Clinical Trials /

Study of alloCART-19 Cell Therapy in Pediatric Patients With Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

NCT04173988

Description:

The purpose of this study is to evaluate the safety and tolerability of CD19-Directed Allogeneic Chimeric Antigen Receptor T- cell (alloCART-19)therapy in pediatric patients with relapsed/refractory acute lymphoblastic leukemia(ALL).

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of alloCART-19 Cell Therapy in Pediatric Patients With Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
  • Official Title: A Single Center, Open Label, Single Arm Exploratory Clinical Study of CD19-Directed Allogeneic Chimeric Antigen Receptor CART-cell Immunotherapy Cell Therapy in Pediatric Patients With Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 2019-272
  • NCT ID: NCT04173988

Conditions

  • ALL, Childhood B-Cell

Interventions

DrugSynonymsArms
Cyclophosphamideno other intervention namesalloCART-19
Fludarabineno other intervention namesalloCART-19

Purpose

The purpose of this study is to evaluate the safety and tolerability of CD19-Directed Allogeneic Chimeric Antigen Receptor T- cell (alloCART-19)therapy in pediatric patients with relapsed/refractory acute lymphoblastic leukemiaALL).

Detailed Description

      This is a single center, open label, single arm, dose escalation study to explore the safety,
      tolerability, and pharmacokinetic / pharmacodynamic profile of CD19-Directed Allogeneic
      Chimeric Antigen Receptor T- cell (alloCART-19) in pediatric patients with relapsed or
      refractory B-cell acute lymphoblastic leukemia. The study will also assess the preliminary
      efficacy of CD19-Directed Allogeneic Chimeric Antigen Receptor T- cell (alloCART-19). For
      this exploratory clinical trial, approximately 3-6 patients will be enrolled. During dose
      escalation, at least one evaluable patient will be enrolled at each dose level. Once DLT is
      reached, 1 to 3 additional patients will be enrolled at the dose level below DLT, which has
      been tested and determined to be safe in the trial, to evaluate the optimal safe and
      therapeutic dose to be approved by the investigator and sponsor.
    

Trial Arms

NameTypeDescriptionInterventions
alloCART-19ExperimentalFor the very first patient, the initial dose could be administered via one or three intravenous infusions within 1 to 5 days. Starting from the second patient, the investigator will decide whether to use single or multiple alloCART-19 infusions, based on the treatment experience at previous dose level(s) and the patient's baseline disease burdens. A lymphodepletion conditioning with cyclophosphamide and fludarabine will be conducted before alloCART-19 infusion.
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria

          -  Signed informed consent and assent forms if applicable must be obtained prior to the
             start of any research procedure

          -  Age 1 year at the time of screening to age 18 years at the time of initial diagnosis

          -  Relapsed/refractory pediatric ALL that meet one of the following conditions:

               1. Incomplete patients with conventional chemotherapy regimens, or primary
                  refractory patients who failed to complete remission with 2 courses of standard
                  chemotherapy regimen, or did not achieve complete remission after first-line or
                  multi-line salvage chemotherapy

               2. Early recurrence after complete remission (< 12 months) or late recurrence after
                  complete remission (≥ 12 months) and chemotherapy was not completely relieved by
                  the standardized two course induction regimens

               3. Recurrence after autologous or allogeneic hematopoietic stem cell transplantation

          -  Patients who are Philadelphia chromosome-positive (Ph+) are eligible if they have
             failed at least 2 lines of chemotherapy and have failed two lines of TKI therapy or if
             TKI therapy is contraindicated.

          -  For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral
             blood by flow cytometry within 3 months of study entry

          -  Karnofsky performance status of > 60 at screening

          -  During the screening period and within 10 days of treatment, adequate organ function
             defined as:

               1. Renal Function: serum creatinine ≤ 2 x ULN

               2. Liver Function: ALT and/or AST ≤ 10 x ULN (depending on age), bilirubin ≤ 5 x ULN

               3. Pulmonary Function: oxygen saturation ≥ 91%

               4. Heart Function: echocardiogram (ECHO): left ventricular ejection fraction (LVEF)
                  ≥ 45%

          -  Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening or
             immunological/molecular biological results with persistent MRD

          -  Female subjects of childbearing age must have a negative serum or urine pregnancy test
             during the screening period and agree to take effective contraceptive measures during
             the trial period until the last follow-up

        Exclusion Criteria

          -  Pregnant or lactating women

          -  Unable to tolerate venipuncture

          -  Prior history of:

               1. Allogeneic cell therapy (including hematopoietic stem cell transplantation)
                  within 6 weeks of alloCART-19 infusion

