Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma
|First Received Date ICMJE||May 5, 2012|
|Last Updated Date||August 29, 2014|
|Start Date ICMJE||April 2012|
|Estimated Primary Completion Date||January 2020 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Safety & amp; Feasibility [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
||To determine the safety and feasibility of administering escalating doses of anti- CD19-CAR engineered peripheral blood lymphocytes in two strata prior allogeneic stem cell transplant ASCT vs. no prior ASCT in children plus young adults with B c...|
|Change History||Complete list of historical versions of study NCT01593696 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma|
|Official Title ICMJE||Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies|
- Although progress has been made in treating children with B-cell cancers such as leukemia or lymphoma, many children do not respond to the standard treatments. One possible treatment involves collecting white blood cells called T cells from the person with cancer and modifying the cells to attack the B-cell cancer. The cells can then be given back to the participant. This study will use T cells that have been modified to attack the CD19 protein, which is found on the surface of some B-cell cancers.
- To see if anti-CD19 modified white blood cells are a safe and effective treatment for children and young adults with advanced B-cell cancer.
Chimeric antigen receptors (CAR) that recognize the CD19 antigen have been constructed and are in clinical trials at several institutions. In this trial, the POB will utilize a chimeric receptor containing the signaling domains of CD28 and CD3-zeta, currently under study in the CCR in adults, for children and young adults with CD19 expressing malignancies.
In co-cultures with CD19-expressing acute lymphoblastic leukemia cells, anti-CD19-CAR-transduced T cells show robust killing, and in xenograft models, can rapidly clear CD19- expressing ALL cell lines.
Patients 1-30 years of age, at least 15 kg, with a CD19-expressing B-cell malignancy that has recurred after or not responded to one or more standard chemotherapy-containing regimens for their malignancy and is deemed incurable by standard therapy. Patients with a history of allogeneic stem cell transplant who meet all eligibility criteria are eligible to participate.
Arm 1: Patients will begin preparative regimen comprising fludarabine 25 mg/m2 on Days 4, 3 and 2 and cyclophosphamide 900 mg/m2 on day 2.
Arm 2: Patients with high-disease burden will be treated with intensive standard of care chemotherapy to decrease disease burden during cell manufacturing.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Biological: Anti-CD19- CAR
Cells extracted, followed by induction chemotherapy before CD19-CAR infusion (dose escalation.)
|Study Arm (s)||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||48|
|Estimated Completion Date||January 2020|
|Estimated Primary Completion Date||January 2020 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
2.2.1- Patient must have a CD19-expressing B cell ALL or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy and one salvage regimen. In view of the PI and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have disease activity that prohibits SCT at this time.
2.2.2 - CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 30% by flow cytometry in a CLIA approved test in the Laboratory of Pathology, CCR, NCI, NIH or from the referring institution or reference laboratory. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. In general immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples.
2.2.3 - Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
2.2.4 - Greater than or equal to 1 year of age (and at least 15 kg) and less than or equal to 30 years of age.
2.2.5 - Adequate absolute CD3 count estimated to be required to obtain target cell dose based on discussion with DTM apheresis and Cell Processing Section, DTM.
2.2.6 - Subjects with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:
220.127.116.11 CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs;
18.104.22.168 CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm
22.214.171.124 CNS3 with marrow disease who has failed salvage systemic and intensive IT chemotherapy (and therefore not eligible for radiation)
126.96.36.199 Patients with isolated CNS relapse will be eligible if they have previously been treated with cranial radiation (at least 1800 cGy).
2.2.7- Ability to give informed consent. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
2.2.8 - Clinical performance status: Patients > 10 years of age: Karnofsky greater than or equal to 50%; Patients less than or equal to 10 years of age: Lansky scale greater than or equal to 50% (see Appendix A in Section 12.1 for conversion). Subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
2.2.9 - Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
2.2.10 - Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.
2.2.11 - Cardiac function: Left ventricular ejection fraction is greater than or equal to 40% by MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by ECHO or left ventricular ejection fraction greater than or equal to 50% by ECHO.
2.2.12 - Patients with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active GVHD (See Appendix C in Section 12.3) and no longer taking immunosuppressive agents for at least 30 days prior to enrollment.
Subjects meeting any of the following criteria are not eligible for participation in the study:
2.3.1 - Recurrent or refractory ALL limited to isolated testicular disease.
2.3.2 - Hepatic function: Inadequate liver function defined as total bilirubin > 2x upper limit of normal (ULN) (except in the case of subjects with documented Gilbert s disease > 3x ULN) or transaminase (ALT and AST) > 5x ULN based on age- and laboratory specific normal ranges;
2.3.3 - Renal function: Greater than age-adjusted normal serum creatinine (see Table below) and a creatinine clearance < 60 mL/min/1.73 m2.
Age (Years) Maximum Serum Creatinine (mg/dL)
less than or equal to 5 0.8
5< age less than or equal to 10 1.0
> 10 1.2
2.3.4 - Hematologic function:
2.3.5 - Hyperleukocytosis ( (Bullet) 50,000 blasts/ L) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy;
2.3.6 - Pregnant or breast-feeding females;
2.3.7 - Recent prior therapy:
188.8.131.52 Systemic chemotherapy less than or equal to 2 weeks (6 weeks for nitrosoureas) or radiation therapy less than or equal to 3 weeks prior to apheresis; Exceptions:
184.108.40.206 Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (i.e. start of protocol therapy);
220.127.116.11 Subjects must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion.
2.3.8 - HIV/HBV/HCV Infection:
2.3.9 - Monoclonal antibody therapy administered within 30 days of the agent prior to apheresis;
2.3.10 - Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject;
2.3.11 - Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission;
2.3.12 - History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells (i.e. gentamicin);
|Ages||1 Year to 30 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01593696|
|Other Study ID Numbers ICMJE||120112, 12-C-0112|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )|
|Study Sponsor ICMJE||National Cancer Institute (NCI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||August 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP