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. ...
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
39
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.
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.
Screening, end of treatment and safety follow-up.
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).
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).
Biopsy for immune analysis: Baseline/Day 1, and odd numbered Weeks (Week 1, Week 3, Week 5, and Week 7 onwards).
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: Pre-Treatment (Baseline) and anytime between Week 4-5 post treatment
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: study end, an average of 6 months