HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PDL1/TGF-Beta Trap (M7824) in Subjects With HPV Associated Cancers

Phase I/II Trial of HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PD-L1/TGF-Beta Trap (M7824) in Subjects With HPV Positive Cancers

Background:

For some cancers associated with human papillomavirus (HPV), standard treatments are not helpful. Researchers want to see if a vaccine for HPV combined with a drug called M7824 (MSB0011359C) has a better effect on these cancers than when they work alone.

Objective:

To find a safe dose of HPV vaccine alone or combined with M7824. Also, to test if either HPV vaccine alone or combined with M7824 causes a better immune response.

Eligibility:

People ages 18 and older with locally advanced or metastatic HPV associated cancer (Phase I) or stage II or III p16-positive oropharyngeal cancer (Phase II)

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Possible photos of skin lesions

Computed tomography (CT), magnetic resonance imaging (MRI), or nuclear bone scan: Participants will lie in a machine that takes pictures of the body. For the CT scan, they may have a contrast agent injected into a vein.

Participants may have up to 2 tumor biopsies. For participants in Phase II, this may be performed with a thin tube placed through the nose into the airway.

Participants will receive the HPV vaccine alone or with M7824. For participants on the Phase II, they will receive two doses of HPV vaccine under the skin either alone or with M7824 as an infusion spaced two weeks apart. This will be done prior to their planned chemoradiation or surgery. For participants on the Phase I, they will get the HPV vaccine injected under the skin 2 to 3 times in the first month. Then they will have a booster every 4 weeks. They will receive M7824 as an infusion into a vein every 2 weeks. Treatment will last up to 1 year.

After they stop treatment, participants will have a visit within 4 weeks. They will then be contacted for long-term follow-up every year, for the rest of their lives.

...

Study Overview

• Status: Completed
• Conditions: Cervical Cancer; Anal Cancer; Oropharyngeal Cancer; Vulvar, Vaginal, Penile, Rectal Cancer; HPV Positive Cancer
• Intervention / Treatment: Biological: M7824; Biological: PRGN-2009; Diagnostic test: EKG; Diagnostic test: CT Scan; Diagnostic test: Brain MRI; Procedure: Biopsy

Detailed Description

Background

• Metastatic human papillomavirus (HPV) associated malignancies (cervical, anal, oropharyngeal cancers, etc.) are often incurable and poorly palliated by standard therapies.
• HPV-positive (p16+) oropharyngeal cancers are the most common HPV-associated malignancy in the United States and are increasing in incidence.
• Stage II and III HPV-positive oropharyngeal cancer is primarily treated with definitive therapy.
• Although the prognosis for stage I HPV+ oropharyngeal cancer is favorable, about 20 percent of patients with stage II disease and 35 percent of patients with stage III disease will die within four years.
• Attempts to de-intensify treatment of HPV-positive oropharyngeal cancer by replacing high-dose cisplatin with cetuximab concurrent with radiotherapy have failed.
• Induction and neoadjuvant immunotherapy are an area of active study in this type of cancer. The aims of induction immunotherapy are to induce antigen-specific immunity prior to definitive therapy and to reduce the risk of disease relapse for patients with stage II and III disease.
• Therapeutic vaccines targeting HPV alone or in combination with M7824 (MSB0011359C) (dual programmed death-ligand 1 (PD-L1) and transforming growth factor beta (TGF- beta) inhibitor) have demonstrated induction of HPV antigen-specific responses and tumor growth inhibition in multiple pre-clinical models of HPV-positive malignancy.
• In clinical studies done in the Center for Cancer Research (CCR), M7824 as monotherapy has produced a notable objective response rate (35-40%) for metastatic HPV + cancers including Oropharyngeal Squamous Cell Carcinoma (OPSCC) and preclinical studies support the addition of an investigational HPV vaccine with therapeutic intent (PRGN-2009, a gorilla adenoviral based vaccine) to further increase anti-tumor efficacy.

Objectives:

Phase I in participants with recurrent/metastatic HPV positive cancer:

-Primary objective: To determine the safety and recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg every 2 weeks (q2w).

