Study of IDO Inhibitor in Combination With Checkpoint Inhibitors for Adult Patients With Metastatic Melanoma

The incidence of melanoma is increasing. Based upon data obtained between 2004 and 2006, the
lifetime probability of developing melanoma in the United States is estimated to be 1 in 37
for men and 1 in 56 for women. In the United States, melanoma is the fifth leading cancer in
men and the seventh in women. Locally confined, fully-resectable disease may be curable with
current therapy; but Stage IV metastatic disease (or relapsed/recurrent disease) is highly
refractory to therapy. Thus, experimental clinical trials provide an accepted treatment
option for metastatic or relapsed/refractory melanoma.

The current study is designed as a prospective trial to evaluate the combination of indoximod
and checkpoint inhibitors in adult patients with metastatic melanoma. Ipilimumab,
pembrolizumab and nivolumab will be used at the recommended approved doses for this
indication.

The current trial will be done in two phases: a Phase 1b dose escalation of indoximod in
combination with ipilimumab, starting at half the recommended single-agent dose, to establish
the recommended Phase 2 dose for the combination.

This will be followed by a three arm expansion study testing a fixed dose of indoximod (at
the recommended Phase 2 dose) combined with standard-dose ipilimumab, pembrolizumab or
nivolumab.

Treatment will be administered on an outpatient basis. No investigational or commercial
cancer directed agents or therapies other than those described below may be administered.

Safety assessment will follow the guidelines provided in the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI-CTCAE) Version.4.03.

Patients will be followed both clinically and radiographically starting 12 weeks after
initiation of treatment then every 8 weeks for tumor evaluation. Post-treatment scans will be
compared to the baseline scan and responses will be assessed based using mWHO and immune
related response criteria (irRC) described by Wolchok et al. (Wolchok et al., 2009).

Inclusion Criteria:

- Unresectable Stage III or Stage IV melanoma.

- Patients must have measurable disease, defined as lesions that can be accurately
measure in in 2 perpendicular diameters with at least one diameter > 20mm and the
other >10mm on conventional CT or MRI or 10mm x 10 mm by spiral CT.

- No systemic treatment in the previous 28 days.

- Age ≥18 years. Because no dosing or adverse event data are currently available on the
use of ipilimumab or indoximod in patients <18 years of age, children are excluded
from this study.

- ECOG performance status ≤2 (Karnofsky ≥60% )

- Patients with known brain metastases will only be eligible after their tumors have
been treated with definitive resection and/or radiotherapy and they are neurologically
stable for at least 1 month off steroids.

Exclusion Criteria:

- Patients who have had molecular targeted therapy (including vemurafenib) or
radiotherapy within 4 weeks prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients who have had prior therapy with immune checkpoint inhibition or or indoximod
are excluded from the trial.

- Any other cancer, unless the patient has been disease-free for ≥5 years

- Patients with laboratory evidence of pancreatitis are excluded.

- Patients with autoimmune disease

- Chronic use of immune-suppressive drugs (ie, systemic corticosteroids used in the
management of cancer or non-cancer related illnesses, eg, COPD).