Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Digestive System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Uterine Cervical Neoplasms

Anus Neoplasms

Oropharyngeal Neoplasms

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Anus Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Anal Cancer

Camurati-Engelmann Disease

Antineoplastic Agents

All Drugs and Chemicals

Atezolizumab

Vaccines

Immunomodulating Agents

Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)

Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.

Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.

Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.

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.

PRGN-2009 (Phase I)

On the phase II portion of the protocol PRGN-2009 will be administered on just Day (D)1 and D15.

PRGN-2009 (Phase II)

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.

M7824

MRI (with gadolinium) of the neck, chest, skull, and/or sinonasal, if indicated, will be used when computed tomography (CT) scan is not an option to follow the disease.

Bone scans and other imaging assessments may also be performed as clinically indicated.

Bone scan

Imaging of the neck, chest, skull, and/or sinonasal, if indicated, will be performed every 8 weeks. In the event of a partial response (PR) or complete response (CR) tumor imaging assessments may be performed every 3 months (+/- 2 weeks) at the discretion of the investigator.

CT scan

Performed at baseline and may also be performed as clinically indicated by development of new specific symptoms or on the discretion of the Principal Investigator.

Brain CT

Brain MRI

Where feasible, optional biopsies may be done at baseline as well as at week 9 and will likely be computed tomography (CT) guided. If a recent (≤ 6 months preferred) outside biopsy has been performed that specimen may be used in lieu of a baseline biopsy for phase I participants.

For participants with lesions amenable to biopsy, two biopsies may be performed at baseline and at Week 9 (phase I participants).

Biopsy (Phase I)

Where feasible, biopsies will be done at baseline as well as at week 4-5. Biopsies will be done by ear, nose and throat (ENT) under direct visualization. Where feasible at least 2 cores will be obtained. If a recent (≤ 6 months preferred) outside biopsy has been performed that specimen may be used in lieu of a baseline biopsy.

For participants with lesions amenable to biopsy, two biopsies may be performed at baseline and at Week 4-5 (phase II participants).

Biopsy (Phase II)

Charalampos Floudas, M.D.

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.

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

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).

Phase I: In participants with recurrent/metastatic HPV positive cancer - 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 - To determine if HPV vaccine alone (Arm 2A) is able to result in a equal to or greater than 2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment in p16-positive oropharyngeal cancer.

Phase 1: To assess ratio of participants that are hospitalized because of adverse events attributed to disease progression.

Phase II: To determine the 3-year overall and relapse-free survival rate for PRGN-2009 alone (Arm 2A) as neoadjuvant/ induction therapy before definitive standard of care therapy for this population.

Phase 1: To assess overall survival (OS).

Phase 1: To assess progression-free survival time (PFS).

Phase II: To assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone in this participant population.

Phase II: To determine if the use of PRGN-2009 alone results in significantly prolonged survival as compared to the expected 80% three-year historical survival for this population.

Phase 1: To assess overall response rate (ORR) according to RECIST 1.1.

Spots Global Cancer Trial Database for biopsy (phase i)