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CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Children or Young Adults With Recurrent or Refractory CD19 Positive B Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT03241940
Recruitment Status : Recruiting
First Posted : August 8, 2017
Last Update Posted : December 20, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Crystal Mackall, MD, Stanford University

Brief Summary:
This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating children or young adults with B acute lymphoblastic leukemia.

Condition or disease Intervention/treatment Phase
B Acute Lymphoblastic Leukemia CD19 Positive Minimal Residual Disease Philadelphia Chromosome Positive Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Refractory Acute Lymphoblastic Leukemia Biological: Chimeric Antigen Receptor T-Cell Therapy Drug: Cyclophosphamide Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Other: Questionnaire Administration Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established release criteria.

II. Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells that meet established release specifications in children and young adults with hematologic malignancies following a cyclophosphamide/fludarabine phosphate (fludarabine) conditioning regimen.

SECONDARY OBJECTIVES:

I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with B-acute lymphoblastic leukemia (ALL).

TERTIARY OBJECTIVES:

I. Analyze alterations in early B cell development induced by immune pressure exerted via CD19/CD22-CAR T cells.

II. Evaluate whether subjects receiving CD19/CD22-CAR T cells relapse with loss or diminished expression of CD19 and/or CD22, when feasible.

III. Measure persistence of CD19/CD22-CAR T cells in the blood, bone marrow and cerebral spinal fluid (CSF), and explore correlations between CD19/CD22-CAR T cell properties and CAR T cell efficacy and persistence.

IV. Establish the utility of chromatin structure and epigenomic technology to characterize CAR T cell therapies.

V. Explore the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with refractory B cell lymphoma in a non-statistical cohort due to expectations of low accrual.

OUTLINE: This is a dose-escalation study of CD19/CD22-CAR T cells.

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.

After completion of study treatment, patients are followed up daily until day 14, twice weekly until day 28, at 2 and 3 months, every 3 months until month 12, every 6-12 months up to year 5, and then annually for years 6-15.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies
Actual Study Start Date : October 20, 2017
Estimated Primary Completion Date : August 1, 2025
Estimated Study Completion Date : August 1, 2035


Arm Intervention/treatment
Experimental: Treatment (CD19/CD22-CAR T cells, chemotherapy)
Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.
Biological: Chimeric Antigen Receptor T-Cell Therapy
Given CD19/CD22-CAR T cells IV
Other Name: CAR T-cell therapy

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 28 days ]
    Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.

  2. Rate of successful manufacture and expansion of the CD19/CD22 chimeric antigen receptor (CAR) T cells to satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis (COA) [ Time Frame: 10-14 days after apheresis or thawing of cryopreserved peripheral blood mononuclear cell ]
    The number of subjects which can successfully manufacture the targeted dose number will be determined for each dose cohort.


Secondary Outcome Measures :
  1. The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 15 years ]
    Will be assessed by the Response Criteria for Lymphoma and the Response Criteria for Acute Lymphoblastic Leukemia.


Other Outcome Measures:
  1. Alterations in early B cell development induced by immune pressure exerted via CD19/CD22-CAR T cells [ Time Frame: Up to 15 years ]
    Will be analyzed.

  2. CD19/CD22 chimeric antigen receptor (CAR) T cell properties [ Time Frame: Up to 15 years ]
    Will explore correlations with CAR T cell efficacy and persistence.

  3. Frequency of CD22+ expression on lymphoma cells [ Time Frame: Up to 15 years ]
    Will determine site density when possible.

  4. Persistence of CD19/CD22 chimeric antigen receptor (CAR) T cells blood, bone marrow, and cerebral spinal fluid (CSF) [ Time Frame: Up to 15 years ]
    Will be measured.

  5. Relapse with loss or diminished expression of CD19 and/or CD22 [ Time Frame: Up to 15 years ]
    Will be evaluated when feasible.



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Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

1.1 INCLUSION CRITERIA

  1. Diagnosis: ALL In view of the PI and the primary oncologist, there must be no available alternative curative therapies or subject has declined to pursue alternative therapy; and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits SCT at the time of enrollment.

    1. Chemotherapy refractory disease in subjects with B-ALL is defined as progression or stable disease after two lines of therapies
    2. Recurrence of disease after achieving a complete response (CR).
    3. Subjects with persistent or relapsed minimal residual disease (MRD) (by flow cytometry, PCR, FISH, or next generation sequencing) require verification of MRD positivity on two occasions at least 4 weeks apart.
    4. 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).
    5. Subjects with recurrence of isolated CNS relapse after achieving complete remission (CR); if relapsed with MRD, will require verification of MRD positivity on two occasions at least 4 weeks apart.
  2. Diagnosis: Lymphoma Subjects with lymphoma must have progressed, had SD, or recurred after initial treatment regimens that include an anthracycline and an anti CD20 monoclonal antibody. Subjects who relapse ≥12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant.
  3. CD19 expression CD19 expression is required at any time since diagnosis. If patient has received anti-CD19 targeted therapy (i.e. Blinatumomab), then CD19 expression must be subsequently demonstrated. CD19 expression. must be detected on greater than 50% of the malignant cells by immunohistochemistry or ≥ 90% by flow cytometry. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each subject. In general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples.
  4. Subjects who have undergone autologous SCT with disease progression or relapse following SCT will be eligible if all other eligibility criteria are met. Subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they are at least 100 days post-transplant, they have no evidence of active GVHD and have been without immunosuppressive agents for at least 30 days.
  5. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy will be eligible if < 5% of circulating levels of CD3+ cells express the previous CAR by flow cytometry.
  6. Must have evaluable or measurable disease; subjects with lymphoma must have evaluable or measurable disease according to the revised IWG Response Criteria for Malignant Lymphoma[66] must be present. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
  7. 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.

