UCDCC#271: Phase I/II Trial of Epacadostat, Intralesional SD101, Radiotherapy in Patients With Lymphoma

Checkpoint blockade immunotherapy has revolutionized the management of a variety of advanced
malignancies. Monoclonal antibodies targeting the PD-1 / PD-L1 interaction have received FDA
approvals for non-small cell lung cancer, melanoma, Merkel cell carcinoma, renal cell
carcinoma, hepatocellular, squamous cell carcinoma of the head and neck, microsatellite
instability high colorectal carcinoma, urothelial carcinoma, and classical Hodgkin's
lymphoma. Despite the promising evidence for deep and durable responses with these agents,
the majority of patients either fail to respond or develop resistance to treatment. Thus,
there is interested in developing alternative immunotherapeutic strategies. The investigators
hypothesize that a novel immunotherapeutic combination of radiotherapy (RT)with intralesional
CpG and indolamine-2,3-dioxygenase (IDO) blockade may offer significant clinical benefit to
patients and proposing a microtrial testing this combination for advanced/refractory solid
tumors and lymphoma.

Unmethylated CpG DNA is a component bacterial genomes and is the agonist of Toll Like
Receptor-9, an endosomal pattern recognition receptor of antigen presenting cells. TLR9
activation results in downstream production of IFN-α, interleukin-6 interleukin-12. These
cytokines induce naive T cells to differentiate to helper T cells. CpG has demonstrated
significant synergy with radiotherapy to induce regression of refractory systemic and
cutaneous lymphomas both within radiation treatment field and un-irradiated metastases.
SD-101 is a synthetic oligodeoxynucleotide enriched with CpG motifs.

IDO is an enzyme that converts the essential amino acid tryptophan to kynurenine. The
availability of tryptophan is essential to sustaining both helper T cell and effector T cell
activation. Overexpression of IDO by tumor cells or antigen presenting cells serves to arrest
T cell activation thus acting as an immunosuppressive enzyme. Epacadostat (INCB024360) is an
inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) that has shown promise in the
treatment of solid tumors and lymphomas in ongoing Phase I/II studies.

The investigators have shown in animal studies that IDO upregulation limits tumor response to
RT + CpG and that addition of IDO blockade improves therapeutic efficacy. On the basis of
these data, the investigators hypothesize that IDO inhibition will improve upon the known
historical efficacy of RT + CpG therapy, and will be highly effective and well tolerated in
the management of advanced solid tumors and lymphomas.

This is a phase I/II study. For the phase I portion the primary endpoint is to determine the
maximum tolerated dose of epacadostat in combination with radiotherapy and SD-101. For the
phase II portion the primary endpoint is safety and toxicity per CTCAE v4.03 criteriae. The
secondary endpoint is the abscopal response rate defined as the objective response rate at
un-irradiated lesions per irRECIST criteria.

Up to three dose levels of epacadostat will be evaluated: 100 mg bid, 200 mg bid and 300 mg
bid each day of the study. Radiotherapy will be delivered to the treatment lesion during the
first week using standard-of-care palliative fractionation regimens of 8 Gy x 3 fractions, 4
Gy x 5 fractions, or 2 Gy x 2 fractions. Four milligrams of SD-101 will be delivered into the
treatment lesion by intralesional injection on days 1, 8, 15, with optional additional
injections on days 22, and 29. On Day 1, biopsy will precede intralesional injection, RT, or
epacadostat. Intralesional injections will be performed by palpation of the lesion or under
ultrasound or CT guidance as indicated. CT response assessments and labs will be performed
every 60 days. Patients will continue on epacadostat until progression.

Inclusion Criteria:

1. Adults >18 years of age with histologically proven solid malignancy, high-grade
lymphoma or low-grade lymphoma.

2. Patients with incurable, advanced or metastatic disease refractory to at least one
previous line of standard of care therapy.

