Conditions: Human Papilloma Virus Cervical Cancer Oropharyngeal Cancer Anal Cancer Vaginal or Penile Cancer
Keywords: TGFR1 pathway signaling and overexpression PD-1 inhibitors Manageable Safety Profile Bifunctional Fusion Protein Refractory/Recurrent HPV Associated Malignancies
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
Background:

In the United States, each year there are more than 30,000 cases of human papillomavirus (HPV) associated cancers. Some of these cancers are often incurable and are not improved by standard therapies. Researchers want to see if a new drug M7824, which targets and blocks a pathway that prevents the immune system from effectively fighting the cancer can shrink tumors in people with some HPV cancers.

Objectives:

To see if the drug M7824 causes tumors to shrink.

Eligibility:

Adults age 18 and older who have a cancer associated with HPV infection.

Design:

Participants will be screened with medical history and physical exam. They will review their symptoms and how they perform normal activities. They will have body scans. They will give blood and urine samples. They will have a sample of their tumor tissue taken if one is not available.

Participants will have an electrocardiogram to evaluate their heart. Then they will get the study drug through a thin tube in an arm vein.

Participants will get the drug every 2 weeks for 26 times (1 year). This is 1 course.

After the course, participants will be monitored but will not take the study drug. If their condition gets worse, they will start another course with the drug. This process can be repeated as many times as needed.

Treatment will stop if the participant has bad side effects or the drug stops working.

Throughout the study, participants will repeat some or all the screening tests.

After participants stop taking the drug, they will have a follow-up visit and repeat some screening tests. They will get periodic follow-up phone calls.

Detailed description:
Background:

* Metastatic or refractory/recurrent human papillomavirus (HPV) associated malignancies (cervical, anal, oropharyngeal cancers etc.) are often incurable and poorly palliated by standard therapies.

  * Transforming growth factor receptor type 1 (TGF R1) pathway signaling and overexpression are significantly associated with HPV+ cancers.
  * Programmed cell death protein 1 (PD-1) inhibitors have produced a 12-20% response rate for these diseases
  * M7824 is a novel bifunctional fusion protein composed of monoclonal antibodies against human programmed death-ligand 1 (PD- L1) and soluble extracellular domain of human TGF- receptor II (TGF- RII), which functions as a TGF- "trap."
  * Early data from a small cohort of patients with HPV associated malignancies in a phase I trial of M7824 has shown promising activity (NCT02517398). As of May 30, 2017, 4 of 9 patients (44%) with HPV associated malignancies have had preliminary evidence of clinical benefit including:
* Patient with metastatic cervical cancer with a 25% reduction in her disease at 3 months
* Patient with metastatic P16 positive (P16+) head and neck cancer with an unconfirmed partial response (PR) at 6 weeks
* Patient with metastatic anal cancer with a durable PR ongoing 9 months after starting treatment
* Patient with metastatic cervical cancer with a durable complete response (CR) ongoing 15 months after starting treatment.
* Notably, the P16+ head and neck cancer patient with unconfirmed PR, anal cancer patient with durable PR and cervical cancer patient with durable CR all have HPV+ disease.

  * Immune related adverse events with M7824 in the phase I trial to date have been on par with other PD-1/PD-L1 inhibitors, suggesting a manageable safety profile.
  * EMD Serono has an ongoing expansion cohort evaluating M7824 in patients with head and neck squamous cell carcinoma (HNSCC) as well as in cervical cancer excluding neuroendocrine cervical cancer.

Objective:

-To determine the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in subjects with recurrent or metastatic HPV associated malignancies.

Eligibility:

* Age greater than or equal to 18 years old
* Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV

associated malignancies including:

* Non-Neuroendocrine Cervical cancers
* P16+ Oropharyngeal cancers
* Anal cancers
* Vulvar, vaginal, penile, squamous cell rectal and neuroendocrine cervical cancers
* Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are known HPV+

  * Subjects must have measurable disease.

Design:

-This is a Phase II trial of M7824 in patients with recurrent or metastatic HPV associated

malignancies.

* Patients will be scheduled to receive 1,200 mg of M7824 intravenous (IV) every 2 weeks until off treatment criteria are met.
* There will be six cohorts: (1) Patients with anal cancer whose disease is naive to checkpoint inhibition, (2) Patients with non-neuroendocrine cervical cancer naive to checkpoint inhibition,

  (3) Patients with P16+ oropharyngeal cancers naive to checkpoint inhibition, and (4) Patients with other rare HPV associated tumors (e.g. squamous cell rectal, vulvar, vaginal, penile cancer, neuroendocrine cervical) naive to checkpoint inhibition, (5) Patients with any HPV associated cancers whose disease is refractory to checkpoint inhibition. Patients who are determined to be HPV negative after enrolling will be taken off of their previously assigned cohort and reassigned to cohort 6 and their slot on their previously assigned cohort will be replaced.
* Cohorts 1-5 of the trial will be conducted using a Simon two-stage phase II trial design.

Arms:
arm 1: M7824 at a flat dose of 1,200 mg intravenous (IV) once every 2 weeks

Interventions: intervention 1: M7824
Intervention descriptions: intervention 1: Flat dose of 1,200 mg of M7824 intravenous (IV) once every 2 weeks

Protocol document:
ICF_002.pdf: 
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