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A Phase I Clinical Trial Using Genetically Engineered Autologous T Cells to Express Chimeric Antigen Receptor (CAR) for Treatment of Patients With Refractory or Relapsed CD19-positive B Lymphoid Malignancies (CARTHIAE-1)

Primary Purpose

Acute Lymphoblastic Leukemia, in Relapse, Acute Lymphoblastic Leukemia Refractory, B-cell Lymphoma Recurrent

Status
Not yet recruiting
Phase
Phase 1
Locations
Brazil
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine
Chimeric antigen receptor T cells to be implemented in a "3 + 3" design on day 0
Sponsored by
Hospital Israelita Albert Einstein
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia, in Relapse focused on measuring CAR T cell, CD19+ B-cell Malignancies

Eligibility Criteria

2 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Subjects must have relapsed or refractory ALL, lymphoma or CLL treated with at least two lines of therapy. Disease must have either progressed after the last regimen or presented failure to achieve partial or complete remission with the last regimen. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL) subjects are eligible if they progressed, had stable disease or relapsed after two lines of therapy, including tyrosine kinase inhibitors (TKIs). Subjects with DLBCL must have progressed, had SD, or recurred after initial treatment regimens that include an anthracycline and an anti-CD20 monoclonal antibody. Subjects with transformed FL, MZL, or CLL/SLL must have progressed, had SD or recurred with transformed disease after initial treatment for DLBCL. Subjects who relapse ≥12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant. 2. The patient's disease must be CD19 positive, either by immunohistochemistry or flow cytometry analysis on the last biopsy available. Age 2 to 70 years. Performance status: Adult Subjects: ECOG ≤ 2 for patients ≥ 16 years; Subjects < 16 years of age: lansky ≥ 50% Normal Organ and Marrow Functioning (supportive treatment is allowed according to institutional standards, i.e. filgrastim, transfusion) • Total Bilirubin ≤ 2; AST (SGOT) ≤ 5 times the upper limit of normal; ALT (SGTP) ≤ 5 times the upper limit of normal; Serum creatinine ≤ 1.5; Pulse oximetry >91% on room air; No dyspnea or mild dyspnea (≤ Grade 1); Forced expiratory volume in 1 s (FEV1) ≥50% or carbon monoxide diffusion test (DLCO) ≥50% of predicted level; Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram; Subjects must have the following hematologic function parameters: Neutrophils > 1000/uL; Absolute Lymphocyte Count > 100/uL; Platelets ≥ 50,000/L Patient should not be excluded if change of the above parameters due to spinal cord disease infiltration; Prior therapy wash-out - At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives, Blinatumomab with 4 months prior CAR-T infusion. For women of reproductive potential: use a highly effective contraceptive for at least 1 month prior to screening and agree to use a method during study participation and for an additional 4 months after CAR T-cell administration has ended. Subjects must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Autologous transplant within 6 weeks of planned CAR-T cell infusion; History of allogeneic stem cell transplant 4 months prior CAR T cell infusion. Use of immunosuppression therapy; • Patients must have completed immunosuppression therapy; Systemic corticosteroid therapy must be stopped more than 72 hours after infusion; Systemic drugs for graft-versus-host disease should be withheld at least 4 weeks prior to infusion; Presence of graft-versus-host disease Grade ≥ 2; Receiving CAR T cell treatment outside of this protocol; Active central nervous system or meningeal involvement by tumor. Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast-enhanced MRI imaging for at least 90 days prior to registration. History of active malignancy other than non-melanoma skin cancer, carcinoma in situ (e.g. cervix, bladder, breast). HIV infection; HTLV Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) Serious and/or potentially fatal medical conditions Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease. History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage therapies for treatment related toxicities;

Sites / Locations

  • Hospital Israelita Albert Einstein

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cyclophosphamide + Fludarabine + Infusion of CAR-T Cells

Arm Description

Lymphodepleting regimen, consisting of Cyclophosphamide 60mg/kg IV on day -6 and Fludarabine 25mg/m2 IV on days -5 to -3. Followed by infusion of Chimeric antigen receptor T-cells (CAR-T) on day 0

Outcomes

Primary Outcome Measures

Determination of the recommended dose of CAR-T cells for a future phase II study
The RP2D will be the maximum tolerated dose (MTD) or the highest dose studied if an MTD is not obtained.

