A Randomized Phase 2 Study of Cemiplimab ± ISA101b in HPV16-Positive OPC

This study will assess the ability of ISA101b to improve Overall Response Rate in subjects
with platinum refractory (progression on or within 6 months of platinum therapy) HPV16
positive OPC, when combined with cemiplimab, an investigational anti-PD-1 antibody being
developed by Regeneron Pharmaceuticals. ISA101b is a therapeutic cancer vaccine that induces
specific immune responses to the oncogenic E6 and E7 antigens from HPV16. Trials in HPV16
driven malignancies indicate it has activity in HPV16 driven malignancies including
oropharyngeal and cervical cancers. Cemiplimab, also known as REGN2810, is in late stage
trials and appears to have similar activity to approved anti PD-1 antibodies in a number of
malignancies .

Inclusion Criteria:

- Males and females, ≥ 18 years of age.

- Sign and date an Institutional Review Board/Independent Ethics Committee
(IRB)/(IEC)-approved written informed consent form (ICF) 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.

- Be willing and able to comply with scheduled visits, treatment schedule, laboratory
testing, and other requirements of the study.

- Diagnosed with histologically confirmed recurrent or metastatic HPV16 positive OPC,
not amenable to any therapy with curative intent. Subjects with HPV-16 positive
squamous cell carcinoma (SCC) of occult primary site, presenting with lymph node(s) in
the neck, are also eligible.

- HPV-16 genotyping will be performed by the specified central reference laboratory.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

- Tumor progression or recurrence within 6 months after the last dose of
platinum-containing chemotherapy (up to 2 lines of prior chemotherapy) administered as
adjuvant therapy or in the context of primary or recurrent disease.

- Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per
RECIST 1.1 criteria.

- Prior curative radiation therapy must have been completed at least 4 weeks prior to
study drug administration. Prior focal palliative radiotherapy must have been
completed at least 2 weeks before study drug administration.

- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of study drug.

Exclusion criteria:

- Subjects with known active brain metastases or leptomeningeal metastases are not
allowed.

- Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results.

- History of other malignancy ≤ 3 years prior to entry into this trial with the
exception of basal cell or squamous cell skin carcinoma which were treated with local
resection only, or carcinoma in situ of the cervix, prostate or breast, or low grade
non-muscle invasive superficial bladder cancer (TaLG)/carcinoma in situ of the
bladder.

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

- Subjects with a condition requiring immunosuppressive doses of systemic medication
such as steroids or absorbed topical steroids (doses ≥ 10 mg/day prednisone or
equivalent) or other immunosuppressive medications within 14 days of study drug
administration. Inhaled or topical steroids and adrenal replacement doses < 10 mg
daily prednisone equivalents are permitted in the absence of active autoimmune
disease.

- Prior treatment with an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab,
cemiplimab), as well as an antibody targeting anti-PL-L1 anti-PD-L2, anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell co stimulation
or immune checkpoint pathways.

- Prior treatment with therapeutic anti-HPV vaccines including ISA101 or ISA101b.
Subjects may have received a preventive HPV vaccine.

- All toxicities attributed to systemic prior anti-cancer therapy other than alopecia
and fatigue must have resolved to Grade 1 (NCI CTCAE) or baseline before
administration of study drug. Subjects with toxicities attributed to systemic prior
anticancer therapy that are not expected to resolve and result in long lasting
sequelae, such as neuropathy after platinum based therapy, are permitted to enroll.

- Treatment with any chemotherapy, radiation therapy, biologics for cancer, or
investigational therapy within 28 days of first administration of study treatment.

- History of allergy to ISA101/ISA101b study drug components, e.g., ISA101/101b,
Montanide, or Macrogolglycerol Ricinoleate, also known as cremophore.

- History of allergy to cemiplimab and its excipients.