A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers
- Conditions
- Oropharyngeal CancerVaginal CancerNeck CancerAnal CancerColon CancerHuman PapillomavirusCervical CancerVulvar CancerHPVPenile Cancer
- Interventions
- Registration Number
- NCT04708470
- Lead Sponsor
- National Cancer Institute (NCI)
- 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.
- Detailed Description
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 (PDS01ADC) 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 (PDS01ADC), 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 PDS01ADC 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, PDS01ADC, 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, PDS01ADC 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 PDS01ADC (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 PDS01ADC 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 PDS01ADC (without bintrafusp alfa).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 55
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 1/Arm 1 Entinostat Dose escalation/de-escalation of entinostat and dose escalation of PDS01ADC with fixed dose of bintrafusp alfa 1/Arm 1 Bintrafusp Alfa Dose escalation/de-escalation of entinostat and dose escalation of PDS01ADC with fixed dose of bintrafusp alfa 1/Arm 1 PDS01ADC Dose escalation/de-escalation of entinostat and dose escalation of PDS01ADC with fixed dose of bintrafusp alfa 2/Arm 2 Bintrafusp Alfa RP2D of entinostat, PDS01ADC, and bintrafusp alfa 2/Arm 2 PDS01ADC RP2D of entinostat, PDS01ADC, and bintrafusp alfa 2/Arm 2 Entinostat RP2D of entinostat, PDS01ADC, and bintrafusp alfa 3/Arm3 PDS01ADC Entinostat and PDS01ADC (without bintrafusp alfa) 3/Arm3 Entinostat Entinostat and PDS01ADC (without bintrafusp alfa)
- Primary Outcome Measures
Name Time Method Ojective response rate (ORR) of triple combination two years 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
Determine RP2D of entinostat two years Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination with PDS01ADC and bintrafusp alfa
- Secondary Outcome Measures
Name Time Method Safety of Triple Combination Therapy two years Phase II: To evaluate the safety of the combination of entinostat, PDS01ADC, and bintrafusp alfa in subjects with advanced malignancies
Progression-Free Survival (PFS) two years Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1.
Hospitalization due to AEs attributed to PD two years Phase II: To assess proportion of participants that are hospitalized because of adverse events attributed to disease progression.
Duration of Response (DoR) two years Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1.
Trial Locations
- Locations (2)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States