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Tislelizumab for the Treatment of Recurrent Mismatch Repair Deficient Endometrial Cancer

Primary Purpose

Lynch Syndrome, Recurrent Endometrial Carcinoma, Recurrent Endometrial Clear Cell Adenocarcinoma

Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Biopsy
Carboplatin
Paclitaxel
Tislelizumab
Sponsored by
Floor Backes
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lynch Syndrome

Eligibility Criteria

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

Inclusion Criteria:

  • Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
  • Age >= 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place)
  • All patients with recurrent endometrial carcinoma, of any histology including clear cell, serous papillary carcinomas, and carcinosarcoma, whose disease is not amenable to definitive local therapy (including surgery and/or radiation therapy)
  • Patients must have deficient mismatch repair as demonstrated by lack of expression of at least 1 mismatch repair protein by immunohistochemistry, or evidence of microsatellite instability (MSI) high, or evidence of Lynch syndrome
  • The patient must have a lesion that is amenable to safe biopsy and the patient must agree to pre-and post-treatment biopsies
  • Patients may have received radiation for the treatment of endometrial cancer
  • Patient must have recovered from toxicity related to prior treatment to grade 2 or less
  • At least two weeks should have elapsed since completion of prior chemotherapy or 5 half-lives (whichever is shorter), or 4 weeks from radiation involving the whole pelvis or over 50% of the spine
  • At least 1 measurable lesion as defined per RECIST v1.1 that is amenable to biopsy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (must not have required a blood transfusion or growth factor support =< 14 days before sample collection at screening) (during screening or =< 14 days prior to first dose of study drug)
  • Platelets >= 75 x 10^9/L (must not have required a blood transfusion or growth factor support =< 14 days before sample collection at screening) (during screening or =< 14 days prior to first dose of study drug)
  • Hemoglobin >= 9.0 g/dL (must not have required a blood transfusion or growth factor support =< 14 days before sample collection at screening) (during screening or =< 14 days prior to first dose of study drug)
  • Serum creatinine =< 1.5 x ULN (upper limit of normal) or estimated glomerular filtration rate >= 30 mL/min/1.73 m^2 by Chronic Kidney Disease Epidemiology Collaboration equation (during screening or =< 14 days prior to first dose of study drug)
  • Serum total bilirubin =< 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome) (during screening or =< 14 days prior to first dose of study drug)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (during screening or =< 14 days prior to first dose of study drug)
  • Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and >= 120 days after the last dose of tislelizumab, and have a negative urine or serum pregnancy test =< 7 days of first dose of study drug

Exclusion Criteria:

  • Prior therapies targeting PD-1 or PD-L1
  • Patients with symptomatic pleural effusion are excluded
  • Active leptomeningeal disease or uncontrolled brain metastasis.

    • Following treatment, these patients may then be eligible, provided all other criteria, including those for patients with a history of brain metastases, are met
  • Active autoimmune diseases or history of autoimmune diseases that may relapse.
  • Any active malignancy =< 2 years before first dose of study drug except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast)
  • Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication =< 14 days before first dose of study drug
  • With uncontrolled diabetes or laboratory test abnormalities > grade 1 in potassium, sodium, or corrected calcium despite standard medical management or >= grade 3 hypoalbuminemia =< 14 days before first dose of study drug
  • With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.
  • With severe chronic or active infections (including tuberculosis infection, etc.) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to randomization or first dose of study drugs
  • Human immunodeficiency virus (HIV) testing is not required by protocol unless clinically indicated. Known HIV positive patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; and cirrhosis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Any major surgical procedure requiring general anesthesia =< 28 days before first dose of study drug
  • Prior allogeneic stem cell transplantation or organ transplantation
  • Any of the following cardiovascular risk factors:

    • Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, =< 28 days before first dose of study drug
    • Symptomatic pulmonary embolism =< 28 days before first dose of study drug
    • Any history of acute myocardial infarction =< 6 months before first dose of study drug
    • Any history of heart failure meeting New York Heart Association (NYHA) classification III or IV =< 6 months before first dose of study drug
    • Any event of ventricular arrhythmia >= grade 2 in severity =< 6 months before first dose of study drug
    • Any history of cerebrovascular accident =< 6 months before first dose of study drug
    • Uncontrolled hypertension: systolic pressure >= 160 mmHg or diastolic pressure >= 100 mmHg despite anti-hypertension medications =< 28 days before randomization or first dose of drug
    • Any episode of syncope or seizure =< 28 days before first dose of study drug
  • A history of severe hypersensitivity reactions to tislelizumab
  • Has received any chemotherapy, immunotherapy (e.g., interleukin, interferon, thymoxin) or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) of the first study drug administration
  • Has received any herbal medicine used to control cancer within 14 days of the first study drug administration
  • Was administered a live vaccine =< 4 weeks before first dose of study drug

    • Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines, and are not allowed
  • Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct
  • Concurrent participation in another therapeutic clinical study

Sites / Locations

  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (tislelizumab)

Arm Description

Chemo naïve patients receive tislelizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients who are chemotherapy naive with progressive disease, stable disease, or partial response, also receive carboplatin IV and paclitaxel IV every 21 days per standard of care for 6-9 cycles at the discretion of the treating physician. Patients who have received prior chemotherapy will receive single agent tislelizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

T-cell receptor (TCR) profiles
1) Measurements of TCRB clonal expansion in peripheral blood. Measurements of TCR in peripheral blood/-tissue
T-cell receptor (TCR) clonality
Measurements of TCRB clonal expansion in peripheral blood.
T-cell receptor (TCR) diversity
Measurements of TCRB diversity in peripheral blood

Secondary Outcome Measures

Tumor mutational profiles
Evaluated using whole exome sequencing
PD-L1 expression and other immune markers in tissue
Evaluated using immunohistochemistry
Overall response rate (objective response rate complete response [CR] and partial response [PR]; clinical benefit rate CR + PR + stable)
Evaluated by Response Evaluation Criteria in Solid Tumors version 1.1.
Progression-free survival
Estimated using Kaplan-Meier method.
Overall survival
Estimated using Kaplan-Meier method.
Incidence of adverse events
Assessed using CTCAE v5.0

Full Information

First Posted
March 22, 2021
Last Updated
September 16, 2022
Sponsor
Floor Backes
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1. Study Identification

Unique Protocol Identification Number
NCT04906382
Brief Title
Tislelizumab for the Treatment of Recurrent Mismatch Repair Deficient Endometrial Cancer
Official Title
Pilot Study of Tislelizumab (BGB-A317) in Recurrent Mismatch Repair Deficient Endometrial Cancer and the Effect on the Tumor Microenvironment
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Terminated
Why Stopped
Sponsor reorganization
Study Start Date
July 1, 2021 (Actual)
Primary Completion Date
September 1, 2022 (Actual)
Study Completion Date
September 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Floor Backes