Secondary Outcome Measures

Response to treatment for each timepoint.
ORR in ALL (Rate of CR/CRh)
Response to treatment for each timepoint
ORR in NHL/CLL (Rate of CR/CRh)
Assess overall survival (OS), progression-free survival (PFS).
Overall survival (OS) and progression-free survival (PFS) will be assessed by dose cohort and in the first two groups at the MTD (or at the highest dose studied).
Phenotype and persistence of CAR-T
Blood samples for determination of persistence/phenotyping of infused CAR-T cells will be analysed.

Full Information

First Posted
January 20, 2023
Last Updated
January 20, 2023
Sponsor
Hospital Israelita Albert Einstein
Collaborators
Miltenyi Biotec, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT05705570
Brief Title
A Phase I Clinical Trial Using Genetically Engineered Autologous T Cells to Express Chimeric Antigen Receptor (CAR) for Treatment of Patients With Refractory or Relapsed CD19-positive B Lymphoid Malignancies
Acronym
CARTHIAE-1
Official Title
A Phase I Clinical Trial Using Genetically Engineered Autologous T Cells to Express Chimeric Antigen Receptor (CAR) for Treatment of Patients With Refractory or Relapsed CD19-positive B Lymphoid Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
March 1, 2023 (Anticipated)
Primary Completion Date
May 1, 2023 (Anticipated)
Study Completion Date
December 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospital Israelita Albert Einstein
Collaborators
Miltenyi Biotec, Inc.

4. Oversight

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

5. Study Description

Brief Summary
This is a phase l, single arm, prospective open, dose-escalation study in patients with relapsed or refractory CD19-positive B cell malignancies (ALL, NHL, CLL). The trial will include adult and pediatric patients. There will be three individual cohorts, defined by disease biology: pediatric ALL and aggressive pediatric NHL (Cohort 1), adult ALL (Cohort 2) and adult NHL/CLL (Cohort 3).
Detailed Description
We will evaluate the safety of the MB-CART19.1 and determine the recommended dose levels for the Phase II clinical trial. Dose evaluation will start in Cohorts 1 and 2 with Dose Level 1 (5x10e5 CAR T cells/Kg) and in Cohort 3 with Dose Level 2 1x10e6 CAR T cells/Kg) , sparing Dose Level 1 . Each of the cohorts will evaluate the safety of the CAR-T cells. In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A particular dose level will be expanded to 6 patients if one patient out of 3 patients treated at that particular dose level develops DLT. Once this occurs, further dose-escalations are halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose level will be expanded to 6 patients in total. The highest dose among the dose levels tested at which no more than one out of six patients experiences DLT will be considered the MTD. In Dose Level 3, three additional patients will be treated, if no DLT occurred. Dose Level 0 will be tested only if Dose Level 1 is not tolerable.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, in Relapse, Acute Lymphoblastic Leukemia Refractory, B-cell Lymphoma Recurrent, B-cell Lymphoma Refractory, Chronic Lymphocytic Leukemia Recurrent, Chronic Lymphocytic Leukemia Refractory
Keywords
CAR T cell, CD19+ B-cell Malignancies

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
A phase I study, with a "3+3" dose escalation design
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cyclophosphamide + Fludarabine + Infusion of CAR-T Cells
Arm Type
Experimental
Arm Description
Lymphodepleting regimen, consisting of Cyclophosphamide 60mg/kg IV on day -6 and Fludarabine 25mg/m2 IV on days -5 to -3. Followed by infusion of Chimeric antigen receptor T-cells (CAR-T) on day 0
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide 60mg/Kg on day -6
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
Fludarabine 25mg/m^2 IV on days -5 to -3
Intervention Type
Biological
Intervention Name(s)
Chimeric antigen receptor T cells to be implemented in a "3 + 3" design on day 0
Intervention Description
Level -1 (1 x 105 cells/kg) Level 1 [Starting dose] (5 x 105 cells/kg) Level 2 (1 x 106 cells/kg) Level 3 (2 x 106 cells/kg)
Primary Outcome Measure Information:
Title
Determination of the recommended dose of CAR-T cells for a future phase II study
Description
The RP2D will be the maximum tolerated dose (MTD) or the highest dose studied if an MTD is not obtained.
Time Frame
Until day 28 after CAR-T cells infusion
Secondary Outcome Measure Information:
Title
Response to treatment for each timepoint.
Description
ORR in ALL (Rate of CR/CRh)
Time Frame
day 28
Title
Response to treatment for each timepoint
Description
ORR in NHL/CLL (Rate of CR/CRh)
Time Frame
day 28, patients not in CR on day 28: month 3
Title
Assess overall survival (OS), progression-free survival (PFS).
Description
Overall survival (OS) and progression-free survival (PFS) will be assessed by dose cohort and in the first two groups at the MTD (or at the highest dose studied).
Time Frame
at 1 year after CAR-T infusion
Title
Phenotype and persistence of CAR-T
Description
Blood samples for determination of persistence/phenotyping of infused CAR-T cells will be analysed.
Time Frame
days 2, 7, 10, 14, 28, weeks 8, 12, months 6, 12, 24, 36, 48, 60