Phase II in participants with newly diagnosed stage I (T1, T2 N1)/II/III p16-positive oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB/HPV + sinonasal squamous cell cancer:

-Primary objective: To determine if HPV vaccine alone (Arm 2A) is able to result in a >= 2-fold increase in cluster of differentiation 3 (CD3+) tumor infiltrating T cells post treatment compared with pre-treatment in p16-positive oropharyngeal cancer.

Eligibility:

Phase I:

• Men or women of age >= 18 years old.

• Subjects with cytologically or histologically confirmed locally advanced not amenable to potentially curative local therapies or metastatic HPV associated malignancies:

  • Cervical cancers;
  • p16+ Oropharyngeal cancers;
  • Anal cancers;
  • Vulvar, vaginal, penile, and squamous cell rectal cancers
  • Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are known HPV+.
• Prior first line systemic therapy is required

Phase II:

• Men or women of age >= 18 years old.
• Subjects with newly diagnosed stage I (T1, T2 N1), II or III, II or III p16-positive oropharyngeal squamous cell carcinoma (OPSCC) or stage II/III/IVA/IVB HPV-SNSCC planned for definitive therapy.

Design:

Phase I: Recurrent/metastatic HPV associated cancer:

• A 3+3 dose escalation design will be used which will evaluate PRGN-2009 (HPV vaccine) at two dose levels (1x10^11 and 5x10^11 viral particle (VP) units) given as monotherapy followed by a third dose level evaluating the RP2D dose of PRGN-2009 in combination with 1200 mg (RP2D) of M7824. In addition, the combination of PRGN-2009 at RP2D with 1200 mg of M7824 will be expanded to a total of 10 evaluable participants to gauge the preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with advanced disease.
• There will be a 4-week dose limiting toxicity (DLT) evaluation period for each dose level.
• It is expected that up to 22 participants may enroll.

Phase II:

Newly diagnosed p16-positive oropharyngeal cancer:

• Evaluation of HPV vaccine alone (Arm 2A: Stage I (T1,T2 N1)/II/III) as neoadjuvant/ induction therapy before definitive standard of care therapy.
• Participants will receive neoadjuvant/ induction immunotherapy at National Institutes of Health (NIH) Clinical Center and then be referred back to their home institution for definitive standard of care therapy.
• It is expected that up to 20 participants may enroll.
• Newly diagnosed stage II/III/IVA/IVB HPV-SNSCC:
• Enrollment and treatment will occur similarly as participants with p16+oropharyngeal cancer for exploratory correlates to advise possible future trials. Up to 2 participants may enroll in this group.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

• Subjects with cytologically or histologically confirmed locally advanced not amenable to potentially curative local therapies or metastatic human papillomavirus (HPV) associated malignancies (Phase I only):

  • Cervical cancers;
  • p16+ Oropharyngeal cancers;
  • Anal cancers;
  • Vulvar, vaginal, penile, and squamous cell rectal cancers;
  • Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are known HPV+.
• Subjects with cytologically or histologically confirmed newly diagnosed stage II or III p16-positive oropharyngeal squamous cell carcinoma planned for definitive therapy or with newly diagnosed stage II or III or IVA or IVB HPV-positive sinonasal squamous carcinoma (HPV-SNSCC) eligible for primary surgery (Phase II only).
• Subjects must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Phase 1 only).
• Phase I only: Participants must have received one prior line of systemic chemotherapy in the recurrent/metastatic setting as well as checkpoint blockade therapy in tumors with Food and Drug Administration (FDA) approval (head and neck squamous cell cancer and programmed death-ligand 1 (PDL1+) cervical cancer). Exceptions to this include participants not eligible to receive standard therapy.
• Men or Women; Age >=18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Adequate hematologic function at screening, as follows:

  • Absolute neutrophil count (ANC) >=1 x 109/L;
  • Hemoglobin >= 9 g/dL;
  • Platelets >= 75,000/microliter.

• Adequate renal and hepatic function at screening, as follows:

  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance >= 40 mL/min for participant with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl);
  • Bilirubin =< 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin =< 3.0 x ULN;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN, unless liver metastases are present, then values must be =< 3 x ULN).
• The effects of the immunotherapies (PRGN-2009 vaccine and M7824) on the developing human fetus are unknown. For this reason and because M7824 and PRGN-2009 used in this trial are possibly teratogenic, women of child-bearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and up to 2 months following the last dose of M7824 study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Participants serologically positive for human immunodeficiency virus (HIV), Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative polymerase chain reaction (PCR). HIV positive participants must have cluster of differentiation 4 (CD4) count >= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or Castleman's disease within 12 months prior to enrollment.