4. Oversight

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

5. Study Description

Brief Summary
This clinical trial evaluates the effect of tislelizumab in treating patients with mismatch repair deficient endometrial cancer that has come back (recurrent). Deoxyribonucleic acid (DNA) mismatch repair (MMR) is a system for recognizing and repairing DNA errors and damage. Mismatch repair deficient tumors (dMMR) may have difficulty repairing DNA mutations during replication that may affect tumor's response to therapy. Immunotherapy with monoclonal antibodies, such as tislelizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tislelizumab may help treat patients with mismatch repair deficient endometrial cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the effect of tislelizumab (BGB-A317) on the diversity and dynamics of the T cell receptor repertoire in responders versus non-responders. SECONDARY OBJECTIVES: I. To evaluate the effect of tislelizumab on tumor mutational profiles between responders and non-responders. II. To evaluate the effect of tislelizumab +/- carboplatin/paclitaxel on PD-1/PD-L1 expression and other immune markers in tumor biopsies between responders and non-responders. III. To evaluate the safety and tolerability of tislelizumab +/- carboplatin/paclitaxel in patients with MMR deficient recurrent endometrial cancer. EXPLORATORY OBJECTIVES: I. To explore the effect of adding carboplatin/paclitaxel to tislelizumab on tumor mutational profiles. II. To explore the effect of adding carboplatin/paclitaxel to tislelizumab (BGB-A317) on the diversity and dynamics of the T cell receptor repertoire. III. To explore the objective antitumor activity (complete and partial response) of tislelizumab as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria. IV. To explore the objective antitumor activity (complete and partial response) of tislelizumab/carboplatin/paclitaxel after single agent tislelizumab as measured by RECIST v1.1 criteria V. To explore the progression free survival in patients with mismatch repair deficiency (dMMR) recurrent endometrial cancer treated with tislelizumab +/- carboplatin/paclitaxel. OUTLINE: Patients receive tislelizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients who are chemotherapy naive with progressive disease, stable disease, or partial response, also receive carboplatin IV and paclitaxel IV every 21 days per standard of care for 6-9 cycles at the discretion of the treating physician. After completion of study treatment, patients are followed up at 30, 60, and 90 days, and then periodically thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lynch Syndrome, Recurrent Endometrial Carcinoma, Recurrent Endometrial Clear Cell Adenocarcinoma, Recurrent Uterine Corpus Carcinosarcoma, Mismatch Repair Deficiency, Recurrent Endometrial Cancer, Metastatic Endometrial Cancer

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (tislelizumab)
Arm Type
Experimental
Arm Description
Chemo naïve patients receive tislelizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients who are chemotherapy naive with progressive disease, stable disease, or partial response, also receive carboplatin IV and paclitaxel IV every 21 days per standard of care for 6-9 cycles at the discretion of the treating physician. Patients who have received prior chemotherapy will receive single agent tislelizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
Intervention Type
Procedure
Intervention Name(s)
Biopsy
Other Intervention Name(s)
BIOPSY_TYPE, Bx
Intervention Description
Undergo biopsy
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Other Intervention Name(s)
Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Other Intervention Name(s)
Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Tislelizumab
Other Intervention Name(s)
BGB-A317
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
T-cell receptor (TCR) profiles
Description
1) Measurements of TCRB clonal expansion in peripheral blood. Measurements of TCR in peripheral blood/-tissue
Time Frame
Up to 24 months
Title
T-cell receptor (TCR) clonality
Description
Measurements of TCRB clonal expansion in peripheral blood.
Time Frame
Up 24 month
Title
T-cell receptor (TCR) diversity
Description
Measurements of TCRB diversity in peripheral blood
Time Frame
Up to 24 months
Secondary Outcome Measure Information:
Title
Tumor mutational profiles
Description
Evaluated using whole exome sequencing
Time Frame
Up to 3 years
Title
PD-L1 expression and other immune markers in tissue
Description
Evaluated using immunohistochemistry
Time Frame
up to 24 weeks
Title
Overall response rate (objective response rate complete response [CR] and partial response [PR]; clinical benefit rate CR + PR + stable)
Description
Evaluated by Response Evaluation Criteria in Solid Tumors version 1.1.
Time Frame
Up to 3 years
Title
Progression-free survival
Description
Estimated using Kaplan-Meier method.
Time Frame
From date of enrollment to date of progressive disease, assessed up to 5 years
Title
Overall survival
Description
Estimated using Kaplan-Meier method.
Time Frame
Up to 5 years
Title
Incidence of adverse events
Description
Assessed using CTCAE v5.0
Time Frame
Up to 2 years

