Hypofractionated Radiation Therapy and Bintrafusp Alfa for the Treatment of Advanced Intrahepatic Cholangiocarcinoma

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Brief Title

Hypofractionated Radiation Therapy and Bintrafusp Alfa for the Treatment of Advanced Intrahepatic Cholangiocarcinoma

Official Title

"Window of Opportunity" Phase I Trial of Focal Radiotherapy and Bintrafusp Alfa In Patients With Advanced Intrahepatic Cholangiocarcinoma

Brief Summary

      This phase I trial is to find out the best dose, possible benefits, and/or side effects of
      hypofractionated radiation therapy and bintrafusp alfa in treating patients with bile duct
      cancer that has spread to other places in the body (advanced intrahepatic
      cholangiocarcinoma). Hypofractionated radiation therapy delivers higher doses of radiation
      therapy over a shorter period of time and may kill more tumor cells and have fewer side
      effects. Immunotherapy with bintrafusp alfa, a bifunctional fusion protein composed of the
      monoclonal antibody avelumab and TGF-beta, may help the body's immune system attack the
      cancer, and may interfere with the ability of tumor cells to grow and spread. The combination
      of hypofractionated radiation therapy and bintrafusp alfa may help to control intrahepatic
      cholangiocarcinoma.
    

Detailed Description

      PRIMARY OBJECTIVE:

      I. To examine the safety of bintrafusp alfa in combination with hypofractionated radiation
      therapy for patients with advanced intrahepatic cholangiocarcinoma and recommend a phase II
      radiation dose.

      SECONDARY OBJECTIVES:

      I. To estimate objective response rate, local progression free survival, progression free
      survival, overall survival with the study regimen.

      II. To correlate expression of TGF-beta related pathways with clinical outcomes.

      III. To examine intratumoral pharmacodynamic changes in the immune microenvironment using
      paired biopsies before and after therapy with the study agents.

      EXPLORATORY OBJECTIVE:

      I. To correlate immune biomarkers from pre- and post-treatment tissue, blood, and stool with
      clinical study endpoints.

      OUTLINE: This is a dose de-escalation study of radiation therapy followed by a dose-expansion
      study.

      Patients undergo hypofractionated radiation therapy once daily (QD) on weekdays
      (Monday-Friday) for 15 fractions in the absence of disease progression or unacceptable
      toxicity. Beginning 1 week after completion of radiation therapy, patients receive bintrafusp
      alfa intravenously (IV) over 1 hour on day 1. Cycles repeat every 14 days for up to 2 years
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 12 weeks for up to 2
      years.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Incidence of adverse events (AEs)

Secondary Outcome

 Objective response rate

Condition

Locally Advanced Intrahepatic Cholangiocarcinoma

Intervention

Bintrafusp Alfa

Study Arms / Comparison Groups

 Treatment (hypofractionated radiation, bintrafusp alfa)
Description:  Patients undergo hypofractionated radiation therapy QD on weekdays (Monday-Friday) for 15 fractions in the absence of disease progression or unacceptable toxicity. Beginning 1 week after completion of radiation therapy, patients receive bintrafusp alfa IV over 1 hour on day 1. Cycles repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

15

Start Date

May 1, 2021

Completion Date

August 28, 2023

Primary Completion Date

August 28, 2023

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be male or female >= 18 years of age

          -  Patients with histologically or cytologically confirmed intrahepatic
             cholangiocarcinoma. There must be at least two measurable tumors. One larger mass that
             will be radiated and a secondary metastatic site that is amenable to biopsies

          -  Patients must have received at least one standard first-line chemotherapy regimen or
             have refused chemotherapy

          -  Patients with measurable disease assessed at baseline by computed tomography (CT) (or
             magnetic resonance imaging [MRI] where CT is contraindicated) will be entered in this
             study

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky > 70)

          -  Leukocytes >= 3,000 cells/mm^3

          -  Absolute neutrophil count >= 1,500 cells/mm^3

          -  Platelets >= 100,000 cells/mm^3

          -  Hemoglobin >= 9 g/dl (no blood transfusions within 4 weeks prior to enrollment)

