- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05281809
Local Manufacture of CAR T-Cell Products for the Treatment of B-Cell Lymphoma and B-Acute Lymphoblastic Leukemia
A Feasibility Study Following a Phase 2a Design to Demonstrate Successful Local Manufacture of Chimeric Antigen Receptor (CAR) T-Cell Products for the Treatment of B-Cell Lymphoma and B-Acute Lymphoblastic Leukemia
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
On this study the following procedures are sequentially performed: eligibility determination and informed consent; cell collection by apheresis; CAR T-cell manufacturing and lymphodepleting chemotherapy all followed by CAR T-cell infusion on day 0. The first 3 subjects will be followed in hospital from day 0 until +14 for CRS, ICANS and other toxicity. The PI and two physicians not affiliated with the study (Nathan Bahary, MD, PhD and Gene Finley, MD) will review the outcome of the first three patients to assure the interim analysis meets criteria for continuing accrual. This analysis will be submitted to the IRB prior to continuing with accrual. The toxicity profile of the first three subjects will be scrutinized. Should toxicity be minimal with CRS ≤ 2 and ICANS grade ≤1 then the PI might propose modification to hospitalization between days 0 and +14 according to comparison with prior experience with commercially available product. A protocol amendment would be submitted in this case. Should no CAR T-cell related toxicity be identified on day +15, the subject will be discharged from the hospital and followed in the Medical Short Stay Unit (or designated substitute inpatient unit) daily to day 30. At the discretion of the Investigator (based upon each subject's medical condition or status), this follow-up could be reduced to thrice weekly basis (e.g. Monday-Wednesday-Friday). CAR T-cell monitoring by flow cytometry will occur on day +30 and day +100. Response will be assessed at day +30 and the subject will be discharged for outpatient follow up. Response will be assessed monthly by clinical examination to day +100 and then every 3 months to day +730. Thereafter, clinical follow up will occur every 6 months to five years and then yearly up to 15 years, or until death (whichever occurs first). All subjects treated on this study must consent to reporting of de-identified data to the Center for International Blood and Marrow Transplantation Research (CIBMTR). (See Table 1: Schedule of Study Procedures, Figure 1: Study Diagram, Table 2: Laboratory Investigation and Table 3: Response Evaluation for details of study conduct.) The clinical care of subjects enrolled on this study is entirely within the standard of care employed for patients who receive commercial product. There are no drugs, surgical procedures, radiological investigations, laboratory tests or examinations that are considered experimental except for a peripheral blood sample to detect CAR T-cells (by flow cytometry) and the actual production/manufacture of CAR T-cells occurring in the local Cell Processing Laboratory.
For this reason, the intent of this protocol is to ensure that the standard of care is strictly followed as outlined in the SOP documents, screenshots and documents included in the appendix of this document. Thus, patients receiving commercial product and those treated on this protocol should receive the same supportive care. In addition to immune effector cells, these documents often describe methods and cellular therapy products not relevant to this investigation and for our purpose these sections can be ignored.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: John Lister, MD
- Phone Number: 412-578-4484
- Email: john.lister@ahn.org
Study Contact Backup
- Name: Richard Wonder
- Email: rich.wonder@ahn.org
Study Locations
-
-
Pennsylvania
-
Pittsburgh, Pennsylvania, United States, 15224
- Recruiting
- AHN Cancer Institute - West Penn Hospital
-
Contact:
- John Lister, MD
- Phone Number: 412-578-4484
- Email: john.lister@ahn.org
-
Contact:
- AHN Clinical Trials Contact
- Phone Number: 412-330-6011
- Email: clinicaltrials@ahn.com
-
Sub-Investigator:
- Cyrus Khan, MD
-
Sub-Investigator:
- Salman Fazal, MD
-
Sub-Investigator:
- Anna Koget, DO
-
Sub-Investigator:
- Prerna Mewawalla, MD
-
Sub-Investigator:
- Santhosh Sadashiv, MD
-
Sub-Investigator:
- Yazan Samhouri, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Subjects with CD19+ B-cell lymphoma or B-Cell Acute Lymphoblastic Leukemia (B-ALL) with no currently available curative treatment option (such as autologous or allogeneic Hematopoietic stem cell transplantation (HSCT)) who have a limited prognosis (<2-year projected survival) will be enrolled. Participation on this trial is permitted as a bridge to HSCT.
- Peripheral blood CD3 count > 200/µL by flow cytometry. Please note that this test might need to be repeated multiple times as standard practice to optimize collection efficiency.
