This is a global, multi-center, Phase 3 study that is randomized 1:1, controlled, and open label to evaluate PDS0101 (Versamune + HPVMix) in combination with pembrolizumab vs. pembrolizumab monotherapy as first-line treatment in patients with unresectable recurrent or metastatic HPV16-positive HNSCC expressing programmed cell death ligand-1 (PD-L1) with combined positive score (CPS) ≥1.

PDS0101 is a T cell activating immunotherapy designed to induce HPV-specific CD8 and CD4 T cells. A Phase 2 study has shown promising signs of safety and efficacy when PDS0101 is combined with pembrolizumab in patients with HPV16-positive R/M HNSCC with CPS ≥1, which is the population for this study.

The dual primary objectives of this study are to compare the effect of the combination of PDS0101 plus pembrolizumab vs. pembrolizumab monotherapy on progression-free survival (PFS) and overall survival (OS). Secondary objectives for this study include comparison of effects on objective response rate (ORR), disease control rate (DCR), and duration of response (DOR).

Inclusion Criteria:

1. Subject (or legally acceptable representative, if applicable) provides written informed consent for the study.

2. Subject is ≥18 years of age on the day of signing the informed consent.

3. Have a history of histologically- or cytologically-confirmed diagnosis of recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC) with:

   1. Eligible primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx.
   2. HPV16 tumor positivity (central testing).
   3. Tumor PD-L1 expression defined as a CPS ≥ 1 using the FDA- approved pembrolizumab (KEYTRUDA®) assay (local testing).
   4. No prior systemic anticancer therapy administered in the incurable recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization, if given as part of multimodal treatment for locally advanced disease, is allowed.

4. Have measurable disease based on RECIST 1.1 as determined by the site and confirmed by BICR. As a guidance to the site investigators, tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

5. Subject has adequate organ function defined by the following parameters (all specimens must be collected within 15 days prior to randomization):

   • Hematological: Absolute neutrophil count (ANC) ≥1500/μL, Platelets ≥100,000/μL; Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L;
   • Renal: Estimated glomerular filtration rate ≥30 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
   • Hepatic: Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5 × ULN, Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤2.5 ULN (if approved by Medical Monitor, ≤5 × ULN for subjects with liver metastases; AST and ALT >5 to 20 x ULN may be included if asymptomatic).
   • Coagulation: INR, prothrombin time (PT) ≤1.5 × ULN; if subject is receiving anticoagulant therapy, INR or PT- should be within therapeutic range of anticoagulant.

6. For female subjects defined as women of childbearing potential (WOCBP), a negative pregnancy test must be obtained during screening. If a urine test cannot be confirmed as negative, a serum pregnancy test will be required. Women who are surgically sterile or at least 2 years postmenopausal do not require pregnancy testing.

7. Male subjects of childbearing potential must agree to use a condom as an effective method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion Criteria:

1. Primary tumor location of nasopharynx (any histology).

2. If the pregnancy test is positive. If a urine test cannot be confirmed as negative, a serum pregnancy test will be required.

3. Has received prior therapy with HPV-specific immunotherapy including therapeutic cancer vaccines and cellular immunotherapy. Note: subjects who have received prophylactic HPV vaccines are eligible for enrollment.

4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD- L2 agent or with an agent directed to another stimulatory or co- inhibitory T cell receptor including but not limited to CTLA-4, OX40, CD137.

5. Has had major surgery, including surgical resection of tumor, within 30 days prior to randomization, and has not fully recovered as assessed by the investigator.

6. Has received radiotherapy prior to randomization outside of the following minimum washout periods, and has not fully recovered as assessed by the investigator:

   • Fractionated radiotherapy, 2 weeks
   • Stereotactic radiosurgery, 1 week
   • Palliative radiation therapy, 1 week

7. Has received a live vaccine within 30 days prior to randomization.

   Examples of live vaccines include, but are not limited to, the following:

   measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist ® ) or live attenuated vaccines are not allowed within 30 days prior to randomization.

8. Has received immunomodulatory or immunosuppressive agents (e.g., interferons (IFNs), tumor necrosis factor, interleukins, immunoglobulins or other biological response modifiers (granulocyte colony-stimulating factor [GCSF] or granulocyte macrophage stimulating factor [GMCSF]) within 30 days prior to randomization.

9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 30 days prior to randomization. Note: Subjects who entered the follow-up phase of an investigational study may participate as long as it is permitted in that study consent and has been 30 days after the last dose of the previous investigational agent.

10. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. Note: Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft- versus-host disease [GVHD].

11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (I a dose exceeding 10 mg daily of prednisone equivalent). Note: Current or recent use of intranasal, intra-articular, and topical steroids are allowed for symptom management are clinically indicated.

12. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ, superficial [non- infiltrated] bladder tumors) or other malignant tumors that have undergone potentially curative therapy are eligible for enrollment.

13. Has known carcinomatous meningitis and/or active central nervous system (CNS) metastases as defined by new brain metastases or progressive brain metastases that have not been subjected to CNS-directed therapy since documented progression. Note: Subjects with previously treated brain metastases are eligible if all the following criteria are met:

    1. radiologically stable, i.e., without evidence of progression for at least 30 days by repeat imaging (note that repeat imaging should be performed during study screening),
    2. neurologically stable, and
    3. without requirement of steroid treatment for at least 14 days prior to randomization.

14. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered systemic treatment and is allowed.

15. Has a history of interstitial lung disease or has current pneumonitis. Note: Subjects with a history of radiation pneumonitis who are fully recovered are eligible.

16. Has an active infection requiring systemic therapy (e.g., IV or oral anti-infective).

17. Has known human immunodeficiency virus (HIV) and CD4 count < 350 cells/μL and/or a history of an AIDS-defining opportunistic infection within the past 12 months. Note: Subjects who are on stable antiretroviral therapy for at least 30 days and have an HIV viral load less than 400 copies/mL and who do not meet the above exclusion criterion may be enrolled.

18. Has a history of hepatitis B (HBV) infection or known to be positive for HBV antigen (HbsAg)/HBV virus DNA.

19. Has active hepatitis C defined by a known positive C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay. Note: Subjects with a history of HCV infection who have completed curative antiviral treatment and have HCV viral load below the limit of quantification may be enrolled.

20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

21. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.

22. Is breastfeeding within the projected duration of the study, starting with the screening visit through 120 days after the last dose of any study treatment.

23. Has had an allogenic tissue/solid organ transplant.

24. Female subjects defined as WOCBP unwilling or unable to use highly effective contraception method(s) for the duration of the study:

    1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation.
    2. Progestogen-only hormonal contraception
    3. Intrauterine device
    4. Intrauterine hormone-releasing system
    5. Bilateral tubal occlusion
    6. Vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the women of childbearing potential (WOCBP) trial participant and that the vasectomized partner has received medical assessment of surgical success.

25. History of allergic or hypersensitivity reactions (≥Grade 3) to pembrolizumab, PDS0101, or their excipients.