- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03676504
Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Cells Expressing a Third-generation CAR
Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Lymphocytes Transduced by RV-SFG.CD19.CD28.4-1BBzeta Retroviral Vector - a Unicenter Phase I/II Clinical Trial
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Prof. Dr. Michael Schmitt
- Phone Number: +49-6221-566614
- Email: michael.schmitt@med.uni-heidelberg.de
Study Locations
-
-
-
Heidelberg, Germany
- Recruiting
- University Hospital Heidelberg
-
Contact:
- Prof. Dr. Michael Schmitt
- Phone Number: +49-6221-566614
- Email: michael.schmitt@med.uni-heidelberg.de
-
Principal Investigator:
- Prof. Dr. Michael Schmitt
-
Principal Investigator:
- Prof. Dr. Andreas Kulozik
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Stratum I/II (Adults):
- Confirmed CD19+ ALL, CLL, DLBCL, FL or MCL in patients ≥ 18 years
- ALL (Ph+ and Ph-): Confirmed CD19+ ALL by cytology and flow cytometry (FACS) AND
Relapsed or refractory disease (including "molecular relapse" with minimal residual disease (MRD) levels > 10^-3 at two occasions > 2 weeks apart) with confirmed CD19 expression on malignant cells in relapse
- Any relapse after allogeneic stem cell transplantation (alloSCT) (≥ 6 months from alloSCT at time of CAR T cell infusion) OR
- Any relapse failing to achieve an MRD level of < 10^-3 after ≥ 2 lines of treatment OR
- Primary refractory as defined by not achieving a complete remission (CR) after ≥ 2 lines of treatment
CLL/NHL: Confirmed CD19+ CLL/NHL (including CLL, DLBCL, FL or MCL) with
CLL in need of treatment with:
- Early relapse (within 2 years) after end of chemoimmunotherapy or chemoimmunotherapy refractoriness plus failure or intolerance of both Bruton's tyrosine kinase Inhibitor (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i) OR
- Relapse after alloSCT, ineligible for or refractory to standard interventions (donor lymphocyte infusions (DLI), CD20 antibodies, chemoimmunotherapy)
DLBCL with:
- Refractoriness to a 2nd or later line of chemoimmunotherapy OR
- Relapse after autologous stem cell transplantation (autoSCT) plus ineligibility for alloSCT (including refractoriness to one line of salvage chemoimmunotherapy) OR
- Relapse after alloSCT
FL in need of treatment with:
- Relapse <2 years after chemoimmunotherapy AND ineligibility for or failure of autologous stem cell transplantation (autoSCT) AND ineligibility for or failure of idelalisib OR
- Relapse after alloSCT, ineligible for or refractory to standard interventions (DLI, CD20 antibodies, chemoimmunotherapy)
MCL with:
- Relapse after standard first-line therapy AND ineligibility for or failure to BTKi salvage therapy OR
- Relapse after alloSCT AND ineligibility for or failure to BTKi salvage therapy
- Measurable disease/MRD at time of enrollment
- Life expectancy ≥ 12 weeks
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at the time of screening
Adequate organ function:
- Renal function defined as: serum creatinine of ≤ 2 x ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2
- Liver function defined as:
- ALT ≤ 5 times the ULN for the respective age
- Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert-Meulengracht syndrome (may be included if total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) or extrahepatic disease (e.g. chronic hemolytic anemia)
- minimum level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation > 90% on room air
- Hemodynamic stability and left ventricular ejection fraction (LVEF) ≥ 40% as confirmed by echocardiogram
- Absolute neutrophil count (ANC) ≥ 500/mm3
- Absolute lymphocyte count (ALC) ≥ 100/mm3
- Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for one year following CD19.CAR T cell therapy
- Ability to understand the nature of the trial and the trial related procedures
- Written informed consent must be obtained prior to any screening procedures
Stratum III (Children and Adolescents with ALL):
- Age of > 3 years until < 18 years at the time of screening
- CD19+ ALL (Ph+ and Ph-) confirmed by cytology and flow cytometry (FACS) AND
