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Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma

Primary Purpose

Malignant Pleural Mesothelioma (MPM)

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
cyclophosphamide
CAR T cells
Sponsored by
Memorial Sloan Kettering Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Pleural Mesothelioma (MPM) focused on measuring Genetically Engineered Autologous T Cells, 20-328

Eligibility Criteria

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

Inclusion Criteria:

  1. Aged ≥18 years
  2. Karnofsky performance status ≥70%
  3. Pathologically confirmed MPM

    1. Epithelioid or biphasic histologic diagnosis provided that ≥10% of the tumor expresses MSLN by IHC analysis
    2. Patients with peritoneal mesothelioma with pleural involvement are eligible only if there is radiographic and pathologic confirmation of mesothelioma in the pleural cavity and ≥10% of the tumor expresses MSLN by IHC analysis.
  4. Previously treated with at least 1 treatment regimen
  5. Measurable or evaluable disease (disease is considered evaluable but not measurable if it does not meet the eligibility criteria for mRECIST but is a manifestation of malignancy that can be followed qualitatively as an indicator of disease progression or treatment response)
  6. Chemotherapy, targeted therapy, or radiotherapy must be completed at least 7 days before leukapheresis.

    a. CPI must be completed at least 21 days before leukapheresis.

  7. Chemotherapy, targeted therapy, or therapeutic radiotherapy must be completed at least 14 days before administration of T cells.

    1. Palliative radiotherapy can be completed 2 days before lymphodepletion. Immunotherapy with CPI must be completed at least 42 days before administration of T cells.

9. Any major thoracic (thoracotomy with lung or esophageal resection) or abdominal (laparotomy with organ resection) operation must have occurred at least 28 days before study enrollment. Patients who have undergone diagnostic VATS or laparoscopy can be included in the study.

10. All acute toxic effects of any previous therapeutic or palliative radiotherapy, chemotherapy, or surgical procedures must have resolved to grade 1 (CTCAE v5.0).

11. Lab requirements (hematology):

a. Absolute neutrophil count ≥1.5 K/mcL b. Platelet count ≥100 K/mcL

12. Lab requirements (serum chemistry):

a. Bilirubin ≤1.5x upper limit of normal (ULN) b. Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level ≤5x ULN c. Serum creatinine level ≤1.5x ULN or creatinine >1.5x ULN but calculated clearances of >60 by Cockcroft-Gault Equation

13. Negative screen for infectious disease markers including Hepatitis B core antibody, Hepatitis B surface antigen, Hepatitis C antibody, HIV 1-2 antibody, HTLV 1-2 and Syphilis (rapid plasma regain profile) Note - Patients with history of prior hepatitis B virus (HBV) infection are eligible if the HBV viral load is undetectable. Patients with a history of hepatitis C virus (HCV) infection who were treated for hepatitis C and cured are eligible if hepatitis C viral load is undetectable.

14. Life expectancy at the time of screening ≥4 months

Exclusion Criteria:

  1. Patients receiving therapy for concurrent active malignancy

    a. Patients receiving treatment for in situ skin malignancies are not excluded.

  2. Patients who received prior CAR T-cell therapy
  3. Untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible if all the following criteria are met:

    1. Presence of measurable or evaluable disease outside of the CNS
    2. Radiographic demonstration of improvement upon completion of CNS-directed therapy and no evidence of interim progression between completion of CNSdirected therapy and the screening radiographic study
    3. Completion of radiotherapy ≥8 weeks before the screening radiographic study
    4. Discontinuation of corticosteroids and anticonvulsants ≥4 weeks before the screening radiographic study
  4. History of seizure disorder
  5. Active autoimmune disease that has required systemic treatment in the past year (with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs)

    a. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

  6. Patients who are receiving daily systemic corticosteroids that are above physiological doses for any reason or who are under immunosuppressive or immunomodulatory treatment
  7. Patients with the below cardiac conditions:

    1. New York Heart Association stage III or IV congestive heart failure
    2. Myocardial infarction ≤6 months before enrollment
    3. History of myocarditis
    4. Serious uncontrolled cardiac arrhythmia, unstable angina, or uncontrolled infection
  8. Patients with left ventricular ejection fraction ≤40%
  9. Patients with active interstitial lung disease/pneumonitis or a history of interstitial lung disease/pneumonitis requiring treatment with systemic steroids
  10. Baseline pulse oximetry <90% on room air at the screening timepoint
  11. Pregnant or lactating women

    a. Subjects and their partners with reproductive potential must agree to use an effective form of contraception during treatment and for 1 year following treatment.

