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

Trial Status: Active

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 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 CT, 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. ...

Inclusion Criteria

  • - INCLUSION CRITERIA: - Subjects with cytologically or histologically confirmed locally advanced or metastatic 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 squamos carcinoma (HPV-SNSCC) eligible for primary surgery (Phase II only). - Subjects must have measurable disease, per RECIST 1.1. - Subjects must have received prior standard systemic therapy unless the patient is not eligible to receive standard therapy or declines standard treatment (Phase I only). Specifically, for patients enrolled to the phase I portion of the study with oropharyngeal cancer patients should have previously received platinum based chemotherapy and PD(L)1 inhibitor based therapy, for patients with enrolled to the phase I portion of the study with cervical, anal or penile cancer patients should have previously received platinum based chemotherapy, for other rare HPV associated cancers where standard of care first line therapy does not exist (e.g., vulvar, vaginal) prior first line therapy is not required. - Men or Women; Age >=18 years. - 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. - Patients serologically positive for HIV, Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative PCR. HIV positive patients must have 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: - Patients 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 patient is otherwise suitable for enrollment. Patients 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 patients must have repeated CNS imaging at least a month after definitive treatment showing stable CNS disease. Patients with evidence of intratumoral 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. - 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. - 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 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. 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 CLL). For patients enrolled on the phase I portion of the protocol a second HPV driven malignancy is allowed. - Subjects with a known severe hypersensitivity reaction to monoclonal antibodies or its excipients (grade >/= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to enrollment. - Receipt of prior lymphodepleting chemotherapy (e.g., cyclophosphamide, fludarabine) or any organ transplantation requiring ongoing immunosuppression. - For patients who may receive M7824, previous life-threatening side effects resulting from prior checkpoint inhibitor therapy. - Subject with pulse oximetry < 92% on room air at screening. - Participants unable to provide informed consent. - Participants whose inclusion in the trail would in the judgement of the PI lead to time from diagnosis to initiation of curative treatment of >70 days (Arms 2A and 2B only).


National Institutes of Health Clinical Center
Status: ACTIVE
Contact: National Cancer Institute Referral Office
Phone: 888-624-1937


- Metastatic 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


- 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

highdose 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 (dual PD-L1 and

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 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.


Phase I in patients 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 q2w.

Phase II in patients with newly diagnosed stage II/III p16-positive oropharyngeal cancer and

patients with newly diagnosed operable stage II/III/IVA/IVB/HPV + sinonasal squamos cell


-Primary objective: To determine if either HPV vaccine alone (Arm 2A) or in combination with

M7824 (Arm 2B) is able to result in a ^3 2-fold increase in CD3+ tumor infiltrating T cells

post treatment compared with pre-treatment in p16-positive oropharyngeal cancer.


Phase I:

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

- Subjects with cytologically or histologically confirmed locally advanced 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


- Prior first line systemic therapy is required unless the patient declines standard

treatment after appropriate counseling has been provided.

Phase II:

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

- Subjects with newly diagnosed stage II or III p16-positive oropharyngeal squamous cell

carcinoma (OPSCC) or stage II/III/IVA/IVB HPV-SNSCC planned for definitive therapy.


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 to the 11th power and 5x10 to the 11th power 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

patients to gauge the preliminary efficacy of the combination of PRGN-2009 and M7824 in

patients with advanced disease.

- There will be a 4-week DLT evaluation period for each dose level.

- It is expected that up to 22 patients may enroll in 6 months.

Phase II: Newly diagnosed stage II/III p16-positive oropharyngeal cancer:

- Sequential two-arm evaluation of HPV vaccine alone (Arm 2A) or HPV vaccine plus M7824

(Arm 2B) as neoadjuvant/ induction therapy before definitive standard of care therapy

(20 patients each arm).

- Patients will receive neoadjuvant/ induction immunotherapy at NIH Clinical Center and

then be referred back to their home institution for definitive standard of care therapy.

- It is expected that up to 40 patients may enroll in 2 years.

- Newly diagnosed stage II/III/IVA/IVB HPV-SSNSCC

- Enrollment and treatment will occur similarly as patients with p16+oropharyngeal cancer

for exploratory correlates to advise possible future trials. Up to 4 patients may enroll

in this group.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
National Cancer Institute

Principal Investigator
Julius Y. Strauss

  • Primary ID 200104
  • Secondary IDs NCI-2020-04540, 20-C-0104
  • ID NCT04432597