3. ECOG (Eastern Cooperative Oncology Group) performance status score of 0 - 2 (Appendix
1).

4. Presence of a candidate treatment lesion (subcutaneous, nodal, or visceral) accessible
and safe for radiotherapy and serial intralesional injections as specified by the
protocol.

5. Presence of at least one target lesion (distinct from treatment lesion and outside of
treatment lesion radiation field) evaluable for response by irRECIST.

6. 14 day wash-out period from any previous chemotherapy, targeted therapy or
radiotherapy, 21 day washout period from previous immunotherapy.

7. Life expectancy ≥ 6 months.

8. Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 14 days of the first study treatment:

o ANC > 1500 cells/ul; WBC count > 2500/uL; Lymphocyte count >500/uL; Platelet count >
100,000/uL; Hemoglobin > 9 g/dL

9. Liver function tests meeting one of the following criteria:

1. AST and ALT < 2.5 x ULN with alkaline phosphatase < 2.5 x ULN OR

2. AST and ALT < 1.5 x ULN, with alkaline phosphatase > 2.5 x ULN

3. Serum bilirubin < 1.0 x ULN. Direct bili < 40% if total bili > ULN in patients
with Gilbert's syndrome.

10. INR and aPTT < 1.5 x ULN.

11. Serum Cr < 1.5 X ULN or CrCl > 50 ml/min.

12. No active auto-immune disease and not on therapy for auto-immune disease. Patients
with a history of autoimmune-related hypothyroidism on a stable dose of thyroid
replacement hormone are eligible. Patients who have adrenal insufficiency and
hypophysitis from prior immunotherapy if they are on stable medical replacement doses
are eligible.

13. No other active malignancy.

14. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
eligible.

15. For female patients of childbearing potential and male patients with partners of
childbearing potential agreement (by patient and/or partner) to use highly effective
form(s) of contraception (i.e., one that results in a low failure rate [<1% per year]
when used consistently and correctly) and to continue its use for 6 months after trial
completion.

16. Signed informed consent.

17. At least 9 months from stem cell transplant with no active graft versus host disease.

18. Ability to comply with the protocol.

Exclusion Criteria:

1. Uncontrolled concomitant disease that in the opinion of the investigator would
interfere with the patient's safety or compliance on trial.

2. Significant cardiovascular disease (NYHA Class II or greater); myocardial infarction
within 3 month prior to randomization, unstable arrhythmias, unstable angina or a
patient with a known LVEF (Left Ventricular Ejection Fraction) < 40%

3. Severe infection that in the opinion of the investigator would interfere with the
patients safety or compliance on trial within 2 weeks prior to enrollment. Oral or IV
antibiotics within 2 weeks or 5 half-lives prior to enrollment.

4. Active tuberculosis

5. History of severe autoimmune disease that in the opinion of the investigator would
interfere with patient safety or compliance on trial.

6. Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface
Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid
[HCV RNA] (qualitative) is detected)

7. Previous treatment with epacadostat, SD-101, or any other IDO inhibitor or CpG
molecule.

8. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications within past 4 weeks or 5 half-lives whichever is shorter. Use of inhaled
or topical steroids or systemic corticosteroids < 10 mg/ day of prednisone (or
equivalent) is permitted.

9. Pregnant and/or lactating women.

10. Evidence of active interstitial lung disease or active non-infectious pneumonitis

11. Receipt of live attenuated vaccine within 30 days before the first dose of study
treatment.

12. Use of any UGT1A9 inhibitor while on active study treatment, including the following:
diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid.

13. Known allergy or reaction to any component of either study drug formulation.

14. Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or drug which has significant
MAOI activity (meperidine, linezolid, methylene blue) from 21 days prior to Day 1
through 2 weeks after the final dose of epacadostat has been administered.

15. Any history of Serotonin Syndrome (SS) after receiving serotonergic drugs.

16. Known contraindications to radiotherapy including but not limited to radiation
sensitivity syndromes such as xeroderma pigmentosum and ataxia telangiectasia mutated.