Relapsed or refractory disease (including "molecular relapse" with polymerase chain reaction (PCR) MRD > 10^-3 at two occasions > 2 weeks apart) with confirmed CD19 expression on malignant cells in relapse
- Any relapse after alloSCT (≥ 6 months from alloSCT at time of CAR T cell infusion) OR
- Any relapse failing to achieve an MRD level of < 10^-3 after ≥ 2 lines of treatment OR
- Primary refractory as defined by not achieving a CR after ≥ 2 lines of treatment
- Measurable disease/MRD at time of enrollment
- Life expectancy ≥ 12 weeks
- ECOG performance status ≤ 2 (age ≥ 16 years) or Lansky performance status ≥ 50 (age < 16 years) at the time of screening
Adequate organ function:
- Renal function defined as serum creatinine-clearance ≥ 30 mL/min/1.73 m^2
- Liver function defined as:
- ALT ≤ 5 times the ULN for the respective age
- Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert-Meulengracht syndrome or extrahepatic disease (e.g. chronic hemolytic anemia)
- minimum level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation > 90% on room air
- Hemodynamic stability and LVEF ≥ 40% or shortening fraction > 29% as confirmed by echocardiogram
- ANC) ≥ 500/mm3
- ALC ≥ 100/mm3
- Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and postpubertal male participants must agree to use highly effective methods of contraception for one year following CD19.CAR T cell therapy
- Written informed consent of the study patient and/or the legal representative must be obtained prior to any screening procedures
Exclusion Criteria:
Stratum I/II (Adults):
The following medications are excluded:
- Immunosuppressive medication with the exception of ≤ 30 mg prednisolone/d or equivalent at the time of CAR T cell transfusion
- Bridging/maintenance therapy including chemo- and immunotherapy must be stopped ≥ 2 weeks prior to leukapheresis, but can be continued between leukapheresis and lymphodepletion
- Intrathecal chemotherapy is possible at any time, but not during lymphodepletion until 14 days after CD19.CAR T cell transfusion
- Any DLI must be completed > 6 weeks prior to CD19.CAR T cell infusion
- Florid/acute or chronic Graft-versus-Host disease (GvHD)
- Uncontrolled active hepatitis B or C
- HIV-positivity
- Uncontrolled acute life-threatening bacterial, viral or fungal infection
- Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure New York Heart Association (NYHA) III-IV, uncontrolled diabetes mellitus, uncontrolled hyperlipidemia)
- Unstable angina and/or myocardial infarction within 3 months prior to screening
- Any previous or concurrent malignancy.
The following exceptions do NOT constitute exclusion criteria:
- Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
- In situ carcinoma of the cervix or breast, treated curatively without evidence of recurrence ≥ 3 years prior to the study
- CLL or FL transformed into an aggressive B cell lymphoma
A primary malignancy which is in complete remission for ≥ 5 years
- Pregnant or nursing (lactating) women
- Intolerance to the excipients of the cell product
- Active central nervous System (CNS) involvement in ALL patient at the time of screening is not an exclusion criterion, but patients with CNS 3 status at clinical screening (d-14) are not eligible for CD19.CAR T cell transfusion
- Participation in another clinical trial at the time of screening
Stratum III (Children and Adolescents with ALL):
The following medications are excluded:
- immunosuppressive medication with the exception of < 0.5 mg/d*kg body weight (BW) prednisolone-equivalent at the time of CD19.CAR T cell transfusion
- Bridging/Maintenance therapy including chemo- and immunotherapy must be stopped ≥ 2 weeks prior to leukapheresis, but can be continued between leukapheresis and lymphodepletion
- Intrathecal chemotherapy is possible at any time, but not during lymphodepletion until 14 days after CD19.CAR T cell transfusion
- Any DLI must be completed > 6 weeks prior to CD19.CAR T cell infusion
- Florid/acute or chronic GvHD
- Uncontrolled active hepatitis B or C
- HIV-positivity
- Uncontrolled acute life-threatening bacterial, viral or fungal infection
- Severe concomitant disease (e.g. any life-limiting genetic disorder). Patients with Down Syndrome will not be excluded.
- Any previous or concurrent malignancy.
