT) ≤ 2.5 X
ULN

- Alkaline Phosphatase Level (ALP) ≤ 2.5 X ULN

- Serum creatinine ≤ 1.5 X ULN or Creatinine Clearance (CrCl) ≥ 50ml/min

- Note: Subjects with bone metastasis and no liver metastasis on screening image
may enroll if ALP is <5 X ULN. Subjects with liver metastasis may enroll if all
of AST/ALT/ALP are <5 X ULN. However, subjects with extensive liver metastasis
occupying more than 50% of liver parenchyma will be excluded.

- Activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless subject is
receiving anticoagulant therapy, as long as partial thromboplastin time (PTT) is
within therapeutic range of intended use of anticoagulants.

- Women of child-bearing potential and men with partners of child-bearing potential must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and for 90
days following completion of therapy. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- A woman of child-bearing potential is any female (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months)

Exclusion Criteria:

Participants meeting any of the exclusion criteria at baseline will be excluded from study
participation.

- Current or anticipated use of other investigational agents while participating in this
study.

- Participation in any other study in which receipt of an investigational study drug
occurred within 28 days or 5 half-lives (whichever is longer) before first dose.

- Subjects who have received an IDO inhibitor. Subjects who have received other immune
checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, and any other treatment targeting
T-cell) will be permitted. Subjects who have received experimental vaccines or other
immune therapies should be discussed with the Principal Investigator (PI) to confirm
eligibility.

- Subjects who have received sirolimus, everolimus, temsirolimus, or any other agent for
current malignancy that theoretically targets Phosphoinositide 3-kinase (PI3K), AKT
and / or mTOR.

- Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy,
including anti-Cytotoxic T-Lymphocyte antigen 4 (CTLA-4) and anti-PD-1/PD-L1
treatment, or any unresolved irAE>Grade 1.

*Note: Previous immune-related ocular toxicity of any grade is excluded.

- Subjects who are receiving an immunosuppressive treatment for any reason, including
chronic use of systemic steroid or prednisone equivalent at doses ≥ 10 milligrams per
day (mg/day) within 14 days prior to the first dose of study treatment. Use of inhaled
or topical steroids or systemic corticosteroids < 10 mg is permitted.

- Subjects who have had prior radiotherapy within 2 weeks of therapy. Subjects must have
recovered from all radiation-related toxicities, not require corticosteroids, and not
have had radiation pneumonitis.

- Patient has received chemotherapy within 3 weeks prior to entering the study or has
not recovered sufficiently (i.e., greater than grade 1. PI will judge patient recovery
status) from adverse events due to agents administered more than 3 weeks earlier.
Exceptions are stable chronic toxicities not expected to resolve, such as peripheral
neurotoxicity, alopecia, and fatigue.

- Prior monoclonal antibody within 4 weeks before study Day 1 or not recovered (≤ Grade
1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.
Exception to this rule would be use of denosumab.

- Brain metastases: Symptomatic, unstable, or disease requiring use of steroid
treatment.

- Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis,
moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or
who are receiving systemic therapy for an autoimmune or inflammatory disease.

*Exceptions include subjects with vitiligo, hypothyroidism stable on hormone
replacement, controlled asthma, Type I diabetes, Graves' disease, Hashimoto's disease,
or with PI approval.

- Evidence of or any history of interstitial lung disease or active, noninfectious
pneumonitis including symptomatic and/or pneumonitis requiring treatment.

- Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV
reactivation. Hepatitis B virus deoxyribonucleic acid (DNA) and testing for HCV
ribonucleic acid (RNA) must be undetectable. At risk for HBV reactivation is defined
as hepatitis B surface antigen positive

- Subjects with clinical condition where subjects may not tolerate immune mediated
hepatotoxicity. This includes extensive liver metastasis (See INCLUSION CRITERIA),
excessive intake of alcohol (Male >4 drinks/day, Female >2 drinks>day), and the use of
acetaminophen >2 gms/day. Per INCB24360 investigator's brochure.

- History or presence of an abnormal ECG which, in the investigator's opinion, is
clinically meaningful. Screening corrected QT interval (QTcF) > 480ms is excluded.
Subjects with left bundle branch block are excluded.

- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the study, interfere with the subject's participation
for the full duration of the study, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Current use or anticipated need for treatment with any medications or substances that
are inhibitors or inducers of CYP3A4.

- Known allergy or reaction to any component of either study drug formulation. Any
history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs.

- Pregnant or nursing. There is a potential for congenital abnormalities and for this
regimen to harm nursing infants.

- Use of any UDP glucuronosyltransferase family 1 member A9 (UGT1A9) inhibitor from
screening through follow-up period, including the following: diclofenac, imipramine,
ketoconazole, mefenamic acid, and probenecid.

- Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or drug which has significant
MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before
screening.