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

Vaginal Neoplasms

Vulvar Neoplasms

Anus Neoplasms

Colonic Neoplasms

Oropharyngeal Neoplasms

Penile Neoplasms

Head and Neck Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Neoplasms

Anus Diseases

Rectal Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Vulvar Diseases

Vaginal Diseases

Genital Neoplasms, Male

Genital Diseases, Male

Penile Diseases

Male Urogenital Diseases

Vaginal Cancer

Penile Cancer

Anal Cancer

Vulvar Cancer

All Drugs and Chemicals

Antineoplastic Agents

Herbal and Botanical

Immunomodulating Agents

Interleukin-12

Entinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

Cola

Dose escalation/de-escalation of entinostat and dose escalation of NHS-IL12 with fixed dose of bintrafusp alfa

RP2D of entinostat, NHS-IL12, and bintrafusp alfa

Entinostat and NHS-IL12 (without bintrafusp alfa)

Subjects will receive bintrafusp alfa via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. Bintrafusp alfa will be administered as a "flat" dose of 300 mg independent of body weight. Bintrafusp alfa is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.

Bintrafusp Alfa

NHS-IL12 will be administered at as dose of 4, 8, 12, or 16.8 micrograms/kg by SC injection every 2 or 4 weeks. The dose of NHS-IL12 will be calculated based on the weight of the subject determined within 72 hours prior to the day of drug administration. The dose of NHS-IL12 used for the previous administration can be repeated if the change in the subject's weight is 10% or less than the weight used for the last dose calculation.

NHS-IL12

The entinostat used in this study is a self-administered investigational agent and will be given orally at a designated dose once a week or as directed. Number of entinostat tablets will be calculated based on the dose for the participant.

National Cancer Institute Referral Offic

National Cancer Institute Medical Oncology Referral Office

Jason M Redman, M.D.

Background:

Often, metastatic human papillomavirus (HPV) associated cancers cannot be cured. They also do not respond well to treatment. Some forms of colon cancer also have poor responses to treatment. Researchers want to see if a new drug treatment can help people with these types of cancers.

Objective:

To find a safe dose of entinostat in combination with NHS-IL12 and bintrafusp alfa and to see if this treatment will cause tumors to shrink.

Eligibility:

Adults ages 18 and older who have cervical, oropharyngeal, anal, vulvar, vaginal, penile, squamous cell rectal, or another cancer that may be associated with HPV infection or microsatellite stable small bowel or colorectal cancer.

Design:

Participants will be screened with a medical history and physical exam. Their ability to do daily activities will be assessed. They may have imaging scans of the brain and/or chest, abdomen, and pelvis. They may have nuclear bone scans. They will have an electrocardiogram to test heart function. They will have blood and urine tests. They may have a tumor biopsy. Participants with skin lesions may have them photographed.

Some screening tests will be repeated during the study.

Treatment will be done in 28-day cycles. Participants will get bintrafusp alfa through an intravenous catheter every 2 weeks. They will get NHS-IL12 as an injection under the skin every 4 weeks. They will take entinostat by mouth once a week. They will complete a medicine diary.

Participants will get treatment for 2 years. They will have 1-2 follow-up visits in the 30 days after treatment ends. Then they will be contacted every 6 months to check on their health....

Background:

* Although PD-1(L1) inhibitors have been approved for the treatment of over a dozen different tumor types in recent years, the majority of patients with advanced cancer still do not respond to these agents, including patients with microsatellite stable (MSS) colon cancer and patients with checkpoint refractory cancers (e.g., oropharyngeal, cervical).
* Clinical studies suggest that treatment with a bifunctional fusion protein targeting PD-L1 and TGF beta (bintrafusp alfa) may help overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
* Preclinical and clinical studies suggest that treatment with a histone deacetylase inhibitor (HDAC inhibitor) concomitantly with anti PD-1(L1) therapy is safe and may help overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
* Preclinical and clinical studies suggest that treatment with a tumor targeted immunocytokine (NHS-IL12) concomitantly with anti PD-1(L1) therapy is safe and may help overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
* Preclinical studies suggest that the use of a combination of multiple immunotherapy agents may have improved anti-tumor efficacy.

