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

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ClinicalTrials.gov Identifier: NCT04708470
Recruitment Status : Not yet recruiting
First Posted : January 14, 2021
Last Update Posted : February 26, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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 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.


Condition or disease Intervention/treatment Phase
Cancer Solid Tumor Metastatic Checkpoint Refractory HPV Associated Malignancies Microsatellite Stable Colon Cancer (MSS) Drug: Bintrafusp Alfa Drug: NHS-IL12 Drug: Entinostat Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer
Estimated Study Start Date : March 3, 2021
Estimated Primary Completion Date : August 14, 2023
Estimated Study Completion Date : August 14, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/Arm 1
Dose escalation/de-escalation of entinostat, with fixed doses of NHS-IL12 and bintrafusp alfa
Drug: 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 1,200 mg independent of body weight. Bintrafusp alfa is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.

Drug: NHS-IL12
NHS-IL12 will be administered at as dose of 16.8 or 12 microgram/kg by SC injection every 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.

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

Experimental: 2/Arm 2
RP2D of entinostat, NHS-IL12, and bintrafusp alfa
Drug: 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 1,200 mg independent of body weight. Bintrafusp alfa is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.

Drug: NHS-IL12
NHS-IL12 will be administered at as dose of 16.8 or 12 microgram/kg by SC injection every 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.

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




Primary Outcome Measures :
  1. Objective response rate (ORR) of triple combination [ Time Frame: two years ]
    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

  2. Determine RP2D of entinostat [ Time Frame: two years ]
    Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination with NHS-IL12 and bintrafusp alfa


Secondary Outcome Measures :
  1. Safety of Triple Combination Therapy [ Time Frame: two years ]
    Phase II: To evaluate the safety of the combination of entinostat, NHS-IL12, and bintrafusp alfa in subjects with advanced malignancies

  2. Progression-Free Survival (PFS) [ Time Frame: 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.

  3. Duration of Response (DoR) [ Time Frame: 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.

  4. Hospitalization due to AEs attributed to PD [ Time Frame: two years ]
    Phase II: To assess duration of response and proportion of patients that are hospitalized because of adverse events attributed to disease progression.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 naive 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04708470


Contacts
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Contact: Deneise Francis (240) 858-3974 deneise.francis@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Houssein Abdul Sater, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04708470    
Other Study ID Numbers: 210007
21-C-0007
First Posted: January 14, 2021    Key Record Dates
Last Update Posted: February 26, 2021
Last Verified: January 13, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Bintrafusp Alfa M7824
Entinostat
NHS-IL12 M9241
PD-1(L1)
Additional relevant MeSH terms:
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Neoplasms
Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Entinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action