EXCLUSION CRITERIA:

• Participants with prior investigational drug, live vaccine, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the participant is otherwise suitable for enrollment. Participants may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).
• Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
• Known active brain or central nervous system metastasis (less than a month out from definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3 months) or clinically significant cerebrovascular accident (<3 months). In order to be eligible participants must have repeated central nervous system (CNS) imaging at least a month after definitive treatment showing stable CNS disease. Participants with evidence of intra-tumoral or peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is grade =< 1 and has been shown to be stable on two consecutive imaging scans.
• Pregnant women are excluded from this study because M7824 and PRGN-2009 vaccine have not been tested in pregnant women and there is potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these immunotherapies, breastfeeding should be discontinued if the mother is treated on this protocol.

• Only for Phase I, Arm 1B: Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with exception of:

  • Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or other mild autoimmune disorders not requiring immunosuppressive treatment;
  • Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable;
  • Subjects on systemic intravenous or oral corticosteroid therapy with the exception of

physiologic doses of corticosteroids (=< the equivalent of prednisone 10 mg/day) or other immunosuppressors such as azathioprine or cyclosporin A are excluded on the basis of potential immune suppression. For these subjects these excluded treatments must be discontinued at least 1 weeks prior to enrollment for recent short course use (=< 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (> 14 days). In addition, the use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study.

