Utomilumab and ISA101b Vaccination in Patients With HPV-16-Positive Incurable Oropharyngeal Cancer

Study Drug Administration:

There are 28 days in each study cycle.

You will receive utomilumab by vein every 4 weeks for up to 12 doses beginning on Cycle 1 Day
1. The drug will be given over about 1 hour each time you receive it.

You will receive ISA101b as an injection under the skin every 4 weeks for 3 doses. You will
receive 2 injections each time. One may be in your arm and one in your leg.

Length of Study:

You may continue taking utomilumab for up to 1 year as long as your doctor thinks it is in
your best interest. You will no longer be able to take the study drug(s) if intolerable side
effects occur or if you are unable to follow study directions. You may not be able to take
the study drug(s) if the disease gets worse, which is explained below.

Your participation on the study will be over after the follow-up visits.

Study Visits:

On Day 1 of Cycles 1-12:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be collected for routine tests, thyroid function tests,
and liver function tests.

- If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
pregnancy test.

- During Cycles 1, 2, 3, 4, 8, and 12, blood (up to 10 tablespoons) will be drawn for
biomarker testing (including genetic biomarkers).

At the end of Cycle 2 and every 8 weeks after that, you will have an MRI or CT scan to check
the status of the disease.

Study Continuation:

If the disease appears to have gotten worse, you may still be eligible to continue receiving
your assigned study drug(s). This is because you may be benefitting from the study drug(s)
even though the tumor(s) got larger. Your doctor will discuss this with you.

If this happens, your doctor will talk to you about whether or not you want to continue. If
you do continue taking part in the study, you will follow the study visits as described
above.

However, there are risks of continuing to receive the study drug(s) because the disease may
actually be getting worse. You are still at risk for side effects due to utomilumab and
ISA101b. Continuing on this study could also delay starting other treatments. The disease may
get worse to the point that you are no longer able to receive other treatments. There are
also risks from the additional tests that may be performed, such as biopsies and blood draws.
You and your doctor will discuss these possible risks, and you will be asked to decide if you
want to continue receiving the study drug(s).

End-of-Treatment and Follow-up Visits:

At about 30 days after your last study drug dose:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be collected for routine tests, thyroid function tests,
and liver function tests.

- If you are able to become pregnant, blood (about ½ teaspoon) or urine will be collected
for a pregnancy test.

At about 70 days after your last study drug dose:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be collected for routine tests, thyroid function tests,
and liver function tests.

- If you are able to become pregnant, blood (about ½ teaspoon) or urine will be collected
for a pregnancy test.

You will also be called every 3 months up to 1½ years and asked about your health. Each call
should last about 10-15 minutes.

If you stopped taking the study drug for reasons other than the disease getting worse, you
will continue to have MRI/CT scans every 8 weeks. If the disease appears to get worse, or you
start a new anticancer therapy, these scans will stop.

Inclusion Criteria:

1. Subjects must have signed and dated an IRB/IEC approved written informed consent form
in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol related procedures that are not part of normal
subject care.

2. Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests and other requirements of the study.

3. Men and women >/= 18 years of age.

4. Eastern Cooperative Oncology Group (ECOG) performance status of
5. Subjects with histologically- or cytologically-documented incurable Human
Papillomavirus (HPV)-positive OPSCC. HPV-16 serotype will be assessed by Cervista
assay.

6. Subjects can be treatment naïve or may have had two prior regimens for recurrent
cancer. They must be naive to treatment with PD-1/L1 or CTLA-4 inhibitors.

7. Subjects must have progression within 6 months of platin exposure during definitive or
palliative therapy.

8. Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria;
Radiographic Tumor Assessment performed within 28 days of study inclusion.

9. Target lesions may be located in a previously irradiated field if there is documented
(radiographic) disease progression in that site.

10. Subject entering the study will need to consent for mandatory biopsy at study entrance
and as an optional procedure prior to C3 for biomarker evaluation. Biopsy should be
excisional, incisional or core needle. Fine needle aspiration is insufficient.

11. Prior chemotherapy, monoclonal antibody therapy, must have been completed at least 4
weeks prior to start. Radiotherapy or radiosurgery must have been completed at least 2
weeks prior to start.