- Subjects will have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), CLL, Marginal Zone Lymphoma (MZL), Lymphoplasmacytic Lymphoma (LPL) or B-ALL and will have failed at least 2 lines of therapy in the case of lymphoma and one line if the diagnosis is B-ALL or be refractory (no response or progressive disease) to first line therapy. A line of therapy must include conventional (immuno) chemotherapy (e.g. rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) or Bendamustine plus Rituximab (BR) in the case of lymphoma) administered for at least 2 cycles. Second or greater lines of therapy must be administered for at least two cycles. Single agent anti-CD20 monoclonal antibody (e.g. rituximab, obinutuzumab) is not considered for the purposes of these criteria to count as a line of therapy. The definition of a line of therapy is taken according to recommended regimens for first and second line therapy in the relevant sections of the National Comprehensive Cancer Network (NCCN) guidelines. The most recent version of the guidelines will be used for eligibility determination. In the unlikely event that a subject received a first or second line regimen no longer listed in the most recent guidelines, but previously present in the version of the guidelines active at the time the therapy was administered, then the subject would be deemed to have received a line of therapy.
- Subjects with pathological and clinical evidence of transformed indolent lymphoma (FL, CLL, MZL or LPL) are eligible for participation on this trial if they have received at least one line of therapy for transformed disease for at least two cycles regardless of response.
- Demonstration of CD19 expression by immunohistochemistry or flow cytometry on a pathological specimen of lymphoma or ALL cells at any time in the course of prior treatment.
- Subjects who are unable to receive commercially available CD19-CAR T-cell therapy.
- Patients with lymphoma must have measurable or assessable disease. Patients in complete remission with no evidence of disease are not eligible.
- Patients with B-ALL must have at least measurable detectable disease on two separate occasions at least 2 weeks apart to be eligible.
- Subjects who relapse at > 100 days after autologous or allogeneic HSCT are eligible for participation on this trial. Allogeneic HSCT recipients must be off all immunosuppression for a minimum of 4 weeks before leukapheresis is performed and be free of active acute and chronic Graft Versus Host Disease (GVHD).
- Subjects will be ≥ 18 and < 80 years of age.
- Female subjects of childbearing potential must have a negative urine or serum pregnancy test and if sexually active must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive. Active contraception should continue for at least one year after CAR T-cell infusion.
- Male participants must be willing to practice birth control from the time of enrollment on this study and for 6 months after receiving the preparative regimen.
- Cardiac ejection fraction ≥ 0.45 by MUGA (multigated acquisition) or echocardiography.
- No requirement for supplemental oxygen and no dyspnea at rest. DLCO (diffusing capacity of the lungs for carbon monoxide) and FEV (forced expiratory volume)1 ≥ 0.65 of predicted.
- Karnofsky performance score ≥ 70.
- Subjects must have an expected survival > 12 weeks.
- Subjects must be able to comprehend the risks and methods used in this clinical trial and independently consent to participate.
- Subjects must consent to anonymous reporting of data to the CIBMTR (Center for International Blood and Marrow Transplant Research).
Exclusion Criteria:
- Infection with HIV (human immunodeficiency virus) and active viral replication. Patients with an undetectable viral load on ART (antiretroviral treatment) can be considered for participation on this protocol.
- Infection with hepatitis B and active viral replication.
- Infection with hepatitis C and active viral replication.
- Active untreated CNS (central nervous system) leukemia or lymphoma. Patients with treated CNS leptomeningeal or parenchymal disease might be eligible if the CNS disease is inactive. The CSF (cerebrospinal fluid) must be clear on two separate occasions at least 4 weeks apart. Brain imaging must demonstrate no evidence of progressive disease on two separate occasions at least 4 weeks apart.
- Active bacterial, fungal or viral infection.
- Concurrent second malignancy requiring active therapy. Patients with breast or prostate cancer stable on hormonal therapy might be considered for participation if otherwise unimpaired.
- Documented myocardial infarction within 6 months of study participation and/or symptomatic coronary artery or valvular disease or uncontrolled arrhythmia.
- Investigational drug use within 30 days before leukapheresis.
- Anti-cancer therapy administration within 4 weeks of leukapheresis including antiCD19 directed therapy, monoclonal antibody therapy, bi-specific T-cell engager therapy and targeted therapy such as Abelson tyrosine kinase inhibitors, Bruton's tyrosine kinase inhibitors, venetoclax and Lenalidomide or other IMiD (Immunomodulatory Drug).
- Involved field radiation therapy is permitted if it terminates at least 15 days before leukapheresis and associated toxicity is grade 2 or less. Radiation therapy within 14 days of leukapheresis would make the subject ineligible.
- Checkpoint inhibitor therapy within 4 weeks before leukapheresis.
- Corticosteroid therapy at pharmacological dose (> 10 mg of prednisone or biological equivalent) within 4 weeks before leukapheresis.
- Immunosuppressive therapy that cannot be stopped for 4 weeks prior to leukapheresis as deemed by the prescribing physician.