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects must have relapsed or refractory ALL, lymphoma or CLL treated with at least two lines of therapy. Disease must have either progressed after the last regimen or presented failure to achieve partial or complete remission with the last regimen. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL) subjects are eligible if they progressed, had stable disease or relapsed after two lines of therapy, including tyrosine kinase inhibitors (TKIs). Subjects with DLBCL must have progressed, had SD, or recurred after initial treatment regimens that include an anthracycline and an anti-CD20 monoclonal antibody. Subjects with transformed FL, MZL, or CLL/SLL must have progressed, had SD or recurred with transformed disease after initial treatment for DLBCL. Subjects who relapse ≥12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant. 2. The patient's disease must be CD19 positive, either by immunohistochemistry or flow cytometry analysis on the last biopsy available. Age 2 to 70 years. Performance status: Adult Subjects: ECOG ≤ 2 for patients ≥ 16 years; Subjects < 16 years of age: lansky ≥ 50% Normal Organ and Marrow Functioning (supportive treatment is allowed according to institutional standards, i.e. filgrastim, transfusion) • Total Bilirubin ≤ 2; AST (SGOT) ≤ 5 times the upper limit of normal; ALT (SGTP) ≤ 5 times the upper limit of normal; Serum creatinine ≤ 1.5; Pulse oximetry >91% on room air; No dyspnea or mild dyspnea (≤ Grade 1); Forced expiratory volume in 1 s (FEV1) ≥50% or carbon monoxide diffusion test (DLCO) ≥50% of predicted level; Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram; Subjects must have the following hematologic function parameters: Neutrophils > 1000/uL; Absolute Lymphocyte Count > 100/uL; Platelets ≥ 50,000/L Patient should not be excluded if change of the above parameters due to spinal cord disease infiltration; Prior therapy wash-out - At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives, Blinatumomab with 4 months prior CAR-T infusion. For women of reproductive potential: use a highly effective contraceptive for at least 1 month prior to screening and agree to use a method during study participation and for an additional 4 months after CAR T-cell administration has ended. Subjects must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Autologous transplant within 6 weeks of planned CAR-T cell infusion; History of allogeneic stem cell transplant 4 months prior CAR T cell infusion. Use of immunosuppression therapy; • Patients must have completed immunosuppression therapy; Systemic corticosteroid therapy must be stopped more than 72 hours after infusion; Systemic drugs for graft-versus-host disease should be withheld at least 4 weeks prior to infusion; Presence of graft-versus-host disease Grade ≥ 2; Receiving CAR T cell treatment outside of this protocol; Active central nervous system or meningeal involvement by tumor. Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast-enhanced MRI imaging for at least 90 days prior to registration. History of active malignancy other than non-melanoma skin cancer, carcinoma in situ (e.g. cervix, bladder, breast). HIV infection; HTLV Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) Serious and/or potentially fatal medical conditions Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease. History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage therapies for treatment related toxicities;
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nelson Hamerschlak, MD, PhH
Phone
+551121517248
Email
hamer@einstein.br
First Name & Middle Initial & Last Name or Official Title & Degree
Lucila Kerbauy, MD, PhD
Phone
+551121517248
Email
lucila.kerbauy@einstein.br
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nelson Hamerschlak, MD, PhH
Organizational Affiliation
Hospital Israelita Albert Einstein
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Israelita Albert Einstein
City
São Paulo
ZIP/Postal Code
05652-900
Country
Brazil
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jose Mauro Kutner, MD, PhD
Phone
+551121517248
Email
jose.kutner@einstein.br
First Name & Middle Initial & Last Name & Degree
Lucila Kerbauy, MD, PhH

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

A Phase I Clinical Trial Using Genetically Engineered Autologous T Cells to Express Chimeric Antigen Receptor (CAR) for Treatment of Patients With Refractory or Relapsed CD19-positive B Lymphoid Malignancies

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