12. All baseline laboratory requirements will be assessed and should be obtained within
-14 days of study registration. Screening laboratory values must meet the following
criteria i) White blood cells (WBCs) >/= 2000/microL ii) Neutrophils >/= 1500/microL
iii) Platelets >/= 100 x 10^3/microL iv) Hemoglobin >/= 9.0 g/dL Patients must not be
transfused for at least 14 days prior to study entry v) Serum creatinine of upper limit of normal(ULN) or creatinine clearance(CrCl) > 50 mL/minute (using
Cockcroft/Gault formula) Female CrCl= 0.85 x [(140 - age in years) x weight in kg]/(72
x serum creatinine in mg/dL) Male CrCl= 1.00 x [(140 - age in years) x weight in
kg]/(72 x serum creatinine in mg/dL) vi) AST viii) Total bilirubin have total bilirubin <3.0 mg/dl).

13. Women of childbearing potential (WOCBP) must use method(s) of contraception for 30
days + 5 half-lives (60 days) of the study drugs. For a teratogenic study drug and/or
when there is insufficient information to assess teratogenicity (preclinical studies
have not been done), a highly effective method(s) of contraception (failure rate of
less than 1% per year) is required. Highly effective birth control in this study is
defined as a double barrier method. Examples include a condom (with spermicide) in
combination with a diaphragm, cervical cap, or intrauterine device (IUD). The
individual methods of contraception should be determined in consultation with the
investigator.

14. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
or equivalent units of HCG) within 24 hours prior to the start of investigational
product.

15. Women must not be breastfeeding.

16. Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. The investigator shall review contraception
methods and the time period that contraception must be followed. Men that are sexually
active with WOCBP must follow instructions for birth control for a period of 90 days
plus the time required for the investigational drug to undergo 5 half- lives (60
days).

Exclusion Criteria:

1. Subjects with active CNS metastases are excluded. Subjects are eligible if CNS
metastases are adequately treated and subjects are neurologically returned to baseline
(except for residual signs or symptoms related to the CNS treatment) for at least 4
weeks prior to enrollment. In addition, subjects must be either off corticosteroids,
or on a stable or decreasing dose of weeks.

2. Subjects with carcinomatous meningitis.

3. Subjects with active, known or suspected systemic autoimmune disease. Subjects with
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
thyroiditis only requiring hormone replacement, or conditions not expected to recur in
the absence of an external trigger are permitted to enroll.

4. Subjects with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of start. Inhaled or topical steroids, and adrenal replacement steroid doses > 10
mg daily prednisone equivalent, are permitted in the absence of active autoimmune
disease.

5. Prior therapy with anti-CD137 or ISA101.

6. Subjects with a history of interstitial lung disease.

7. Other active malignancy requiring concurrent intervention.

8. Subjects with previous malignancies (except non-melanoma skin cancers, and the
following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia,
melanoma, or breast) are excluded unless a complete remission was achieved at least 2
years prior to study entry AND no additional therapy is required during the study
period.

9. Subjects with toxicities attributed to prior anti-cancer therapy other than alopecia
and fatigue that have not resolved to grade 1 (NCI CTCAE version 4.03) or baseline
before administration of study drug.

10. Subjects who have not recovered from the effects of major surgery or significant
traumatic injury at least 14 days before the first dose of study treatment.

11. Treatment with any investigational agent within 28 days of first administration of
study treatment.

12. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

13. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
ribonucleic acid (HCV RNA) indicating acute or chronic infection.

14. History of allergy or intolerance (unacceptable adverse event) to study drugs
components.

15. WOCBP who are pregnant or breastfeeding.

16. Women with a positive pregnancy test at enrollment or prior to administration of study
medication.

17. Any other serious or uncontrolled medical disorder, active infection, physical exam
finding, laboratory finding, altered mental status, or psychiatric condition that, in
the opinion of the investigator, would limit a subject's ability to comply with the
study requirements, substantially increase risk to the subject, or impact the
interpretability of study results.

18. Prisoners or subjects who are involuntarily incarcerated.

19. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.