The following exceptions do not constitute exclusion criteria:
- Lymphoblastic lymphoma transformed into a CD19+ acute lymphoblastic leukemia
A primary malignancy which is in complete remission for ≥ 5 years
- Pregnant or nursing (lactating) women
- Intolerance to the excipients of the cell product
- Active CNS involvement at the time of screening is not an exclusion criterion, but patients with CNS 3 status at clinical screening (d-14) are not eligible for CD19.CAR T cell transfusion
- Participation in another clinical trial at the time of screening
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Stratum I
Adult patients with relapsed or refractory ALL
|
Dose Level 1: 1×10^6 transduced cells/m^2; Dose Level 2: 5×10^6 transduced cells/m^2; Dose Level 3: 20×10^6 transduced cells/m^2; Dose Level 4: 5x10^7 transduced cells/m^2; Dose Level 5: 10x10^7 transduced cells/m^2; Dose Level 6: 20x10^7 transduced cells/m^2
3 days of fludarabine 30 mg/m^2/day
3 days of cyclophosphamide 500 mg/m^2/day
|
Experimental: Stratum II
Adult patients with relapsed or refractory CLL, DLBCL, FL or MCL
|
Dose Level 1: 1×10^6 transduced cells/m^2; Dose Level 2: 5×10^6 transduced cells/m^2; Dose Level 3: 20×10^6 transduced cells/m^2; Dose Level 4: 5x10^7 transduced cells/m^2; Dose Level 5: 10x10^7 transduced cells/m^2; Dose Level 6: 20x10^7 transduced cells/m^2
3 days of fludarabine 30 mg/m^2/day
3 days of cyclophosphamide 500 mg/m^2/day
|
Experimental: Stratum III
Pediatric patients with relapsed or refractory ALL
|
Dose Level 1: 1×10^6 transduced cells/m^2; Dose Level 2: 5×10^6 transduced cells/m^2; Dose Level 3: 20×10^6 transduced cells/m^2; Dose Level 4: 5x10^7 transduced cells/m^2; Dose Level 5: 10x10^7 transduced cells/m^2; Dose Level 6: 20x10^7 transduced cells/m^2
3 days of fludarabine 30 mg/m^2/day
3 days of cyclophosphamide 500 mg/m^2/day
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Safety of CD19.CAR T cell administration assessing grade and frequency of toxicities including cytokine release syndrome (CRS) and neurotoxicity according to Common Toxicity Criteria for Adverse Events (CTCAE)
Time Frame: Up to 90 days after CD19.CAR T cell administration
|
Up to 90 days after CD19.CAR T cell administration
|
Feasibility of CD19.CAR T cell manufacturing assessing the number of transduced T cells
Time Frame: Within 45 days prior to CD19.CAR T cell administration
|
Within 45 days prior to CD19.CAR T cell administration
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Prof. Dr. Michael Schmitt, University Hospital Heidelberg, Department V
- Principal Investigator: Prof. Dr. Andreas Kulozik, University Hospital Heidelberg, University Medical Center for Children and Adolescents
Publications and helpful links
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 (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Lymphoma, Non-Hodgkin
- Disease Attributes
- Leukemia, B-Cell
- Lymphoma, B-Cell
- Chronic Disease
- Lymphoma
- Lymphoma, Large B-Cell, Diffuse
- Leukemia
- Lymphoma, Mantle-Cell
- 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
- HD-CAR-1
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
-
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
-
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
-
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 CD19.CAR T Cells
-
Zhejiang UniversityYake Biotechnology Ltd.RecruitingNon-hodgkin Lymphoma,B CellChina
-
Zhejiang UniversityYake Biotechnology Ltd.RecruitingAcute Lymphoblastic Leukemia | Non-hodgkin Lymphoma,B CellChina
-
Zhejiang UniversityYake Biotechnology Ltd.RecruitingVasculitis | Amyloidosis | Autoimmune Hemolytic Anemia | POEMS SyndromeChina
-
Miltenyi Biomedicine GmbHRecruitingB-cell Lymphoma Refractory | B-cell Lymphoma Recurrent | Acute Lymphoblastic Leukemia Recurrent | Chronic Lymphocytic Leukemia Recurrent | Chronic Lymphocytic Leukemia RefractoryGermany
-
Southwest Hospital, ChinaUnknownLymphoma, Large B-Cell, DiffuseChina
-
University College, LondonEnrolling by invitationMultiple MyelomaUnited Kingdom
-
Zhejiang UniversityShanghai YaKe Biotechnology Ltd.Recruiting
-
Miltenyi Biomedicine GmbHNot yet recruiting
-
Shanghai Unicar-Therapy Bio-medicine Technology...The First Affiliated Hospital of Soochow UniversityRecruitingB-cell Acute Lymphocytic LeukemiaChina
-
Sheba Medical CenterUnknownAcute Lymphoblastic Leukemia, B-precursor | Non-Hodgkin Lymphoma, B-cellIsrael