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.
...
Background
- 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
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.
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 q2w.
Phase II in participants 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
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 ^3 2-fold increase in 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 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 unless the participant 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.
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 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
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 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 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.
- 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 participant is
not eligible to receive standard therapy or declines standard treatment (Phase I
only). Specifically, for participants enrolled to the phase I portion of the study
with oropharyngeal cancer participants should have previously received platinum based
chemotherapy and PD(L)1 inhibitor based therapy, for participants with enrolled to the
phase I portion of the study with cervical, anal or penile cancer participants 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.
- 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.
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
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.
- 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 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.
- 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).