               2. Any live vaccine within 4 weeks of alloCART-19 infusion and/or plan to receive
                  live vaccine after enrollment

               3. Immunosuppressants for GvHD treatment within 4 weeks of alloCART-19 infusion

               4. Systemic corticosteroid treatment at doses greater than 5 mg/day prednisone*3
                  days (or equivalent corticosteroids) within 72 hours prior to alloCART-19
                  treatment

               5. Before receiving alloCART-19 treatment, had received the following
                  anti-neoplastic therapies: Tyrosine kinase inhibitors and hydroxyurea within 72
                  hours; Vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg/m2,
                  cytosine arabinoside < 100 mg/m2/day, or asparaginase (non-pegylated) within
                  1-week; Pegylated-asparaginase within 4 weeks; Central nervous system disease
                  prophylaxis (e.g. intrathecal methotrexate) within 1 week; Investigational drug
                  treatment within 4 weeks

               6. Had received the following anti-neoplastic radiotherapy before receiving
                  alloCART-19 treatment: Radiotherapy for non-CNS sites within 2 weeks;
                  Radiotherapy for the CNS site within 8 weeks

          -  Have the following medical history:

               1. Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)

               2. Isolated extramedullary disease recurrence (e.g. central nervous system and
                  testis)

               3. Previous or active central nervous system (CNS) diseases such as seizures,
                  cerebral ischemia/bleeding, dementia, cerebellar disease or any autoimmune
                  disease involving CNS

               4. Previous malignant tumors (excluding curative trends and inactive skin cancer in
                  situ or cervical cancer)

               5. Genetic syndromes associated with bone marrow failure states: such as Fanconi
                  anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow
                  failure syndrome (excluding Down syndrome)

               6. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of
                  screening period)

               7. History of HIV, or HIV-positive test within 8 weeks of screening period

               8. Any uncontrolled serious infection during the screening period

               9. Severe, poorly controlled concomitant diseases such as, but not limited to,
                  nervous system, kidney, liver, endocrine or gastrointestinal disorders that may
                  be deemed by the investigator to interfere with the inclusion of the subject in
                  the study.

              10. Any clinical abnormalities including but not limited to the nervous system,
                  cardiovascular system, blood and lymphatic system, immune system, kidney, liver,
                  gastrointestinal tract, respiratory system, metabolism and bones that may be
                  deemed by the investigator to interfere with the inclusion of a subject in the
                  study.

          -  The following treatments and/or medications must be excluded:

               1. Simultaneous application of other anti-neoplastic drugs, including traditional
                  Chinese herbal medicines

               2. Drugs that prolong the QT interval (including Ia and III antiarrhythmic drugs)

               3. Daily oxygen therapy

               4. long-term use of corticosteroids (except for inhaled and topical use)

          -  Any circumstance or condition that in the judgement of the investigator may interfere
             with the subject's participation in the trial.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity
Time Frame:Day 28 after the first alloCART-19 infusion
Safety Issue:
Description:Dose Limiting Toxicity (DLT) is defined as patients with the adverse event (AE) or laboratory abnormality per Lee DW and Locke FL standards and management guideline, and should be possibly related to alloCART-19 cell therapy, and should be unrelated to the disease itself, disease progression, concomitant diseases or concomitant medication. DLT will be analyzed as categorical variable,coded as 1 for DLT occur, 0 for no DLT.

Secondary Outcome Measures

Measure:The occurrence of adverse events
Time Frame:After the first alloCART-19 infusion for 2 year
Safety Issue:
Description:The adverse events (AE) is a composite variable including liver and kidney function damage, nausea, vomiting, arrhythmia and dyspnea. The variable would be coded as 1 if any of these events occurs after the first alloCART-19 infusion while 0 for none . These adverse events would be measured by assessment scale method according to NCI CTC AE v5.0 classification standard.
Measure:Objective Response Rate
Time Frame:Day 28 and 3 months after the first alloCART-19 infusion
Safety Issue:
Description:Objective Response Rate(ORR)is defined as the proportion of patients whose tumor volume shrank to a predetermined value and the minimum time limit required. ORR = complete remission (CR) + incomplete complete remission (CRi)
Measure:Best Overall Response
Time Frame:Day 28 and 3 months after the first alloCART-19 infusion
Safety Issue:
Description:Best Overall Response(BOR)at 28 days and 3 months after drug infusion was evaluated to preliminarily evaluate the optimal efficacy of alloCART-19 infusion in patients.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Children's Hospital of Fudan University

Trial Keywords

  • Allogeneic CAR-T19

Last Updated

November 20, 2019