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

NCT04708470 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 21000721-C-0007
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

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 PDS01ADC 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 PDS01ADC 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....

Conditions

Oropharyngeal Cancer; HPV; Neck Cancer; Human Papillomavirus; Anal Cancer; Cervical Cancer; Penile Cancer; Vulvar Cancer; Vaginal Cancer; Colon Cancer

Keywords

Bintrafusp Alfa M7824; Entinostat; PDS01ADC M9241; PD-1(L1); Immunotherapy

Outcome Measures

Primary Outcomes (2)

• Ojective response rate (ORR) of triple combination

  Phase II: To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of entinostat, PDS01ADC, and bintrafusp alfa in two separate populations: checkpoint refractory HPV associated malignancies and MSS small bowel or colorectal cancer

  two years

• Determine RP2D of entinostat

  Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination with PDS01ADC and bintrafusp alfa

  two years

Secondary Outcomes (4)

• Safety of Triple Combination Therapy

  two years

• Progression-Free Survival (PFS)

  two years

• Hospitalization due to AEs attributed to PD

  two years

• Duration of Response (DoR)

  two years

Study Arms (3)

1/Arm 1

EXPERIMENTAL

Dose escalation/de-escalation of entinostat and dose escalation of PDS01ADC with fixed dose of bintrafusp alfa

Drug: Bintrafusp Alfa; Drug: PDS01ADC; Drug: Entinostat

2/Arm 2

EXPERIMENTAL

RP2D of entinostat, PDS01ADC, and bintrafusp alfa

Drug: Bintrafusp Alfa; Drug: PDS01ADC; Drug: Entinostat

3/Arm3

EXPERIMENTAL

Entinostat and PDS01ADC (without bintrafusp alfa)

Drug: PDS01ADC; Drug: Entinostat

Interventions

Bintrafusp Alfa DRUG

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.

1/Arm 1; 2/Arm 2

PDS01ADC DRUG

PDS01ADC 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 PDS01ADC will be calculated based on the weight of the subject determined within 72 hours prior to the day of drug administration. The dose of PDS01ADC 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.

1/Arm 1; 2/Arm 2; 3/Arm3

Entinostat DRUG

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.

1/Arm 1; 2/Arm 2; 3/Arm3

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• Cohort 2 includes:
• 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 MSS colorectal or small bowel cancer must have received two prior lines of systemic chemotherapy. Subjects with HPV associated malignancies must have received one prior line of systemic chemotherapy as well as checkpoint therapy if checkpoint therapy is FDA approved for that specific tumor type (e.g., HNSCC and PDL1+ cervical cancer). Prior checkpoint therapy is not needed where checkpoint therapy has not been FDA approved for that specific tumor type (e.g., anal, vaginal, vulvar, penile, PDL1 negative cervical). Exceptions to the above include participant who are not eligible to receive the above therapies or who decline these standard treatment options after appropriate counseling has been provided.
• Subjects must have measurable disease, per RECIST 1.1.
• Age \>=18 years.
• ECOG performance status \<=2
• Adequate hematologic function at screening, as follows:
• Absolute neutrophil count (ANC) \>=1.5 x 10\^9/L;
• Hemoglobin \>= 9 g/dL;

You may not qualify if:

• Participants with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to enrollment except if the investigator has assessed that all residual treatment-related toxicities have resolved or are at grade 1 severity and feel the participant is otherwise suitable for enrollment.
• Administration of live vaccine within 30 days prior to enrollment
• Major surgery within 28 days prior to enrollment (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 repeat CNS imaging at least a month after definitive treatment showing CNS disease that has not progressed. Participants with CNS disease that has not progressed at least a month after definitive treatment and continued on \<=10 mg of prednisone (or equivalent) for treatment of brain or central nervous system metastasis are eligible to enroll in this study. 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.
• 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 hormone replacement or physiologic doses of corticosteroids (\<= the equivalent of prednisone 10 mg/day) or other immunosuppressive drugs 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 unwilling to accept blood products as medically indicated.
• Subjects with conditions associated with significant necrosis of nontumor-bearing tissues: esophageal or gastroduodenal ulcers \< 3 months prior to enrollment, organ infarction \< 3 months prior to enrollment, or active ischemic bowel disease.
• Presence of medically significant third space fluid (symptomatic pericardial effusion, ascites or pleural effusion requiring repetitive paracentesis).
• 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, or other localized malignancy which has been adequately treated or malignancy
• which does not require active systemic treatment (e.g. low risk chronic lymphocytic leukemia (CLL)).
• Subjects with a known severe hypersensitivity reaction to compounds of similar chemical or biologic composition to any of study drugs (grade \>/= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to enrollment.
• Pregnant individuals are excluded from this study because these drugs have not been tested in pregnant individuals 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, nursing should be discontinued if the mother is treated on this protocol.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Oropharyngeal Neoplasms; Head and Neck Neoplasms; Anus Neoplasms; Uterine Cervical Neoplasms; Penile Neoplasms; Vulvar Neoplasms; Vaginal Neoplasms; Colonic Neoplasms

Interventions

bintrafusp alfa protein, human; entinostat

Condition Hierarchy (Ancestors)

Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Neoplasms by Site; Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Genital Diseases, Male; Penile Diseases; Male Urogenital Diseases; Vulvar Diseases; Vaginal Diseases; Colonic Diseases

Study Officials

• Hoyoung M Maeng, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2021
• First Posted: January 14, 2021
• Study Start: October 5, 2021
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2026
• Last Updated: April 1, 2026

Record last verified: 2025-12-19

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)