  12. Known active infection requiring antibiotic treatment 7 days before the start of treatment (Day 0). Note: treatment can be delayed at the discretion of the treating physician to allow the patient to recover from the infection.
  13. Administration of live, attenuated vaccine within 8 weeks before the start of treatment (Day 0) and for 100 days following treatment.
  14. Any other medical condition that, in the opinion of the PI, may interfere with a subject's participation in or compliance with the study
  15. Any patient deemed to be noncompliant by the study team for administration of a high risk treatment agent and for close follow-up after treatment as required by the protocol
  16. Patients with known hematologic malignancy requiring treatment in the preceding 5 years or a known history of lymphoid malignancy.

Sites / Locations

  • Memorial Sloan Kettering Cancer Center (All Protocol Activities)Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Engineered Autologous T Cells

Arm Description

Following eligibility screening and enrollment, patients will undergo leukapheresis for the collection of peripheral blood mononuclear cells (PBMCs), to enable generation of M28z1XXPD1DNR. Following successful M28z1XXPD1DNR CAR T-cell manufacturing, patients will be reevaluated for eligibility. A preconditioning regimen of one dose of intravenous (IV) cyclophosphamide 1.5 g/m2 will be administered 2-7 days before the infusion. A single dose of M28z1XXPD1DNR CAR T cells will be instilled into the pleural cavity via a pleural catheter or through an interventional radiology-guided needle. All patients will be monitored in the hospital for a minimum of 48 h following the administration of CAR T cells.

Outcomes

Primary Outcome Measures

MTD of M28z1XXPD1DNR
CTCAE v5.0 will be used to assess the severity of all treatment emerging toxicities/adverse events regardless

Secondary Outcome Measures

overall response rate (ORR)
modified RECIST (mRECIST; v1.0)

Full Information

First Posted
September 30, 2020
Last Updated
August 8, 2023
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Atara Biotherapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT04577326
Brief Title
Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma
Official Title
A Single-Arm, Open-Label, Phase I Trial to Assess the Safety of Genetically Engineered Autologous T Cells Targeting the Cell Surface Antigen Mesothelin With Cell-Intrinsic Checkpoint Inhibition in Patients With Mesothelioma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 30, 2020 (Actual)
Primary Completion Date
September 2024 (Anticipated)
Study Completion Date
September 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Atara Biotherapeutics

4. Oversight

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

5. Study Description

Brief Summary
This study will test the safety of MSLN-targeted CAR-T cells at different doses to find the safest dose to give to people with MPM. The researchers want to see what effects, if any, the study treatment has on people with this type of cancer. This study is the first time that an MSLN-targeted CAR-T cell treatment with an anti-PD1 component is being given to people.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Pleural Mesothelioma (MPM)
Keywords
Genetically Engineered Autologous T Cells, 20-328