          -  Total bilirubin < 1.5 x institutional upper limit of normal (IULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x IULN without liver metastasis, =< 5 x IULN for patients with liver metastasis

          -  Creatinine within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  Women of childbearing potential (defined as not post-menopausal for 65 days or no
             previous surgical sterilization) and fertile men must agree to use adequate
             contraception for the duration of study participation

          -  All female patients of childbearing potential (defined as not post-menopausal for 65
             days or no previous surgical sterilization) must agree to use adequate birth control
             during study treatment and for 90 days after the last dose of study drug and have a
             negative serum pregnancy test at screening

          -  Fertile males must be willing to employ adequate means of contraception during study
             treatment and for 3 months after the last dose of study drug

          -  Male subjects must agree to refrain from sperm donation during the study and for 125
             days after the last dose of study drugs

          -  Ability to read and/or understand the details of the study and provide written
             evidence of informed consent as approved by Institutional Review Board (IRB)/
             Scientific Review Committee (SRC)

        Exclusion Criteria:

          -  Patients who are pregnant or lactating

          -  Patients with uncontrolled intercurrent illness including symptomatic congestive heart
             failure, unstable angina pectoris, cardiac arrhythmia and myocardial infarction (MI)
             within 3 months of initiation of therapy

          -  Patients with recent bacterial, viral, or fungal infection(s) requiring systemic
             antibiotic therapy within one month of enrolling

          -  Patient has undergone major surgery within 4 weeks prior to day 1 of treatment in this
             study. Diagnostic or minimally invasive surgery (i.e., done to obtain a biopsy for
             diagnosis without removal of an organ or to place an abdominal spacer) are acceptable
             at physician discretion

          -  Patient received radiotherapy, surgery, chemotherapy, or an investigational therapy
             within 2 weeks prior to study entry weeks

          -  Patient has serious medical risk factors involving any of the major organ systems such
             that the investigator considers it unsafe for the patient to receive an experimental
             research drug

          -  Serious psychiatric or medical conditions that could interfere with treatment

          -  Major bleeding in the last 4 weeks

          -  Receipt of prior immune checkpoint inhibitors (e.g., anti-CTLA-4, anti-programmed cell
             death receptor 1, anti-programmed cell death ligand 1 [anti-PD-L1], and any other
             antibody or drug specifically targeting T-cell costimulation)

          -  Receiving an immunologically based treatment for any reason, including chronic use of
             systemic steroid at doses >= 7.5 mg/day prednisone equivalent within 14 days prior to
             the first dose of study treatment. Use of inhaled or topical steroids or systemic
             corticosteroids < 7.5 mg is permitted

          -  Receipt of any anticancer medication in the 21 days prior to receiving the first dose
             of study medication or any unresolved toxicity (> grade 1) from previous anticancer
             therapy, except for stable chronic toxicities not expected to resolve, such as
             peripheral neurotoxicity. Prior treatment with nitrosoureas (e.g., carmustine or
             lomustine) require a 6-week washout prior to the first dose of study treatment

          -  Untreated central nervous system (CNS) metastases, or CNS metastases that have
             progressed (e.g., evidence of new or enlarging CNS metastasis or new neurological
             symptoms attributable to CNS metastases). Subjects with treated and clinically stable
             CNS metastases and off all corticosteroids for at least 2 weeks are eligible

          -  Any active or inactive autoimmune process (e.g. rheumatoid arthritis, moderate or
             severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who are receiving
             systemic therapy for an autoimmune or inflammatory disease

               -  Note: Exceptions include subjects with vitiligo, hypothyroidism stable on hormone
                  replacement, controlled asthma, type I diabetes, Graves' disease, or Hashimoto's
                  disease, or with medical monitor approval
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Eugene J Koay, 713-563-2381, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04708067

Organization ID

2020-0899

Secondary IDs

NCI-2020-13928

Responsible Party

Sponsor

Study Sponsor

M.D. Anderson Cancer Center


Study Sponsor

Eugene J Koay, Principal Investigator, M.D. Anderson Cancer Center


Verification Date

January 2021