- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05705570
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)
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Anticipated)
Phase
- Phase 1
Contacts and Locations
Study Contact
- Name: Nelson Hamerschlak, MD, PhH
- Phone Number: +551121517248
- Email: hamer@einstein.br
Study Contact Backup
- Name: Lucila Kerbauy, MD, PhD
- Phone Number: +551121517248
- Email: lucila.kerbauy@einstein.br
Study Locations
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-
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São Paulo, Brazil, 05652-900
- Hospital Israelita Albert Einstein
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Contact:
- Jose Mauro Kutner, MD, PhD
- Phone Number: +551121517248
- Email: jose.kutner@einstein.br
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Sub-Investigator:
- Lucila Kerbauy, MD, PhH
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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;
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Cyclophosphamide + Fludarabine + Infusion of CAR-T Cells
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
|
Cyclophosphamide 60mg/Kg on day -6
Fludarabine 25mg/m^2 IV on days -5 to -3
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) |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Determination of the recommended dose of CAR-T cells for a future phase II study
Time Frame: Until day 28 after CAR-T cells infusion
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The RP2D will be the maximum tolerated dose (MTD) or the highest dose studied if an MTD is not obtained.
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Until day 28 after CAR-T cells infusion
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Response to treatment for each timepoint.
Time Frame: day 28
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ORR in ALL (Rate of CR/CRh)
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day 28
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Response to treatment for each timepoint
Time Frame: day 28, patients not in CR on day 28: month 3
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ORR in NHL/CLL (Rate of CR/CRh)
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day 28, patients not in CR on day 28: month 3
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Assess overall survival (OS), progression-free survival (PFS).
Time Frame: at 1 year after CAR-T infusion
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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).
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at 1 year after CAR-T infusion
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Phenotype and persistence of CAR-T
Time Frame: days 2, 7, 10, 14, 28, weeks 8, 12, months 6, 12, 24, 36, 48, 60
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Blood samples for determination of persistence/phenotyping of infused CAR-T cells will be analysed.
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days 2, 7, 10, 14, 28, weeks 8, 12, months 6, 12, 24, 36, 48, 60
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Nelson Hamerschlak, MD, PhH, Hospital Israelita Albert Einstein
Study record dates
Study Major Dates
Study Start (ANTICIPATED)
Primary Completion (ANTICIPATED)
Study Completion (ANTICIPATED)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Neoplasms by Histologic Type
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Lymphoma, Non-Hodgkin
- Disease Attributes
- Leukemia, B-Cell
- Neoplasms
- Lymphoma
- Lymphoma, B-Cell
- Leukemia
- Recurrence
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Cyclophosphamide
- Fludarabine
Other Study ID Numbers
- 30173220.5.0000.0071
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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