Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)

Background:

- PD-1/PD-L1 signaling appears to be a major inhibitor of activated T cell anti-tumor
immune responses. The rapid, deep and durable responses seen in various malignancies
with PD-1/PD-L1 targeted agents demonstrate that blockade of this axis is key to
facilitating immune responses within the tumor microenvironment (TME).

- Prostate cancer is poorly recognized by T cells. Lack of an immune response is one
explanation for the lower response rates (<15%) observed with anti-PD-1/PD-L1 therapies
for prostate cancer.

- Increasing response rates will likely require therapeutic nullification of multiple
immune deficits by combining immunotherapies that generate tumor-specific T cells
(vaccine), dampen the inhibitory milieu of the TME, and enhance T and NK cell activity
within the TME.

- A quick efficacy seeking trial, utilizing sequential arms offers a means to identify
signals of activity for combinations of immunotherapy, added sequentially, in metastatic
castrate resistant prostate cancer (mCRPC) patients.

- BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to
induce an enhanced immune response against brachyury, which is overexpressed in many
solid tumor types, including prostate adenocarcinoma. BN-Brachyury collectively refers
to the priming doses (MVA-BN-Brachyury) and the boost doses (FPV-Brachyury) of the
vaccine platform.

- M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1
(PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-
beta) receptor type 2, a TGF-beta trap. M7824 can also mediate antibody-dependent
cellular cytotoxicity in vitro.

- ALT-803 is an IL-15/IL-15R alpha superagonist complex that can enhance NK cell mediated
ADCC and T-cell cytotoxicity.

- Synergistic anti-tumor effects have been observed in vitro when combining M7824 and
ALT-803, and in vivo when combining these agents with tumor vaccine in animal models.

- IDO1 is overexpressed in many solid tumors and can contribute to immune escape by tumor
cells. INCB024360 (Epacadostat) is an IDO1 inhibitor under investigation in combination
with different immunotherapies in treatment of various malignancies.

- In treating of mCRPC, we hypothesize that these agents and their effects will be
complementary. Tumor-specific T cells generated by vaccine may become more functional in
a TME following treatment with M7824 and Epacadostat. ALT-803 can further enhance the
activity of antigen-specific T cells as well as NK cells.

Objective:

-To determine if there is clinical benefit to any of a set of 3 possible treatments for
patients with mCRPC:

- BN-Brachyury + M7824

- BN-Brachyury + M7824 + ALT-803

- BN-Brachyury + M7824 + ALT-803 + Epacadostat

Eligibility:

- Adults with histologically proven mCRPC, or metastatic solid tumor of any type for which
there is no standard treatment or standard treatment has failed.

- Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.

- Patients with acquired immune defects, active systemic autoimmune disease, history of
organ transplant, history of chronic infections, or history of active inflammatory bowel
disease are excluded.

Design:

- Open label Phase I/II trial with following randomization during the expansion. Phase I:
Cohort 1, Arm 1.1

--Up to 18 patients with any solid tumor will be enrolled in dose escalation Cohort 1
for treatment in Arm 1.1 (flat dose of M7824 + different dose levels of ALT-803).

- Phase IIA: expansion with sequential enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

- Concurrently with the enrollment to Arm 1.1, 13 patients with mCRPC will start
enrollment in Cohort 2 for treatment in Arm 2.1 (M7824 + BN-Brachyury).

- When safe dosing of ALT-803 is identified during Phase I, 13 patients have enrolled
in arm 2.1 and the first 6 patients, treated in Arm 2.1, have met safety
requirements, 13 patients with mCRPC will start enrollment in Cohort 2 for
treatment in Arm 2.2 (M7824 + BN-Brachyury + ALT-803).

- When 13 patients have enrolled in Arm 2.2 and the first 6 patients, treated in Arm
2.2, have met safety requirements, 13 patients with mCRPC will start enrollment in
Cohort 2 for treatment in Arm 2.3 (M7824 + BN-Brachyury + ALT-803 + Epacadostat).

- Phase IIB: expansion with randomized enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

- Each Arm in Cohort 2: 2.1, 2.2 and 2.3 will be open for additional enrollment (25
evaluable patients total) when the initial 13 patients have accrued, safety
requirements are meet and a positive signal (defined as Objective Response by
RECIST 1.1 or sustained PSA decrease greater than or equal to 30% sustained for >
21 days) in greater than or equal to 2 patients is shown.

- If only one arm is open for additional enrollment, patients will be directly
assigned to this arm. If 2 arms are open for additional enrollment, patients will
be randomized between these 2 open arms. If 3 arms are open for additional
enrollment, patients will be randomized among these 3 open arms.

- If there are greater than or equal to 6 of 25 patients with a positive signal of
activity in any expansion arm, that arm will be considered of interest for future
studies.

- INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed any solid tumor (Cohort 1) or
prostate cancer (Cohort 2). No prior treatment other than testosterone lowering therapy for
mCRPC is required.

For the Cohort 1, eligible patients must have a histologically, cytologically or
radiographically proven metastatic or locally advanced solid tumor of any type, for which
there is no curative standard therapy or standard therapy has failed.

