Clinical Trials /

Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer

NCT04708470

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
  • Esophageal Carcinoma
  • Lung Carcinoma
  • Malignant Solid Tumor
  • Oropharyngeal Carcinoma
  • Small Intestinal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer
  • Official Title: Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer

Clinical Trial IDs

  • ORG STUDY ID: 210007
  • SECONDARY ID: 21-C-0007
  • NCT ID: NCT04708470

Conditions

  • Cancer
  • Solid Tumor
  • Metastatic Checkpoint Refractory HPV Associated Malignancies
  • Microsatellite Stable Colon Cancer (MSS)

Interventions

DrugSynonymsArms
Bintrafusp Alfa1/Arm 1
NHS-IL121/Arm 1
Entinostat1/Arm 1

Purpose

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) - Patients with checkpoint refractory HPV associated malignancies (Cohort 2) must have progressed on prior anti PD-1(L1) therapy. Patients in Cohort 1 and Cohort 3 can be checkpoint na(SqrRoot) ve or check point refractory. - Prior first line systemic therapy is required unless the patient 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, patients 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) patients will each be enrolled to Arm 2. - If one or more out of twelve patients in a given cohort (2 or 3) has an objective response, accrual will be expanded to enroll 16 evaluable patients on that cohort. - If 3 or more of 16 (18.8%) patients 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.

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 (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)

        -  Patients with checkpoint refractory HPV associated malignancies (Cohort 2) must have
           progressed on prior anti PD-1(L1) therapy. Patients in Cohort 1 and Cohort 3 can be
           checkpoint na(SqrRoot) ve or check point refractory.

        -  Prior first line systemic therapy is required unless the patient 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, patients 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) patients will each be enrolled to Arm 2.

        -  If one or more out of twelve patients in a given cohort (2 or 3) has an objective
           response, accrual will be expanded to enroll 16 evaluable patients on that cohort.

        -  If 3 or more of 16 (18.8%) patients 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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1ExperimentalDose escalation/de-escalation of entinostat, with fixed doses of NHS-IL12 and bintrafusp alfa
  • Bintrafusp Alfa
  • NHS-IL12
  • Entinostat
2/Arm 2ExperimentalRP2D of entinostat, NHS-IL12, and bintrafusp alfa
  • Bintrafusp Alfa
  • NHS-IL12
  • Entinostat

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Phase I: Subjects with cytologically or histologically confirmed locally advanced or
             metastatic solid tumor (Cohort 1).

          2. 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).

             - 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+.

          3. Subjects must have received prior first line systemic therapy unless the patient is
             not eligible to receive standard therapy or declines standard treatment after
             appropriate counseling has been provided.

          4. Patients with checkpoint refractory HPV associated malignancies (Cohort 2) must have
             progressed on prior anti PD-1(L1) therapy. Patients in Cohort 1 and Cohort 3 can be
             checkpoint na(SqrRoot) ve or check point refractory.

          5. Subjects must have measurable disease, per RECIST 1.1.

          6. Age >=18 years.

          7. ECOG performance status < 2

          8. Adequate hematologic function at screening, as follows:

               -  Absolute neutrophil count (ANC) >=1.5 x 10^9/L;

               -  Hemoglobin >= 9 g/dL;

               -  Platelets >= 100,000/microliter.

          9. Adequate renal and hepatic function at screening, as follows:

               -  Measured or calculated creatinine clearance (using the Cockcroft-Gault equation)
                  > 50 mL/min

               -  Bilirubin 1.5 x ULN OR in subjects with Gilbert s syndrome, a total bilirubin <=
                  3.0 x ULN

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN,

             unless liver metastases are present, then values must be 3 x ULN).

         10. The effects of the immunotherapies on the developing human fetus are unknown. For this
             reason and because immunotherapeutic agents as well as other therapeutic agents used
             in this trial are known to be teratogenic, women of child-bearing potential and men
             must agree to use highly effective contraception (hormonal or barrier method of birth
             control; abstinence) at the study entry and for 4 months after the last bintrafusp
             alfa dose, 3 months after the last entinostat dose and 2 months after the last
             NHS-IL12 dose, whichever occurs later. Should a woman become pregnant or suspect she
             is pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

         11. Patients serologically positive for HIV, Hep B, Hep C are eligible as long as the
             viral loads are undetectable by quantitative PCR. HIV positive patients must have CD4
             count >= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral
             therapy for at least 4 weeks and have no reported opportunistic infections or
             Castleman's disease within 12 months prior to enrollment.

         12. Subjects must be able to understand and be willing to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          1. Patients 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
             patient is otherwise suitable for enrollment.

          2. Administration of live vaccine within 30 days prior to enrollment

          3. Major surgery within 28 days prior to enrollment (minimally invasive procedures such
             as diagnostic biopsies are permitted).

          4. 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 patients must have repeat CNS imaging at least a month after definitive
             treatment showing CNS disease that has not progressed. Patients 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. Patients 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.

          5. 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;

          6. 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.

          7. Subjects with a history of serious intercurrent chronic or acute illness, such as
             cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3
             months before enrollment) clinically significant bleeding events, or other illness or
             medical condition considered by the Investigator as high risk for investigational drug
             treatment.

          8. Subjects with conditions associated with significant necrosis of nontumor-bearing
             tissues: esophageal or gastroduodenal ulcers < 6 months prior to enrollment, organ
             infarction < 6 months prior to enrollment, or active ischemic bowel disease.

          9. Presence of medically significant third space fluid (symptomatic pericardial effusion,
             ascites or pleural effusion requiring repetitive paracentesis).

         10. 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)).

         11. 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.

         12. Pregnant women are excluded from this study because these drugs have not been tested
             in pregnant women 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, breastfeeding should
             be discontinued if the mother is treated on this protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) of triple combination
Time Frame:two years
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Safety of Triple Combination Therapy
Time Frame:two years
Safety Issue:
Description:Phase II: To evaluate the safety of the combination of entinostat, NHS-IL12, and bintrafusp alfa in subjects with advanced malignancies
Measure:Progression-Free Survival (PFS)
Time Frame:two years
Safety Issue:
Description:Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1.
Measure:Duration of Response (DoR)
Time Frame:two years
Safety Issue:
Description:Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1.
Measure:Hospitalization due to AEs attributed to PD
Time Frame:two years
Safety Issue:
Description:Phase II: To assess duration of response and proportion of patients that are hospitalized because of adverse events attributed to disease progression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Bintrafusp Alfa M7824
  • Entinostat
  • NHS-IL12 M9241
  • PD-1(L1)

Last Updated

January 15, 2021