  * Specifically, preclinical studies have shown that the combination of three immunotherapy agents (1) an HDAC inhibitor, entinostat (2) a tumor targeted immunocytokine (NHS-IL12), and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta (bintrafusp alfa) produces greater anti-tumor activity than single or dual combinations of these agents.

Objectives:

* Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination with NHS-IL12 and bintrafusp alfa.
* Phase II: To evaluate the objective response rate (ORR) (PR+CR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of entinostat, NHS-IL12, and bintrafusp alfa in two separate populations:

  * Checkpoint refractory human papillomavirus (HPV) associated malignancies;
  * MSS small bowel or colorectal cancer.

Eligibility:

* Age \>= 18 years old.
* Phase I: Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies or MSS small bowel or colorectal cancer (Cohort 1).
* Phase II: Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies (Cohort 2), or MSS small bowel or colorectal cancer (Cohort 3).
* Prior first line systemic therapy is required unless the participant declines standard treatment after appropriate counseling has been provided.
* Subjects must have measurable disease per RECIST 1.1.

Design:

* This is a phase I/II trial of combination immunotherapy.
* Participants will be treated with a one week lead in of entinostat alone followed by the combination of entinostat, NHS-IL12 and bintrafusp alfa (Arm 1 \& Arm 2). Up to 12 additional participants will be treated with a one week lead in of entinostat alone followed by the combination with NHS-IL12 (without bintrafusp alfa, Arm 3).
* Phase I (Arm 1):

  * Arm 1 will be conducted using dose escalation/de-escalation of entinostat and dose escalation of NHS-IL12 with a fixed dose of bintrafusp alfa in Cohort 1 (up to 36 total).
  * Once the combination of all three agents has been determined to be safe, participants from Cohort 2 and Cohort 3 may enroll into -Phase II.
* Phase II (Arm 2 and Arm 3):

  * (Arm 2) will be conducted using a Simon optimal two-stage design.
  * Cohort 2 (checkpoint refractory HPV associated malignancies, 16 total) and cohort 3 (MSS small bowel or colorectal cancer, 16 total) participants will each be enrolled to Arm 2.
  * If one or more out of twelve participants in a given cohort (2 or 3) has an objective response, accrual will be expanded to enroll 16 evaluable participants on that cohort.
  * If 3 or more of 16 (18.8%) participants respond in a given cohort-arm combination, that would be sufficiently interesting to warrant further study of the combination in later trials in that disease type.
  * Arm 3: Up to 12 additional participants with checkpoint refractory HPV associated cancer may enroll to the combination of entinostat plus NHS-IL12 (without bintrafusp alfa).

A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers

.All 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 dbGaP.

Phase II: To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of entinostat, NHS-IL12, and bintrafusp alfa in two separate populations: checkpoint refractory HPV associated malignancies and MSS small bowel or colorectal cancer

Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination with NHS-IL12 and bintrafusp alfa

Phase II: To evaluate the safety of the combination of entinostat, NHS-IL12, and bintrafusp alfa in subjects with advanced malignancies

Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1.

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

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers	NCT04708470	Oropharyngeal C... Neck Cancer Human Papilloma... HPV Anal Cancer Cervical Cancer Penile Cancer Vulvar Cancer Vaginal Cancer Colon Cancer	Bintrafusp Alfa NHS-IL12 Entinostat	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers	NCT04708470	Oropharyngeal C... Neck Cancer Human Papilloma... HPV Anal Cancer Cervical Cancer Penile Cancer Vulvar Cancer Vaginal Cancer Colon Cancer	Bintrafusp Alfa NHS-IL12 Entinostat	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

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