• Only for Phase I: Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events, known left ventricular ejection fraction <50% (confirmation of ejection fraction (EF) > 50% is not required for eligibility), history of myocarditis, or recent myocardial infarction (within 6 months), or other illness considered by the Investigator as high risk for M7824 drug treatment.
• Only for Phase I: Subjects refusing to accept blood products as medically indicated.
• History of second malignancy within 3 years of enrollment except for the following: adequately treated localized skin cancer, cervical carcinoma in situ, superficial bladder cancer, other localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia (CLL)). For participants enrolled on the phase I portion of the protocol a second HPV driven malignancy is allowed.
• Only for Phase I, Arm 1B: Subjects with a known severe hypersensitivity reaction to monoclonal antibodies or its excipients (grade >/= 3 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5) will be evaluated by the allergy/immunology team prior to enrollment.
• Prior allogenic tissue/solid organ transplant.
• For participants who may receive M7824: previous life-threatening side effects resulting from prior checkpoint inhibitor therapy.
• Participants with pulse oximetry < 92% on room air at screening.
• Participants unable to provide informed consent.
• Participants whose inclusion in the trial would in the judgement of the principal investigator (PI) lead to time from diagnosis to initiation of curative treatment of>70 days (Arm 2A only).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Arm 1A; Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)	Biological: PRGN-2009; On the phase I portion of the protocol PRGN-2009 will be administered on Day (D)1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.; Diagnostic test: EKG; Screening, end of treatment and safety follow-up.; Other Names: Electrocardiogram; Diagnostic test: CT Scan; Brain CT Scan at Baseline. Tumor evaluations CT Scan (Screening, Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Computed tomography scan; Diagnostic test: Brain MRI; Brain MRI at Baseline. Tumor evaluations MRI (Screening, Baseline/Day 1, and odd numbered weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Brain magnetic resonance imaging; Procedure: Biopsy; Biopsy for immune analysis: Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Bx
Experimental: 2/Arm 1B; Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.	Biological: M7824; Subjects enrolled to Arm 1B will receive M7824 (MSB0011359C) via intravenous (IV) infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.; Other Names: MSB0011359C; Biological: PRGN-2009; On the phase I portion of the protocol PRGN-2009 will be administered on Day (D)1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.; Diagnostic test: EKG; Screening, end of treatment and safety follow-up.; Other Names: Electrocardiogram; Diagnostic test: CT Scan; Brain CT Scan at Baseline. Tumor evaluations CT Scan (Screening, Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Computed tomography scan; Diagnostic test: Brain MRI; Brain MRI at Baseline. Tumor evaluations MRI (Screening, Baseline/Day 1, and odd numbered weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Brain magnetic resonance imaging; Procedure: Biopsy; Biopsy for immune analysis: Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Bx
Experimental: 3/Arm 2A; Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.	Biological: PRGN-2009; On the phase I portion of the protocol PRGN-2009 will be administered on Day (D)1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.; Diagnostic test: EKG; Screening, end of treatment and safety follow-up.; Other Names: Electrocardiogram; Diagnostic test: CT Scan; Brain CT Scan at Baseline. Tumor evaluations CT Scan (Screening, Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Computed tomography scan; Diagnostic test: Brain MRI; Brain MRI at Baseline. Tumor evaluations MRI (Screening, Baseline/Day 1, and odd numbered weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Brain magnetic resonance imaging; Procedure: Biopsy; Biopsy for immune analysis: Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Bx
Experimental: 4/Arm 2B; Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.	Biological: M7824; Subjects enrolled to Arm 1B will receive M7824 (MSB0011359C) via intravenous (IV) infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.; Other Names: MSB0011359C; Biological: PRGN-2009; On the phase I portion of the protocol PRGN-2009 will be administered on Day (D)1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.; Diagnostic test: EKG; Screening, end of treatment and safety follow-up.; Other Names: Electrocardiogram; Diagnostic test: CT Scan; Brain CT Scan at Baseline. Tumor evaluations CT Scan (Screening, Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Computed tomography scan; Diagnostic test: Brain MRI; Brain MRI at Baseline. Tumor evaluations MRI (Screening, Baseline/Day 1, and odd numbered weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Brain magnetic resonance imaging; Procedure: Biopsy; Biopsy for immune analysis: Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).; Other Names: Bx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Recommended Phase II Dose of PRGN-2009	Phase I: To determine the recommended phase II dose (RP2D) of PRGN-2009 Human Papillomavirus Vaccine (HPV) vaccine alone or in combination with M7824 (MSB0011359C). Recommended Phase 2 Dose, the dose of a drug or drug combination that was identified in a Phase 1 study (dose finding study) that was identified for continued study.	Date treatment consent signed to date off study, approximately 18 months
Phase I: Safety - Number of Treatment-related Serious Adverse Events (AE) of Grades 1, 2, 3, 4 and/or 5 Along With the AE Term	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations.	Date treatment consent signed to date off study, an average of 6 months
Phase II: Percentage of Participants That Had a 2-fold Increase of Cluster of Differentiation 3 (CD3+) Tumor Infiltrating T Cells in Biopsies Performed Post-treatment Compared to Pre-treatment	CD3+ tumor infiltrating T cells post treatment compared with pre-treatment reported with a 95% confidence interval assessed by multiplex CD3+ tumor infiltrating lymphocytes assessed by multiplex immunofluorescence from the surgical/ biopsy tissue collected pre- and post-treatment. The percentage of participants with doubling of baseline CD3+ tumor infiltrating lymphocytes will be provided as well as the 95% confidence interval. The CD3 cells are assessed by multiplex immunofluorescence in the biopsies. Doubling is the desired outcome.	Pre-Treatment (Baseline) and anytime between Week 4-5 post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Proportion of Participants That Are Hospitalized Because of Adverse Events Attributed to Disease Progression	Phase I: proportion of participants that are hospitalized because of adverse events attributed to disease progression. Adverse events were assessed by the Common Terminology Criteria for Adverse Events(CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors(RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression.	Date treatment consent signed to date of progression, an average of 6 months
