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CAR T Cells in Patients With MMP2+ Recurrent or Progressive Glioblastoma

Primary Purpose

Glioblastoma Multiforme of Brain

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CHM-1101 CAR-T cells
Sponsored by
Chimeric Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme of Brain focused on measuring Progressive or recurrent glioblastoma, MMP2+

Eligibility Criteria

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

Inclusion Criteria: Documented informed consent of the subject and/or legally authorized representative. Agreement to allow the use of archival tissue from diagnostic tumor biopsies. Age 18 years and older. ECOG status of 0 or 1. Life expectancy ≥12 weeks. Subject has a prior histologically confirmed diagnosis of a grade 4 glioblastoma multiforme (GBM) or a prior histologically confirmed diagnosis of a grade 2 or 3 malignant glioma and now has radiographic progression consistent with a grade 4 GBM (IDH wild type), grade 4 diffuse astrocytoma (IDH mutant), or has a unifocal relapse of GBM. Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy and ≥ 12 weeks after completion of front-line radiation therapy. Confirmed MMP2+ tumor expression by IHC (≥20% moderate/high MMP2 score [2+ or 3+]). Adequate venous access to perform leukapheresis. No known contraindications to leukapheresis or steroids. In-range baseline laboratory values for WBC (>2000/dL [or ANC ≥1000/mm^3]), platelets (≥75000/mm^3), total bilirubin (≤1.5xULN), AST (≤2.5xULN), ALT (≤2.5xULN), serum creatinine (≤1.5xmg/dL), and oxygen saturation (≥95% on room air) Seronegative for human immunodeficiency virus (HIV) by antigen/antibody (Ag/Ab) testing. Seronegative for hepatitis B and/or hepatitis C virus. Women of childbearing potential must have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. Agreement by women AND men of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of CHM-1101. (Childbearing potential is defined as not being surgically sterilized (women and men) or, for women, having not been free from menses for > 1 year.) Exclusion Criteria: Within 3 months of having received prior bevacizumab therapy at the time of enrollment. Not yet recovered from toxicities of prior therapy. Uncontrolled seizure activity and/or clinically evident progressive encephalopathy. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent. Clinically significant uncontrolled illness. Active infection requiring antibiotics. Known history of HIV or hepatitis B or hepatitis C infection. Other active malignancy. Women only-pregnant or breastfeeding. Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures. Prospective subjects who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

Sites / Locations

  • City of Hope Medical Center
  • St. David's South Austin Medical Center - Sarah Cannon - AustinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Treatment (CAR T cell therapy) 1

Treatment (CAR T cell therapy) 2

Arm Description

Arm 1 participants will undergo resection of their tumor. Participants receive half the CHM-1101 dose via Rickham catheters into the tumor cavity and half into the lateral ventricle. Cycle 1 (28 days) CHM 1101 total dose will be divided across 3 once-weekly administrations. After Cycle 1, additional cycles may be initiated in the absence of disease progression or unacceptable toxicity provided that the principal investigator and participant agree to continue and if adequate autologous CAR-T doses remain.

Arm 2 participants will undergo resection of their tumor. Participants receive half the CHM-1101 dose via Rickham catheters into the tumor cavity and half into the lateral ventricle. Cycle 1 (28 days) CHM 1101 total dose will be divided across 3 once-weekly administrations. After Cycle 1, additional cycles may be initiated in the absence of disease progression or unacceptable toxicity provided that the principal investigator and participant agree to continue and if adequate autologous CAR-T doses remain.

Outcomes

Primary Outcome Measures

Dose-limiting toxicity (DLT)
Assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
Cytokine Release Syndrome (CRS)
Assessed per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading guideline, evaluating levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per µL by flowcytometry).
All other adverse events and toxicities
Assessed per NCI CTCAE v5.0.

