EMD Serono, Inc. Commercial Agents: None 2 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 PRÉCIS Background: • Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, oropharyngeal cancers etc.) are poorly palliated by standard therapies. There is an unmet need for active treatments for these tumors. • In a phase I trial of M7824 (NCT02517398) 15 out of 43 (34.9%) participants with HPV associated malignancies had radiographic tumor responses according to RECIST 1.1 or iRECIST. • While the response rate observed with M7824 appears to be higher than single agent PD-1 inhibitors alone (15- 20%), the majority of patients with these diseases still do not seem to benefit from immunotherapy. • Preclinical studies suggest that the use of a combination of multiple immunotherapy agents may have improved anti- tumor efficacy . o Specifically, preclinical studies have shown that the combination of three immunotherapy agents (1) a therapeutic vaccine against HPV positive cancers (PDS0101), (2) a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824), and (3) a tumor targeted immunocytokine (NHS-IL12) produces greater anti-tumor activity than any single or dual combination of these agents. Objectives: • To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) a therapeutic vaccine against HPV positive cancers (PDS0101), (2) a tumor targeted immunocytokine (NHS- IL12) and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824) in subjects with checkpoint naïve a dvanced HPV associated m alignancies . Eligibility: • Age > 18 years old. • Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies : o Cervical cancers ; o P16+ Oropharyngeal cancers ; o Anal cancers ; o Vulvar, vaginal, penile, and squamous cell rectal cancers ; o Other locally advanced or metastatic solid tumors (e.g. , lung, esophagus) that are known HPV+. • Prior first line systemic therapy is required unless the participant declines standard treatment after appropriate counseling has been provided. • Subjects must have measurable disease. 3 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 Design: • This is a phase I/II trial of combination immunotherapy. • The trial will be conducted using a Simon optimal two -stage design . • Participants will receive HPV vaccine + NHS -IL12 + M7824. • The first six participants will be evaluable for dose limiting toxicities (DLTs) and accrual will only continue to 8 participants who have not been treated with checkpoint inhibitors if less than 2 out of the first 6 participants experience a DLT . • If three or more out of eight participants who have not been treated with checkpoint inhibitors have objective responses accrual will be expanded to enroll 20 evaluable participants . • Patients with cervical cancer with prior pelvic radiation and boost brachytherapy will be enrolled in a separate cohort to evaluate safety and preliminary evidence of efficacy. 4 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 TABLE OF CONTENTS hPRÉCIS ........................................................................................................................................ 2 TABLE OF CONTENTS ................................................................................................................