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments Age >= 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place) All patients with recurrent endometrial carcinoma, of any histology including clear cell, serous papillary carcinomas, and carcinosarcoma, whose disease is not amenable to definitive local therapy (including surgery and/or radiation therapy) Patients must have deficient mismatch repair as demonstrated by lack of expression of at least 1 mismatch repair protein by immunohistochemistry, or evidence of microsatellite instability (MSI) high, or evidence of Lynch syndrome The patient must have a lesion that is amenable to safe biopsy and the patient must agree to pre-and post-treatment biopsies Patients may have received radiation for the treatment of endometrial cancer Patient must have recovered from toxicity related to prior treatment to grade 2 or less At least two weeks should have elapsed since completion of prior chemotherapy or 5 half-lives (whichever is shorter), or 4 weeks from radiation involving the whole pelvis or over 50% of the spine At least 1 measurable lesion as defined per RECIST v1.1 that is amenable to biopsy Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (must not have required a blood transfusion or growth factor support =< 14 days before sample collection at screening) (during screening or =< 14 days prior to first dose of study drug) Platelets >= 75 x 10^9/L (must not have required a blood transfusion or growth factor support =< 14 days before sample collection at screening) (during screening or =< 14 days prior to first dose of study drug) Hemoglobin >= 9.0 g/dL (must not have required a blood transfusion or growth factor support =< 14 days before sample collection at screening) (during screening or =< 14 days prior to first dose of study drug) Serum creatinine =< 1.5 x ULN (upper limit of normal) or estimated glomerular filtration rate >= 30 mL/min/1.73 m^2 by Chronic Kidney Disease Epidemiology Collaboration equation (during screening or =< 14 days prior to first dose of study drug) Serum total bilirubin =< 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome) (during screening or =< 14 days prior to first dose of study drug) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (during screening or =< 14 days prior to first dose of study drug) Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and >= 120 days after the last dose of tislelizumab, and have a negative urine or serum pregnancy test =< 7 days of first dose of study drug Exclusion Criteria: Prior therapies targeting PD-1 or PD-L1 Patients with symptomatic pleural effusion are excluded Active leptomeningeal disease or uncontrolled brain metastasis. Following treatment, these patients may then be eligible, provided all other criteria, including those for patients with a history of brain metastases, are met Active autoimmune diseases or history of autoimmune diseases that may relapse. Any active malignancy =< 2 years before first dose of study drug except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast) Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication =< 14 days before first dose of study drug With uncontrolled diabetes or laboratory test abnormalities > grade 1 in potassium, sodium, or corrected calcium despite standard medical management or >= grade 3 hypoalbuminemia =< 14 days before first dose of study drug With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc. With severe chronic or active infections (including tuberculosis infection, etc.) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to randomization or first dose of study drugs Human immunodeficiency virus (HIV) testing is not required by protocol unless clinically indicated. Known HIV positive patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; and cirrhosis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Any major surgical procedure requiring general anesthesia =< 28 days before first dose of study drug Prior allogeneic stem cell transplantation or organ transplantation Any of the following cardiovascular risk factors: Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, =< 28 days before first dose of study drug Symptomatic pulmonary embolism =< 28 days before first dose of study drug Any history of acute myocardial infarction =< 6 months before first dose of study drug Any history of heart failure meeting New York Heart Association (NYHA) classification III or IV =< 6 months before first dose of study drug Any event of ventricular arrhythmia >= grade 2 in severity =< 6 months before first dose of study drug Any history of cerebrovascular accident =< 6 months before first dose of study drug Uncontrolled hypertension: systolic pressure >= 160 mmHg or diastolic pressure >= 100 mmHg despite anti-hypertension medications =< 28 days before randomization or first dose of drug Any episode of syncope or seizure =< 28 days before first dose of study drug A history of severe hypersensitivity reactions to tislelizumab Has received any chemotherapy, immunotherapy (e.g., interleukin, interferon, thymoxin) or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) of the first study drug administration Has received any herbal medicine used to control cancer within 14 days of the first study drug administration Was administered a live vaccine =< 4 weeks before first dose of study drug Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines, and are not allowed Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct Concurrent participation in another therapeutic clinical study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Floor Backes, MD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://cancer.osu.edu
Description
The Jamesline

Learn more about this trial

Tislelizumab for the Treatment of Recurrent Mismatch Repair Deficient Endometrial Cancer

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