Laboratory abnormalities that indicate clinically significant hematological, hepatobiliary, or renal disease:
AST (Aspartate transaminase)/SGOT(serum glutamic-oxaloacetic transaminase) > 2.0 times the upper limit of normal ALT (alanine aminotransferase)/SGPT (serum glutamic-pyruvic transaminase) > 2.0 times the upper limit of normal Total bilirubin > 2.0 times the upper limit of normal, unless subject has Gilbert's Syndrome (>3.0 times the upper limit of normal) Hemoglobin < 8 gm/dL or dependent upon transfusion to maintain ≥ 8 gm/dL White blood cell count < 2,000/mm3 Platelet count < 50,000/mm3 or dependent upon transfusion to maintain ≥ 50,000 mm Creatinine > 2.0 times the upper limit of normal or calculated creatinine clearance ≤ 40 mL/min.
- Pregnant or lactating females.
- Subjects who, in the opinion of the Investigator, will be non-compliant with study schedules or procedures.
- Subjects who belong to a vulnerable population such as the homeless, the developmentally disabled and prisoners or have any condition that impairs their ability to provide informed consent or comply with study schedules or procedures.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment Arm
CAR -T-cell collection, infusion
|
This protocol describes the use of an automated cell processor and culture system, the CliniMACS Prodigy device sold by Miltenyi Biotec, for the local manufacture of CAR T-cells targeting the CD19 antigen.
The manufacturing process will use a lentiviral vector (CAR19) provided by Lentigen, a wholly owned subsidiary of Miltenyi Biotec, to transfect T-cells collected from eligible patients.
Live cells will be harvested by the device after culture and infused intravenously to the patient from whom the cells were originally obtained.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Successful local CAR T-cell manufacturing
Time Frame: 48 months
|
To demonstrate the feasibility of reliably producing CD19-targeted CAR T-cells at our site using the Prodigy device.
|
48 months
|
Safety of administration
Time Frame: 15 years
|
To demonstrate the safety of administering the manufactured product to subjects as measured by adverse events.
|
15 years
|
Safety of administration
Time Frame: 30 days
|
Cytokine Release Syndrome score
|
30 days
|
Safety of administration
Time Frame: 30 days
|
Immune Effector Cell Associated Neurotoxicity Syndrome Grading for Adults (score) - A score of 10 represents no impairment, 7-9 grade 1 ICANS, 3-6 grade 2 ICANS, and 0-2 grade 3 ICANS.
A score of 0 due to patient being unarousable and unable to perform assessment corresponds to grade 4 ICANS.
|
30 days
|
Safety of administration
Time Frame: 30 days
|
Immune Effector Cell Associated Encephalopathy Score - A score of 10 represents no impairment, 7-9 grade 1 ICANS, 3-6 grade 2 ICANS, and 0-2 grade 3 ICANS.
A score of 0 due to patient being unarousable and unable to perform assessment corresponds to grade 4 ICANS.
|
30 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Response to therapy
Time Frame: 48 months
|
Response evaluation according to Lugano criteria for lymphoma and NCCN guidelines for ALL.
|
48 months
|
Response to therapy
Time Frame: 48 months
|
Response criteria ALL-E and for MRD (minimal residual disease) ALL-F for B-ALL.
|
48 months
|
CAR T-cell kinetics
Time Frame: 100 days
|
CAR T-cell counts by flow cytometry
|
100 days
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: John Lister, MD, AHN
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Lymphoma, Non-Hodgkin
- Disease Attributes
- Hematologic Diseases
- Hemorrhagic Disorders
- Hemostatic Disorders
- Paraproteinemias
- Blood Protein Disorders
- Neoplasms, Plasma Cell
- Leukemia, B-Cell
- Chronic Disease
- Lymphoma
- Lymphoma, B-Cell
- Lymphoma, Large B-Cell, Diffuse
- Leukemia
- Lymphoma, Mantle-Cell
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Waldenstrom Macroglobulinemia
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
Other Study ID Numbers
- 2021-114-WPH
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.
