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

Primary Purpose

Locally Advanced Intrahepatic Cholangiocarcinoma, Metastatic Intrahepatic Cholangiocarcinoma, Stage III Intrahepatic Cholangiocarcinoma AJCC v8

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bintrafusp Alfa
Biopsy
Hypofractionated Radiation Therapy
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Intrahepatic Cholangiocarcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (hypofractionated radiation, bintrafusp alfa)

Arm 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.

Outcomes

Primary Outcome Measures

Incidence of adverse events (AEs)
AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient contributes only once to the count for a given AE preferred term. The number and percentage of patients with any treatment-emergent AE will be summarized for all study patients combined.

Secondary Outcome Measures

Objective response rate
Will estimate the objective response rate by Response Evaluation Criteria in Solid Tumors 1.1 criteria separately with appropriate 95% confidence intervals.
Local progression free survival (LPFS)
Will estimate the LPFS distributions using the Kaplan-Meier product limit method and report summary measures such as the median value and probabilities at selected times with appropriate 95% confidence intervals.
Progression free survival (PFS)
Will estimate the PFS distributions using the Kaplan-Meier product limit method and report summary measures such as the median value and probabilities at selected times with appropriate 95% confidence intervals.
Overall survival (OS)
Will estimate the OS distributions using the Kaplan-Meier product limit method and report summary measures such as the median value and probabilities at selected times with appropriate 95% confidence intervals.

Full Information

First Posted
January 12, 2021
Last Updated
October 2, 2023
Sponsor
M.D. Anderson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04708067
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 31, 2021 (Actual)
Primary Completion Date
February 2, 2027 (Anticipated)
Study Completion Date
February 2, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Intrahepatic Cholangiocarcinoma, Metastatic Intrahepatic Cholangiocarcinoma, Stage III Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8, Stage IV Intrahepatic Cholangiocarcinoma AJCC v8

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (hypofractionated radiation, bintrafusp alfa)
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Bintrafusp Alfa
Other Intervention Name(s)
Anti-PDL1/TGFb Trap MSB0011359C, M7824, MSB0011359C
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Biopsy
Other Intervention Name(s)
BIOPSY_TYPE, Bx
Intervention Description
Undergo biopsy
Intervention Type
Radiation
Intervention Name(s)
Hypofractionated Radiation Therapy
Other Intervention Name(s)
Hypofractionated Radiotherapy, hypofractionation
Intervention Description
Undergo hypofractionated radiation therapy
Primary Outcome Measure Information:
Title
Incidence of adverse events (AEs)
Description
AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient contributes only once to the count for a given AE preferred term. The number and percentage of patients with any treatment-emergent AE will be summarized for all study patients combined.
Time Frame
Up to 60 days
Secondary Outcome Measure Information:
Title
Objective response rate
Description
Will estimate the objective response rate by Response Evaluation Criteria in Solid Tumors 1.1 criteria separately with appropriate 95% confidence intervals.
Time Frame
Up to 2 years post-treatment
Title
Local progression free survival (LPFS)
Description
Will estimate the LPFS distributions using the Kaplan-Meier product limit method and report summary measures such as the median value and probabilities at selected times with appropriate 95% confidence intervals.
Time Frame
Up to 12 months post-treatment
Title
Progression free survival (PFS)
Description
Will estimate the PFS distributions using the Kaplan-Meier product limit method and report summary measures such as the median value and probabilities at selected times with appropriate 95% confidence intervals.
Time Frame
Up to 12 months post-treatment
Title
Overall survival (OS)
Description
Will estimate the OS distributions using the Kaplan-Meier product limit method and report summary measures such as the median value and probabilities at selected times with appropriate 95% confidence intervals.
Time Frame
Up to 12 months post-treatment
Other Pre-specified Outcome Measures:
Title
Biomarker analysis
Description
Will analyze changes in biomarker expression before and after treatment using a paired t-test if the data are normally distributed, and a Wilcoxon signed rank test if not. Will correlate biomarker expression with clinical benefit using receiver operator characteristics curve analysis.
Time Frame
Up to 2 years post-treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Eugene J. Koay
Phone
713-563-2381
Email
ekoay@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eugene J Koay
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eugene J. Koay
Phone
713-563-2381
Email
ekoay@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Eugene J. Koay

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
MDAndersonCancerCenterWebsite

Learn more about this trial

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

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