Phase II: 3-year Overall Survival for PRGN-2009 Alone	Phase II: Overall survival assessed using the Kaplan-Meier method, defined as the time from the date of first treatment to the date of death (any cause). Participants who receive two doses of PRGN-2009 and go on to receive standard definitive therapy will be evaluable for overall survival assessment.	3 years
Phase II: 3 Year Relapse-free Survival for PRGN-2009 Alone	Phase II: 3-year Relapse-free survival assessed using the Kaplan-Meier method, defined as the time from completion of standard of care definitive therapy to the date of disease recurrence or death (any cause) whichever occurs first. Participants who receive two doses of PRGN-2009 and go on to receive standard definitive therapy will be evaluable for overall survival assessment.	3 years
Phase I: Overall Survival (OS)	Phase I: Overall survival assessed using the Kaplan-Meier method, defined as the time from the date of first treatment to the date of death (any cause). Participants who are alive at the end of follow up will be censored at the last known date alive.	The time from the date of first treatment to the date of death (any cause), an average of 12 months
Phase I: Progression-free Survival Time (PFS)	PFS, evaluated using Kaplan-Meier methods, defined as the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first. Disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression.	Date of first treatment to date of disease progression or death (any cause), an average of 6 months
Phase I: Duration of Response (DOR)	Phase 1: DOR is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression.	Date of first treatment to date of disease progression or death (any cause), an average of 4 months
Phase II: Safety - Number of Treatment-related Serious Adverse Events (AE) of Grades 1, 2, 3, 4 and/or 5 Along With the AE Term	Phase II: Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations.	Date treatment consent signed up to 28 days after last treatment
Phase II: Overall Survival at 3 Years Compared With Historical Cohort	Phase II: Assess if PRGN-2009 results in significantly prolonged survival at three years as compared to the expected 80% three-year historical survival in p16-positive oropharyngeal cancer (OPC) participants. Three-year overall survival will be measured using a Kaplan-Meier curve and will be compared descriptively with the historical benchmark. Participants who receive two doses of PRGN-2009 and go on to receive standard definitive therapy will be evaluable for overall survival assessment.	3 years
Phase I: Overall Response Rate (ORR)	Phase 1: overall response rate (ORR) accessed according to the Response Evaluation Criteria in Solid Tumors (RECIST)1.1., defined as a complete response or partial response assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	study end, an average of 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to date off study, approximately 27 months and 1 day, 9 months and 9 days, 30 months and 11 days, and 9 days for each group respectively.
Phase I: Number of Participants With Dose-Limiting Toxicities (DLT)	DLT is defined as any one of the following adverse events, possibly attributable to study drugs, that occur within 28 days of the human papillomavirus (HPV) vaccine monotherapy or 28 days of starting the HPV vaccine + M7824 (MSB0011359C) combination therapy: any grade 3 or higher bleeding episode requiring blood transfusion(s); Any Grade 4 or > adverse drug reactions (ADRs) as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and assessed as possibly related to any agent by the Investigator, except for laboratory values that are asymptomatic or resolve to Grade ≤ 1 or baseline grade within 7 days without medical intervention; discontinuation any Grade 3 ADRs possibly attributed to any agent except for any of the following: Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, headaches, nausea, emesis which can be controlled with conservative medical management. See Protocol for details.	Dose-Limiting Toxicities (DLT) were monitored/assessed from the time of first drug administration through 28 days after starting the trial treatment.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Charalampos Floudas, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Floudas CS, Goswami M, Donahue RN, Strauss J, Pastor DM, Redman JM, Brownell I, Turkbey EB, Steinberg SM, Cordes LM, Marte JL, Khan MH, McMahon S, Lamping E, Manu M, Manukyan M, Brough DE, Lankford A, Jochems C, Schlom J, Gulley JL. PRGN-2009 and bintrafusp alfa for patients with advanced or metastatic human papillomavirus-associated cancer. Cancer Immunol Immunother. 2025 Mar 21;74(5):155. doi: 10.1007/s00262-025-04009-z.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2020
• Primary Completion (Actual): November 22, 2022
• Study Completion (Actual): March 31, 2026

Study Registration Dates

• First Submitted: June 13, 2020
• First Submitted That Met QC Criteria: June 13, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): August 18, 2026
• Last Update Submitted That Met QC Criteria: July 29, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; M7824; HPV Vaccine; HPV Associated Malignancy; PRGN-2009
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Stomatognathic Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Head and Neck Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Otorhinolaryngologic Diseases; Uterine Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Anus Diseases; Rectal Neoplasms; Uterine Cervical Neoplasms; Oropharyngeal Neoplasms; Anus Neoplasms; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Tomography; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Radiography; Heart Function Tests; Electrodiagnosis; Image Interpretation, Computer-Assisted; Radiographic Image Enhancement; Image Enhancement; Photography; Tomography, X-Ray; Biopsy; Electrocardiography; Tomography, X-Ray Computed
• Other Study ID Numbers: 200104; 20-C-0104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No