RTA 408 Capsules in Patients With Melanoma - REVEAL

Malignant melanoma is a leading cause of death from cutaneous malignancies, accounting for
approximately three-fourths of all skin cancer deaths. For metastatic or unresectable
melanomas, standard treatment options include immune checkpoint inhibitors (e.g., ipilimumab
and nivolumab) and other therapies, however, approved therapies are rarely curative.

It is now well accepted that tumors are able to evade detection and eradication by the immune
system, even though many tumor types, particularly melanoma, are capable of eliciting a
strong immune response (Swann, 2007). Substantial mechanistic work in recent years has
revealed the key role of myeloid-derived suppressor cells (MDSCs) in masking cancer cells
from the immune system, promoting both tumor progression and resistance to cancer
immunotherapy. The immune-suppressive effect of MDSCs is dependent on the production of
reactive oxygen species (ROS) and reactive nitrogen species (RNS). High levels of these
reactive molecules and their by-products, such as nitrotyrosine, have been correlated with
poor clinical outcomes in melanoma. Currently available melanoma therapies do not target
MDSCs.

In animals, RTA 408 significantly reduces tumor nitrotyrosine burden, inhibits the activity
of MDSCs, and augments T-cell anticancer activity at relevant doses. Thus, through inhibition
of MDSC activity and suppression of tumor ROS/RNS, RTA 408 may work in combination with
T-cell-activating therapeutics such as ipilimumab to enhance the natural immune anticancer
response. RTA 408 also has direct anticancer effects via inhibition of NF-kappa B. Chronic
activation of NF-kappa B is associated with tumor progression, metastasis, and resistance to
therapy.

This proposed study is designed to assess the safety, efficacy, pharmacodynamics, and
pharmacokinetics of omaveloxolone (RTA 408) in combination with ipilimumab or nivolumab in
patients with unresectable or metastatic melanoma.

In this open-label, multicenter, dose-escalation, Phase 1b/2 study, patients who qualify will
receive omaveloxolone (RTA 408) at the assigned dose level in combination with ipilimumab or
nivolumab. Patients will receive omaveloxolone (RTA 408) orally once daily for 1 week prior
to initiation of ipilimumab or nivolumab. For patients treated with ipilimumab , the run-in
period will be followed by omaveloxolone (RTA 408) orally once daily in combination with
ipilimumab administered at Weeks 1, 4, 7, and 10. After Week 10, patients will receive
maintenance treatment with omaveloxolone (RTA 408) alone once daily. For patients treated
with nivolumab, the run-in period will be followed by omaveloxolone (RTA 408) orally once
daily in combination with nivolumab administered approximately every two weeks as clinically
indicated. Each patient will continue at the assigned omaveloxolone (RTA 408) dose level
until disease progression occurs, toxicity requiring discontinuation from study drug (i.e.,
RTA 408) is experienced, the patient has completed approximately 72 weeks of treatment, the
patient is discontinued from the study drug for another reason, or the patient withdraws
consent. Patients will return 4 weeks after omaveloxolone (RTA 408) treatment completion for
a follow-up visit.

The starting omaveloxolone (RTA 408) dose level for the first dose-escalation cohort in this
study has been selected based on available safety and pharmacodynamic data from a Phase 1
study of RTA 408 (NCT02029729). Subsequent cohorts will be enrolled at dose levels based on
available safety and PD data from this study, but they will not be greater than 2-fold above
the prior dose level.

Phase 1b (dose-escalation): In the phase 1b/2 portion of this study, 12 patients will be
enrolled in each dose cohort, with six patients administered omaveloxolone (RTA 408) plus
ipilimumab and the remaining six administered rTA 408 plus nivolumab. Subsequent cohorts will
assess escalating the doses of omaveloxolone (RTA 408) administered in combination with
ipilimumab or nivolumab. Dose escalation decisions will be based on ongoing review of all
available safety information for enrolled patients.

Phase 2: The Phase 2 portion of the study may include separate expansion cohorts consisting
of patients treated with either of the combination therapies. Each expansion cohort will
include an additional 24 patients enrolled at the selected Phase 2 dose level to achieve a
total of 30 patients at that omaveloxolone (RTA 408) dose in combination with ipilimumab or
nivolumab.