Recruitment

Recruitment Status
Not yet recruiting
Estimated Enrollment
Same as current

Summary

Conditions
  • Cancer
  • Metastatic Checkpoint Refractory HPV Associated Malignancies
  • Microsatellite Stable Colon Cancer (MSS)
  • Solid Tumor
Type
Interventional
Phase
Phase 1Phase 2
Design
Allocation: Non-RandomizedIntervention Model: Parallel AssignmentMasking: None (Open Label)Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

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 ...

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 solid tumor (Cohort 1). Phase II: Subjects with cytologically or histologically confirmed locally advanced or metastatic checkpoint refractory HPV associated malignancies (Cohort 2), or MSS small bowel or colorectal cancer (Cohort 3) Participants with checkpoint refractory HPV associated malignancies (Cohort 2) must have progressed on prior anti PD-1(L1) therapy. Participants in Cohort 1 and Cohort 3 can be checkpoint naive or check point refractory. 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. All participants will be treated with a week lead in of entinostat alone followed by the combination of entinostat, NHS-IL12 and bintrafusp alfa. Phase I (Arm 1) will be conducted using dose escalation/de-escalation of entinostat, with fixed doses of NHS-IL12 and bintrafusp alfa in Cohort 1 (up to 18 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) 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.

Tracking Information

NCT #
NCT04708470
Collaborators
Not Provided
Investigators
Principal Investigator: Houssein Abdul Sater, M.D. National Cancer Institute (NCI)