Secondary Outcome Measures

Chimeric antigen receptor (CAR) T cell
Assess levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per µL by flowcytometry).
Endogenous T cell
Assess level and phenotype detected in TCF, PB, and CSF (absolute number per µL by flowcytometry).
Human anti-CAR antibody (HACA)
Serum samples will be evaluated for HACA against the CLTX(EQ)28ζ therapeutic agent.
Progression free survival (PFS) time
Measured from the date of first infusion of CAR-T cells until the first date when progressive disease (PD) is objectively documented or death from any cause, whichever is earlier.
Overall survival (OS)
Measured from the date of first infusion of CAR-T cells until death.
Disease response
Assessed by modified Response Assessment in Neuro-Oncology Criteria (RANO) criteria.
Clinical benefit rate
The proportion of participants who experience a complete response, a partial response, or stable disease that is 3 months or greater in duration.

Full Information

First Posted
November 16, 2022
Last Updated
August 4, 2023
Sponsor
Chimeric Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT05627323
Brief Title
CAR T Cells in Patients With MMP2+ Recurrent or Progressive Glioblastoma
Official Title
A Phase 1b Study to Evaluate CHM-1101, a CAR T-Cell Therapy With a Chlorotoxin Tumor-Targeting Domain for Patients With Matrix Metallopeptidase 2 Positive (MMP2+) Recurrent or Progressive Glioblastoma Multiforme
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 6, 2023 (Actual)
Primary Completion Date
October 2024 (Anticipated)
Study Completion Date
January 2041 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Chimeric Therapeutics

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 is a phase 1b study to evaluate the safety of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain (ie, CHM-1101, the study treatment) to determine the best dose of CHM-1101, and to assess the effectiveness of CHM-1101 in treating MMP2+ glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive).
Detailed Description
This is a phase 1b, multicenter, feasibility/safety study of the dual delivery (administered through both intracavitary/intratumoral [ICT] and intraventricular [ICV] catheters) of CHM-1101, an autologous chlorotoxin-chimeric antigen receptor (CLTX-CAR) cell product, in participants with recurrent or progressive GBM. The investigational product is identified as CHM-1101 (CLTX(EQ)28ζ/CD19t+ CAR T cells). PRIMARY OBJECTIVE • To determine the recommended phase 2 dose (RP2D) for dual ICT and ICV delivery of CHM-1101 in participants with MMP2+ recurrent or progressive GBM. SECONDARY OBJECTIVES To assess the feasibility and safety of dual delivery of CHM-1101. To describe the persistence, expansion, immunogenicity, and phenotype of CHM-1101 and endogenous cells tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF). In participants who receive at least 2 of the 3 planned doses of CHM-1101 in Cycle 1: Estimate the progression-free survival (PFS) rates Estimate the overall survival (OS) rates To evaluate the disease response rate.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme of Brain
Keywords
Progressive or recurrent glioblastoma, MMP2+

