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

  • End date
    Oct 1, 2023
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 11 January 2022
ct scan
systemic therapy
measurable disease
squamous cell carcinoma
hepatitis b
definitive treatment
neutrophil count
liver metastases
solid tumors
human papillomavirus
hpv vaccine
oropharyngeal cancer
human papilloma virus vaccine
oropharyngeal carcinoma
oropharyngeal squamous cell carcinoma



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.


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.


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)


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.




  • 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 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 (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 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 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 squamos cell cancer:

-Primary objective: To determine if either HPV vaccine alone (Arm 2A) or in combination with M7824 (Arm 2B) is able to result in a >= 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 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.

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 DLT evaluation period for each dose level.
  • It is expected that up to 22 participants may enroll in 6 months.

Phase II:

Newly diagnosed p16-positive oropharyngeal cancer:

  • Sequential two-arm evaluation of HPV vaccine alone (Arm 2A: Stage I (T1,T2 N1)/II/III) or HPV vaccine plus M7824 (Arm 2B: Stage II/III) as neoadjuvant/ induction therapy before definitive standard of care therapy (20 participants each arm).
  • Participants 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 participants may enroll in 2 years.
  • 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 4 participants may enroll in this group.

Condition HPV Positive Cancer, Vulvar, Vaginal, Penile, Rectal Cancer, Anal Cancer, Oropharyngeal Cancer, Cervical Cancer
Treatment M7824, PRGN-2009
Clinical Study IdentifierNCT04432597
SponsorNational Cancer Institute (NCI)
Last Modified on11 January 2022


Yes No Not Sure

Inclusion Criteria

Subjects with cytologically or histologically confirmed locally advanced not amenable to potentially curative local therapies 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
Men or Women; Age >=18 years
sinonasal squamos carcinoma (HPV-SNSCC) eligible for primary surgery (Phase II
ECOG performance status =< 2
Adequate hematologic function at screening, as follows
Subjects must have measurable disease, per RECIST 1.1 (Phase 1 only)
Absolute neutrophil count (ANC) >=1 x 109/L
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 FDA approval (head and neck squamous cell cancer and PDL1+ cervical cancer). Exceptions to this include participants not eligible to receive standard therapy
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)
Participants serologically positive for HIV, Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative PCR. HIV positive participants 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
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

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 CNS imaging at least a month after definitive treatment showing stable CNS disease. Participants 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
Subjects refusing to accept blood products as medically indicated
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
Subject with pulse oximetry < 92% on room air at screening
Subjects with a history of serious intercurrent chronic or acute illness, such as
Participants unable to provide informed consent
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
participants 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 participants who may receive M7824, previous life-threatening side effects
resulting from prior checkpoint inhibitor therapy
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
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