    Exceptions:

    f. There is no time restriction with regard to prior intrathecal chemotherapy (incl. steroids) provided there is complete recovery from any acute toxic effects of such; g. Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis; h. Subjects who are on standard ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy is discontinued at least 1 week prior to apheresis.

    i. Subjects receiving steroid therapy at physiologic replacement doses (≤ 5 mg/day of prednisone or equivalent doses of other corticosteroids) only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis; j. For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port.

  8. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities, such as alopecia, nutritional support measures, electrolyte abnormalities, or those not impacting the investigator's ability to assess treatment emergent toxicities)
  9. Age Greater than or equal to 1 year of age and less than or equal to 30 years of age at time of enrollment; must meet parameters for apheresis per institutional guidelines. NOTE: The first subject in the first dose cohort must be ≥ 18 years of age if an adult has not been treated at that dose cohort on the companion Stanford protocol "Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Adults with Recurrent or Refractory B Cell Malignancies" and undergone safety evaluation at Day 28 without evidence of DLT.
  10. Performance Status: Subjects > 10 years of age: Karnofsky ≥ 50%; Subjects ≤ 10 years of age: Lansky scale ≥ 50% (See Appendix B Section 14.2)
  11. Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)

    1. ANC ≥750/uL*
    2. Platelet count ≥50,000/uL*
    3. Absolute lymphocyte count ≥150/uL*
    4. Adequate renal, hepatic, pulmonary and cardiac function defined as:

      • Serum ALT/AST ≤10 ULN (unless elevated ALT/AST is attributed to leukemia or lymphoma involvement of the liver, in which case this criterion will be waived and not disqualify a patient).
      • Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome.
      • Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, and no clinically significant ECG findings
      • No clinically significant pleural effusion
      • Baseline oxygen saturation >92% on room air at rest
      • creatinine: within age adjusted normal institutional limits (see table below) OR
      • creatinine clearance ≥60 mL/min/1.73 m2 (as estimated by Cockcroft Gault Equation) for subjects with creatinine levels above institutional normal.

    Age (Years) Maximum Serum Creatinine (mg/dL)

    ≤5 0.8 5 < age ≤ 10 1.0 >10 1.2

    * if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia ≥ Grade 3 if it is due to disease, based on the results of bone marrow studies.

  12. CNS Status

    1. Subjects with ALL

      Subjects with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

      • CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs;
      • CNS 2, defined as presence of < 5/µL WBCs in CSF and cytospin positive for blasts, or > 5/µL WBCs but negative by Steinherz/Bleyer algorithm:

        • CNS 2a: <10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;
        • CNS 2b: ≥10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;
        • CNS 2c: ≥10/µL RBCs; ≥5/µL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.
    2. Subjects with lymphoma

    Subjects must have no signs or symptoms of CNS disease or detectable evidence of CNS disease on MRI at the time of screening. Subjects who have previously been treated for CNS disease and who have the following CNS status will be eligible:

    • CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs;
    • CNS 2, defined as presence of < 5/µL WBCs in CSF and cytospin positive for blasts, or > 5/µL WBCs but negative by Steinherz/Bleyer algorithm:

      • CNS 2a: < 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;
      • CNS 2b: ≥ 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;
      • CNS 2c: ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.
  13. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
  14. Contraception Subjects 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 (4) months after receiving the preparative regimen.

    Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous/unknown effects on the fetus.

  15. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give informed consent. For subjects <18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate.

1.2 EXCLUSION CRITERIA

Subjects meeting any of the following criteria are not eligible for participation in the study:

  1. Recurrent or refractory ALL limited to isolated testicular.
  2. Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of ≥ 5/µL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia).
  3. Hyperleukocytosis (≥ 50,000 blasts/µL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy.
  4. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years.
  5. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.

    Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study will pose unacceptable risk. A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.

  6. CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that in the judgment of the investigator may impair the ability to evaluate neurotoxicity.
  7. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment, or have cardiac atrial or cardiac ventricular lymphoma involvement.
  8. Subjects receiving anticoagulation therapy.
  9. Any medical condition that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of study treatment
  10. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  11. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the conditioning lymphodepletion chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential.
  12. In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

May not have primary immunodeficiency or history of systemic autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03241940


Contacts
Contact: Anne Marcy 650-721-9994 acmarcy@stanford.edu

Locations
United States, California
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Anne Marcy    650-721-9994    acmarcy@stanford.edu   
Principal Investigator: Crystal L. Mackall         
Sponsors and Collaborators
Crystal Mackall, MD
National Cancer Institute (NCI)
Investigators
Principal Investigator: Crystal Mackall Stanford University

Responsible Party: Crystal Mackall, MD, Professor of Pediatrics, Stanford University
ClinicalTrials.gov Identifier: NCT03241940     History of Changes
Other Study ID Numbers: PEDSCCT5007
NCI-2017-01415 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PEDSCCT5007 ( Other Identifier: Stanford Cancer Institute )
P30CA124435 ( U.S. NIH Grant/Contract )
First Posted: August 8, 2017    Key Record Dates
Last Update Posted: December 20, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Philadelphia Chromosome
Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Neoplastic Processes
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites