Phase 3 Study of PDS0101 and Pembrolizumab in HPV16+ Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Inclusion Criteria:

1. Subject (or legally acceptable representative, if applicable) provides writteninformed 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 recurrentand/or metastatic squamous cell cancer of the head and neck (HNSCC) with:

4. Eligible primary tumor location of oropharynx, oral cavity, hypopharynx, orlarynx.

5. HPV16 tumor positivity (central testing).

6. Tumor PD-L1 expression defined as a CPS ≥ 1 using the FDA- approvedpembrolizumab (KEYTRUDA®) assay (local testing).

7. No prior systemic anticancer therapy administered in the incurable recurrent ormetastatic setting. Systemic therapy which was completed more than 6 monthsprior to randomization, if given as part of multimodal treatment for locallyadvanced disease, is allowed.

8. Have measurable disease based on RECIST 1.1 as determined by the site and confirmedby BICR. As a guidance to the site investigators, tumor lesions situated in apreviously irradiated area are considered measurable if progression has beendemonstrated in such lesions.

9. Subject has adequate organ function defined by the following parameters (allspecimens 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 KidneyDisease Epidemiology Collaboration (CKD-EPI) equation.

• Hepatic: Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ULN for subjects withtotal bilirubin levels >1.5 × ULN, Aspartate aminotransferase (AST) and Alanineaminotransferase (ALT) ≤2.5 ULN (if approved by Medical Monitor, ≤5 × ULN forsubjects with liver metastases; AST and ALT >5 to 20 x ULN may be included ifasymptomatic).

• Coagulation: INR, prothrombin time (PT) ≤1.5 × ULN; if subject is receivinganticoagulant therapy, INR or PT- should be within therapeutic range ofanticoagulant.

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

7. Male subjects of childbearing potential must agree to use a condom as an effectivemethod of contraception starting with the first dose of study therapy through 120days 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 urine pregnancy test is positive. If the urine test cannot be confirmed asnegative, a serum pregnancy test will be required.

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

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

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

6. Has received radiotherapy prior to randomization outside of the following minimumwashout 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 forinjection are generally killed-virus vaccines and are allowed; however, intranasalinfluenza vaccines (e.g., FluMist ® ) or live attenuated vaccines are not allowedwithin 30 days prior to randomization.

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

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

10. Has undergone prior allogeneic hematopoietic stem cell transplantation within thelast 5 years. Note: Subjects who have had a transplant greater than 5 years ago areeligible 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 recentuse of intranasal, intra-articular, and topical steroids are allowed for symptommanagement are clinically indicated.

12. Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years. Note: Subjects with basal cell carcinoma of theskin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breastcarcinoma, cervical cancer in situ, superficial [non- infiltrated] bladder tumors)or other malignant tumors that have undergone potentially curative therapy areeligible 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 thathave not been subjected to CNS-directed therapy since documented progression. Note:Subjects with previously treated brain metastases are eligible if all the followingcriteria are met:

14. radiologically stable, i.e., without evidence of progression for at least 30days by repeat imaging (note that repeat imaging should be performed duringstudy screening),

15. neurologically stable, and

16. without requirement of steroid treatment for at least 14 days prior torandomization.

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

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

19. Has an active infection requiring systemic therapy (e.g., IV or oralanti-infective).

20. Has known human immunodeficiency virus (HIV) and CD4 count < 350 cells/μL and/or ahistory 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 anHIV viral load less than 400 copies/mL and who do not meet the above exclusioncriterion may be enrolled.

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

22. Has active hepatitis C defined by a known positive C Ab result and knownquantitative HCV RNA results greater than the lower limits of detection of theassay. Note: Subjects with a history of HCV infection who have completed curativeantiviral treatment and have HCV viral load below the limit of quantification may beenrolled.

23. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

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

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

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

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

28. Combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation.

29. Progestogen-only hormonal contraception

30. Intrauterine device

31. Intrauterine hormone-releasing system

32. Bilateral tubal occlusion

33. Vasectomized partner is a highly effective birth control method provided thatthe partner is the sole sexual partner of the women of childbearing potential (WOCBP) trial participant and that the vasectomized partner has receivedmedical assessment of surgical success.

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