Clinical Trials on Follicular Lymphoma
-
Joseph TuscanoNational Cancer Institute (NCI); Genentech, Inc.; Pharmacyclics LLC.RecruitingAnn Arbor Stage II Follicular Lymphoma | Ann Arbor Stage III Follicular Lymphoma | Ann Arbor Stage IV Follicular Lymphoma | Grade 1 Follicular Lymphoma | Grade 2 Follicular Lymphoma | Grade 3a Follicular LymphomaUnited States
-
National Cancer Institute (NCI)RecruitingRecurrent Follicular Lymphoma | Refractory Follicular Lymphoma | Grade 1 Follicular Lymphoma | Grade 2 Follicular Lymphoma | Grade 3a Follicular LymphomaUnited States
-
Memorial Sloan Kettering Cancer CenterFox Chase Cancer Center; Pharmacyclics LLC.TerminatedFollicular Lymphoma | Follicular Lymphoma, Grade 1 | Follicular Lymphoma, Grade 2 | Follicular Lymphoma Grade IIIaUnited States
-
National Cancer Institute (NCI)TerminatedStage III Grade 1 Follicular Lymphoma | Stage III Grade 2 Follicular Lymphoma | Stage III Grade 3 Follicular Lymphoma | Stage IV Grade 1 Follicular Lymphoma | Stage IV Grade 2 Follicular Lymphoma | Stage IV Grade 3 Follicular LymphomaUnited States
-
Robert LowskyNational Cancer Institute (NCI); Janssen, LP; The Leukemia and Lymphoma Society; Rising Tide FoundationCompletedMantle Cell Lymphoma | Marginal Zone Lymphoma | Recurrent Follicular Lymphoma | Refractory Follicular Lymphoma | Grade 1 Follicular Lymphoma | Grade 2 Follicular Lymphoma | Grade 3a Follicular LymphomaUnited States
-
Olivia Newton-John Cancer Research InstituteBristol-Myers Squibb; Barwon Health; Austin Health; Eastern Health; Fiona Stanley... and other collaboratorsRecruitingFollicular Lymphoma Stage II | Follicular Lymphoma Stage III | Follicular Lymphoma Stage IVAustralia
-
Fondazione Italiana Linfomi ONLUSCompletedFollicular Lymphoma, Grade 1 | Follicular Lymphoma, Grade 2 | Follicular Lymphoma Grade 3AItaly
-
Epizyme, Inc.RecruitingFollicular Lymphoma | Relapsed/Refractory Follicular Lymphoma | Refractory Follicular LymphomaUnited States, China, Spain, France, Taiwan, United Kingdom, Australia, Korea, Republic of, Canada, Italy, Hungary, Poland, Belgium, Germany
-
Massachusetts General HospitalTG TherapeuticsActive, not recruitingLymphoma | Follicular Lymphoma | Marginal Zone Lymphoma | Follicular Lymphoma, Grade 1 | Follicular Lymphoma Grade IIIa | Marginal Zone B Cell Lymphoma | Follicular Lymphoma Grade 2United States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingGrade 3a Follicular Lymphoma | Ann Arbor Stage III Grade 1 Follicular Lymphoma | Ann Arbor Stage III Grade 2 Follicular Lymphoma | Ann Arbor Stage IV Grade 1 Follicular Lymphoma | Ann Arbor Stage IV Grade 2 Follicular Lymphoma | Ann Arbor Stage III Grade 3 Follicular Lymphoma | Ann Arbor Stage...United States
Clinical Trials on Chimeric Antigen Receptor (CAR) T-Cell Product (Autologous)
-
Bellicum PharmaceuticalsSuspendedHER2-positive Breast Cancer | HER2-positive Gastric Cancer | Solid Tumor, Adult | HER-2 Gene Amplification | HER-2 Protein OverexpressionUnited States
-
The First Affiliated Hospital of Soochow UniversityShanghai Unicar-Therapy Bio-medicine Technology Co.,Ltd; Suzhou Hongci Hematology...RecruitingLymphoma, B-Cell | Autologous Stem Cell TransplantationChina
-
City of Hope Medical CenterNational Cancer Institute (NCI); California Institute for Regenerative Medicine...RecruitingBreast Cancer | HER2-positive Breast Cancer | Malignant Neoplasm | Metastatic Malignant Neoplasm in the Brain | Metastatic Malignant Neoplasm in the LeptomeningesUnited States
-
The First Affiliated Hospital of Soochow UniversityRecruitingRelapsed/Refractory B-cell Non-Hodgkin's LymphomaChina
-
First Affiliated Hospital of Harbin Medical UniversityShanghai Unicar-Therapy Bio-medicine Technology Co.,LtdUnknownPancreatic Cancer | CARChina
-
PersonGen BioTherapeutics (Suzhou) Co., Ltd.Anhui Provincial HospitalRecruiting
-
Sinobioway Cell Therapy Co., Ltd.Jiangsu Cancer Institute & HospitalUnknown
-
Cellular Biomedicine Group Ltd.Recruiting
-
PersonGen BioTherapeutics (Suzhou) Co., Ltd.Anhui Provincial HospitalRecruitingCAR | Malignant TumorsChina
-
PersonGen BioTherapeutics (Suzhou) Co., Ltd.Anhui Provincial HospitalUnknownFollicular Lymphoma | B Cell Lymphoma | Mantle Cell Lymphoma | Diffuse Large B Cell Lymphoma | Plasma Cell Neoplasm | Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue | Primary Cutaneous Follicle Centre LymphomaChina