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
This is a phase I dose-escalation trial.
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Engineered Autologous T Cells
Arm Type
Experimental
Arm Description
Following eligibility screening and enrollment, patients will undergo leukapheresis for the collection of peripheral blood mononuclear cells (PBMCs), to enable generation of M28z1XXPD1DNR. Following successful M28z1XXPD1DNR CAR T-cell manufacturing, patients will be reevaluated for eligibility. A preconditioning regimen of one dose of intravenous (IV) cyclophosphamide 1.5 g/m2 will be administered 2-7 days before the infusion. A single dose of M28z1XXPD1DNR CAR T cells will be instilled into the pleural cavity via a pleural catheter or through an interventional radiology-guided needle. All patients will be monitored in the hospital for a minimum of 48 h following the administration of CAR T cells.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Description
A preconditioning regimen of one dose of intravenous (IV) cyclophosphamide 1.5 g/m^2 will be administered 2-7 days before the infusion.
Intervention Type
Biological
Intervention Name(s)
CAR T cells
Intervention Description
A single dose of M28z1XXPD1DNR CAR T cells will be instilled into the pleural cavity via a pleural catheter or through an interventional radiology-guided needle. Cohorts of 3 patients will be treated at each dose level, up to a maximum of 3 x 10^7 T cells/kg or until the MTD has been reached.
Primary Outcome Measure Information:
Title
MTD of M28z1XXPD1DNR
Description
CTCAE v5.0 will be used to assess the severity of all treatment emerging toxicities/adverse events regardless
Time Frame
2 years
Secondary Outcome Measure Information:
Title
overall response rate (ORR)
Description
modified RECIST (mRECIST; v1.0)
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged ≥18 years Karnofsky performance status ≥70% Pathologically confirmed MPM Epithelioid or biphasic histologic diagnosis provided that ≥10% of the tumor expresses MSLN by IHC analysis Patients with peritoneal mesothelioma with pleural involvement are eligible only if there is radiographic and pathologic confirmation of mesothelioma in the pleural cavity and ≥10% of the tumor expresses MSLN by IHC analysis. Previously treated with at least 1 treatment regimen Measurable or evaluable disease (disease is considered evaluable but not measurable if it does not meet the eligibility criteria for mRECIST but is a manifestation of malignancy that can be followed qualitatively as an indicator of disease progression or treatment response) Chemotherapy, targeted therapy, or radiotherapy must be completed at least 7 days before leukapheresis. a. CPI must be completed at least 21 days before leukapheresis. Chemotherapy, targeted therapy, or therapeutic radiotherapy must be completed at least 14 days before administration of T cells. Palliative radiotherapy can be completed 2 days before lymphodepletion. Immunotherapy with CPI must be completed at least 42 days before administration of T cells. 9. Any major thoracic (thoracotomy with lung or esophageal resection) or abdominal (laparotomy with organ resection) operation must have occurred at least 28 days before study enrollment. Patients who have undergone diagnostic VATS or laparoscopy can be included in the study. 10. All acute toxic effects of any previous therapeutic or palliative radiotherapy, chemotherapy, or surgical procedures must have resolved to grade 1 (CTCAE v5.0). 11. Lab requirements (hematology): a. Absolute neutrophil count ≥1.5 K/mcL b. Platelet count ≥100 K/mcL 12. Lab requirements (serum chemistry): a. Bilirubin ≤1.5x upper limit of normal (ULN) b. Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level ≤5x ULN c. Serum creatinine level ≤1.5x ULN or creatinine >1.5x ULN but calculated clearances of >60 by Cockcroft-Gault Equation 13. Negative screen for infectious disease markers including Hepatitis B core antibody, Hepatitis B surface antigen, Hepatitis C antibody, HIV 1-2 antibody, HTLV 1-2 and Syphilis (rapid plasma regain profile) Note - Patients with history of prior hepatitis B virus (HBV) infection are eligible if the HBV viral load is undetectable. Patients with a history of hepatitis C virus (HCV) infection who were treated for hepatitis C and cured are eligible if hepatitis C viral load is undetectable. 14. Life expectancy at the time of screening ≥4 months Exclusion Criteria: Patients receiving therapy for concurrent active malignancy a. Patients receiving treatment for in situ skin malignancies are not excluded. Patients who received prior CAR T-cell therapy Untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible if all the following criteria are met: Presence of measurable or evaluable disease outside of the CNS Radiographic demonstration of improvement upon completion of CNS-directed therapy and no evidence of interim progression between completion of CNSdirected therapy and the screening radiographic study Completion of radiotherapy ≥8 weeks before the screening radiographic study Discontinuation of corticosteroids and anticonvulsants ≥4 weeks before the screening radiographic study History of seizure disorder Active autoimmune disease that has required systemic treatment in the past year (with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) a. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Patients who are receiving daily systemic corticosteroids that are above physiological doses for any reason or who are under immunosuppressive or immunomodulatory treatment Patients with the below cardiac conditions: New York Heart Association stage III or IV congestive heart failure Myocardial infarction ≤6 months before enrollment History of myocarditis Serious uncontrolled cardiac arrhythmia, unstable angina, or uncontrolled infection Patients with left ventricular ejection fraction ≤40% Patients with active interstitial lung disease/pneumonitis or a history of interstitial lung disease/pneumonitis requiring treatment with systemic steroids Baseline pulse oximetry <90% on room air at the screening timepoint Pregnant or lactating women a. Subjects and their partners with reproductive potential must agree to use an effective form of contraception during treatment and for 1 year following treatment. Known active infection requiring antibiotic treatment 7 days before the start of treatment (Day 0). Note: treatment can be delayed at the discretion of the treating physician to allow the patient to recover from the infection. Administration of live, attenuated vaccine within 8 weeks before the start of treatment (Day 0) and for 100 days following treatment. Any other medical condition that, in the opinion of the PI, may interfere with a subject's participation in or compliance with the study Any patient deemed to be noncompliant by the study team for administration of a high risk treatment agent and for close follow-up after treatment as required by the protocol Patients with known hematologic malignancy requiring treatment in the preceding 5 years or a known history of lymphoid malignancy.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Roisin O'Cearbhaill, MD
Phone
646-888-4227
Email
cart@mskcc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Adam Schoenfeld, MD
Phone
646-608-4042
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roisin O'Cearbhaill, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan Kettering Cancer Center (All Protocol Activities)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roisin O'Cearbhaill, MD
Phone
646-888-4227
First Name & Middle Initial & Last Name & Degree
Adam Schoenfeld, MD
Phone
646-608-4042
First Name & Middle Initial & Last Name & Degree
Roisin O'Cearbhaill, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
Links:
URL
http://www.mskcc.org/mskcc/html/44.cfm
Description
Memorial Sloan Kettering Cancer Center

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Mesothelin-targeted CAR T-cell Therapy in Patients With Mesothelioma

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