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Two dose levels investigated, with both dose levels proceeding in parallel. Expansion or de-escalation decision rules are based on a traditional 3+3 clinical study design.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
42 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (CAR T cell therapy) 1
Arm Type
Experimental
Arm Description
Arm 1 participants will undergo resection of their tumor. Participants receive half the CHM-1101 dose via Rickham catheters into the tumor cavity and half into the lateral ventricle. Cycle 1 (28 days) CHM 1101 total dose will be divided across 3 once-weekly administrations. After Cycle 1, additional cycles may be initiated in the absence of disease progression or unacceptable toxicity provided that the principal investigator and participant agree to continue and if adequate autologous CAR-T doses remain.
Arm Title
Treatment (CAR T cell therapy) 2
Arm Type
Experimental
Arm Description
Arm 2 participants will undergo resection of their tumor. Participants receive half the CHM-1101 dose via Rickham catheters into the tumor cavity and half into the lateral ventricle. Cycle 1 (28 days) CHM 1101 total dose will be divided across 3 once-weekly administrations. After Cycle 1, additional cycles may be initiated in the absence of disease progression or unacceptable toxicity provided that the principal investigator and participant agree to continue and if adequate autologous CAR-T doses remain.
Intervention Type
Biological
Intervention Name(s)
CHM-1101 CAR-T cells
Other Intervention Name(s)
Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes (via ICT/ICV dual delivery), Chlorotoxin-CD28-CD3z-CD19t-expressing CAR T-cells
Intervention Description
Administered via ICT/ICV dual delivery
Primary Outcome Measure Information:
Title
Dose-limiting toxicity (DLT)
Description
Assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
Time Frame
28 days
Title
Cytokine Release Syndrome (CRS)
Description
Assessed per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading guideline, evaluating levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per µL by flowcytometry).
Time Frame
up tp 15 years
Title
All other adverse events and toxicities
Description
Assessed per NCI CTCAE v5.0.
Time Frame
up to 15 years
Secondary Outcome Measure Information:
Title
Chimeric antigen receptor (CAR) T cell
Description
Assess levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per µL by flowcytometry).
Time Frame
up to 15 years
Title
Endogenous T cell
Description
Assess level and phenotype detected in TCF, PB, and CSF (absolute number per µL by flowcytometry).
Time Frame
up to15 years
Title
Human anti-CAR antibody (HACA)
Description
Serum samples will be evaluated for HACA against the CLTX(EQ)28ζ therapeutic agent.
Time Frame
up to 15 years
Title
Progression free survival (PFS) time
Description
Measured from the date of first infusion of CAR-T cells until the first date when progressive disease (PD) is objectively documented or death from any cause, whichever is earlier.
Time Frame
12 months
Title
Overall survival (OS)
Description
Measured from the date of first infusion of CAR-T cells until death.
Time Frame
up to 15 years
Title
Disease response
Description
Assessed by modified Response Assessment in Neuro-Oncology Criteria (RANO) criteria.
Time Frame
12 months
Title
Clinical benefit rate
Description
The proportion of participants who experience a complete response, a partial response, or stable disease that is 3 months or greater in duration.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Documented informed consent of the subject and/or legally authorized representative. Agreement to allow the use of archival tissue from diagnostic tumor biopsies. Age 18 years and older. ECOG status of 0 or 1. Life expectancy ≥12 weeks. Subject has a prior histologically confirmed diagnosis of a grade 4 glioblastoma multiforme (GBM) or a prior histologically confirmed diagnosis of a grade 2 or 3 malignant glioma and now has radiographic progression consistent with a grade 4 GBM (IDH wild type), grade 4 diffuse astrocytoma (IDH mutant), or has a unifocal relapse of GBM. Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy and ≥ 12 weeks after completion of front-line radiation therapy. Confirmed MMP2+ tumor expression by IHC (≥20% moderate/high MMP2 score [2+ or 3+]). Adequate venous access to perform leukapheresis. No known contraindications to leukapheresis or steroids. In-range baseline laboratory values for WBC (>2000/dL [or ANC ≥1000/mm^3]), platelets (≥75000/mm^3), total bilirubin (≤1.5xULN), AST (≤2.5xULN), ALT (≤2.5xULN), serum creatinine (≤1.5xmg/dL), and oxygen saturation (≥95% on room air) Seronegative for human immunodeficiency virus (HIV) by antigen/antibody (Ag/Ab) testing. Seronegative for hepatitis B and/or hepatitis C virus. Women of childbearing potential must have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. Agreement by women AND men of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of CHM-1101. (Childbearing potential is defined as not being surgically sterilized (women and men) or, for women, having not been free from menses for > 1 year.) Exclusion Criteria: Within 3 months of having received prior bevacizumab therapy at the time of enrollment. Not yet recovered from toxicities of prior therapy. Uncontrolled seizure activity and/or clinically evident progressive encephalopathy. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent. Clinically significant uncontrolled illness. Active infection requiring antibiotics. Known history of HIV or hepatitis B or hepatitis C infection. Other active malignancy. Women only-pregnant or breastfeeding. Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures. Prospective subjects who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chimeric Therapeutics
Phone
1-866-430-1081
Email
clinicaltrials@chimerictherapeutics.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason Litten, MD
Organizational Affiliation
Chimeric Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cara Nolan
Phone
626-825-7996
First Name & Middle Initial & Last Name & Degree
Behnam Badie
Facility Name
St. David's South Austin Medical Center - Sarah Cannon - Austin
City
Austin
State/Province
Texas
ZIP/Postal Code
78704
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Araviad Ramakrishnan, MD
Email
araviad.ramakrishnan@hcahealthcare.com
First Name & Middle Initial & Last Name & Degree
Araviad Ramakrishnan, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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CAR T Cells in Patients With MMP2+ Recurrent or Progressive Glioblastoma

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