Castrate testosterone level (less than 50ng/dl or 1.7nmol /L). (Patients with a malignancy
other than prostate cancer are excluded from this criterion).

Radiological confirmation of metastatic disease, or

Progressive disease at study entry defined as one or more of the following criteria
occurring in the setting of castrate levels of testosterone:

--Radiographic progression defined as any new or enlarging bone lesions or growing lymph
node disease, consistent with prostate cancer

OR

--PSA progression defined by sequence of rising values separated by greater than 1 week

(2 separate increasing values over a minimum of 1 ng/ml (PCWG3 PSA eligibility criteria).
If patients had been on flutamide, PSA progression is documented 4 weeks or more after
withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6
or more weeks after withdrawal. The requirement for a 4-6 week withdrawal period following
discontinuation of flutamide, nilutamide or bicalutamide only applies to patients who have
been on these drugs for at least the prior 6 months. For all other patients they must stop
bicalutamide, nilutamide or flutamide the day prior to enrollment.

Asymptomatic or mildly symptomatic form prostate cancer; no use of regularly scheduled
opiate analgesics for prostate cancer-related pain. (Patients with a malignancy other than
prostate cancer are excluded from this criterion).

Patients must agree to continuation of androgen deprivation therapy (ADT) with a
gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy.

(Patients with a malignancy other than prostate cancer are excluded from this criterion).

Age greater than or equal to 18 years.

ECOG performance status less than or equal to 1

Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1000/mcL

- Platelets greater than or equal to 100,000/mcL

- Hemoglobin greater than or equal to 9.0 g/dL

- Total bilirubin within normal institutional limits; in patients with

Gilbert s, less than or equal to 3.0 mg/dL

- AST (AGOT)/ALT (AGPT) less than or equal to 2.5X upper limit of normal. For subjects
with liver involvement in their tumor, AST less than or equal to 3.5. (SqrRoot) ULN,
ALT less than or equal to 3.5 (SqrRoot) ULN, and bilirubin less than or equal to 3.0
is acceptable

- Creatinine within 1.5X upper limit of normal institutional limits

The effects of BN-Brachyury, M7824, ALT-803, and Epacadostat on the developing human fetus
are unknown. For this reason, men and women must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, during the
study and maintain such contraception until 4 months following the last dose of any study
agent. Should a woman become pregnant or suspect she is pregnant while she or her partner
is participating in this study, she should inform her partner s treating physician
immediately.

Ability of subject to understand and the willingness to sign a written informed consent
document.

Patients with successfully treated HCV are eligible if HCV viral load is undetectable.

EXCLUSION CRITERIA:

Patients who are immunocompromised as follows:

- Human immunodeficiency virus positivity due to the potential for decreased tolerance,
and potential to be at risk for severe side effects with immunotherapies. These
concerns are relevant to all drugs, as drug-drug interactions among antiretrovirals
and immunotherapies are yet uncharacterized.

- Chronic administration (defined as daily or every other day for continued use greater
than 14 days) of systemic corticosteroids or other immune suppressive drugs, within 28
days before treatment on study. Nasal, or inhaled steroid, topical steroid creams and
eye drops for small body areas are allowed.

- Patients who have undergone allogeneic peripheral stem cell transplantation, or solid
organ transplantation requiring immunosuppression

- Active autoimmune disease, except patients with type 1 diabetes mellitus,
vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current
immunosuppression, or with other endocrine disorders on replacement hormones or
are not excluded if the condition is well controlled.

Prostate cancer patients with a history of brain/leptomeningeal metastasis, since these
patients have a very poor prognosis and immunotherapy may take time to lead to beneficial
clinical effects. Patients with brain or CNS metastases enrolling to arm 1.1 are eligible
if they are status post definitive radiotherapy or surgery, and are asymptomatic

History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study agents to be used in the cohort the subject will be enrolled into.

Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or
tobramycin).

Any condition which, in the opinion of the investigator, would prevent full participation
in this trial (including the long-term follow-up), or would interfere with the evaluation
of the trial endpoints.

Patients with prior investigational drug, chemotherapy, immunotherapy or any prior
radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to
enrollment, except if the investigator has assessed that all residual treatment-related
toxicities have resolved or are minimal and feel the patient is otherwise suitable for
enrollment.

Uncontrolled intercurrent acute or chronic illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure (New York Heart Association Class
I), hepatic disease, unstable angina pectoris, serious cardiac arrhythmia, requiring
medication, uncontrolled hypertension (SBP greater than 170/ DBP greater than 105) or
psychiatric illness/social situations within 12 months that would limit compliance with
study requirements.

Use of herbal products that may decrease PSA levels (e.g. saw palmetto)

Patients who have had chemotherapy for metastatic castration-resistant prostate cancer
within the past year. (Patients who have had docetaxel for metastatic castration sensitive
per CHAARTED data may enroll as long as they did not have progressive disease while on
docetaxel and are 3 months removed from treatment, with all treatment related toxicities
resolving to at least grade 1.)

Patients who have undergone major surgery within 4 weeks of enrollment. A biopsy will not
preclude a patient from starting study.

Patients with a history of hepatitis B (HBV) are excluded due to potential risk for viral
reactivation and resulting liver injury in persons with latent HBV