Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients
Condition: B-cell Acute Lymphoblastic Leukemia; Relapsed B-cell Acute Lymphoblastic Leukemia; Refractory B-cell Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Intervention: CTL019 T-cells
Intervention description: A target dose of CTL019 transduced cells will consist of a single infusion of 2.0 to 5.0 x 10^6 CTL019 transduced cells per kg body weight (for patients ≤ 50 kg) and 1.0 to 2.5 x 10^8 CTL019 transduced viable T cells (for patients > 50 kg). The following cell dose ranges may be infused if all other safety release criteria are met: 0.2 to 5.0 x 10^6 CTL019 transduced viable T cells per kg body weight (for patient ≤ 50 kg) and 0.1 to 2.5 x 10^8 CTL019 transduced viable T cells (for patients > 50 kg).
Intervention MeSH terms: Tisagenlecleucel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 75.0
Sex: All
Minimum age: 3 Years
Maximum age: 21 Years
Healthy volunteers: No
Keywords: relapsed/refractory; Philadelphia chromosome positive acute lymphoblastic leukemia; Pharmaceuticals; Philadelphia chromosome positive; Acute Lymphoid Leukemia (ALL); Acute Lymphocytic Leukemia (ALL); CTL019; tisagenlecleucel

Summary:

      This was a single arm, open-label, multi-center, phase II study to determine the efficacy and
      safety of an experimental therapy called CTL019 T-cells in pediatric patients with B-cell
      acute lymphoblastic leukemia, who were refractory to standard chemotherapy regimen or
      relapsed after allogeneic stem cell transplant.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Relapsed or refractory pediatric B-cell ALL and lymphoblastic lymphoma:

               1. 2nd or greater Bone Marrow (BM) relapse OR

               2. Any BM relapse after allogeneic SCT and must be > 6 months from SCT at the time
                  of CTL019 infusion OR

               3. Refractory as defined by not achieving a CR after 2 cycles of a standard
                  chemotherapy regimen chemotherapy regimen or chemorefractory as defined by not
                  achieving a CR after 1 cycle of standard chemotherapy for relapse leukemia OR

               4. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are
                  intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI),
                  or if TKI therapy is contraindicated OR

               5. Ineligible for allogeneic SCT

          -  For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral
             blood by flow cytometry within 3 months of study entry

          -  Adequate organ function defined as:

               1. Renal function defined as (Calculated creatinine clearance or radioisotope
                  Glomerular Filtration Rate (GFR) > 60 mL/min/1.73 m2 OR serum creatinine based on
                  age/gender

               2. Alanine Aminotransferase (ALT) <= 5 times the upper limit of normal (ULN) for
                  age;

               3. Bilirubin < 2.0 mg/dL;

               4. Must have a minimum level of pulmonary reserve defined as ≤Grade 1 dyspnea and
                  pulse oxygenation > 91% on room air

               5. Left Ventricular Shortening Fraction (LVSF) ≥ 28% confirmed by echocardiogram, or
                  Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or
                  MUGA within 7 days of screening

          -  Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening

          -  Life expectancy > 12 weeks

          -  Age 3 at the time of screening per protocol to age 21 at the time of initial diagnosis

          -  Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at
             screening

          -  Signed written informed consent and assent forms (if applicable) must be obtained
             prior to any study procedures

          -  Once all other eligibility criteria are confirmed, must have an apheresis product of
             non-mobilized cells received and accepted by the manufacturing site. Note: Apheresis
             product will not be shipped to or assessed for acceptance by the manufacturing site
             until documented confirmation of all other eligibility criteria is received.

          -  Patients with active CNS leukemia involvement defined as CNS-3 by CSF findings only
             are eligible but will have their CTL019 infusion delayed until CNS disease is reduced
             to CNS-1 or CNS-2 by CSF findings. Patients with other forms of active CNS-3 leukemic
             involvement such as CNS parenchymal or ocular disease, cranial nerve involvement or
             significant leptomeningeal disease are not eligible. However, such patients with other
             forms of CNS-3 leukemic involvement (non-CSF involvement) are eligible if there is
             documented evidence of disease stabilization for at least 3 months prior to CTL019
             infusion. Patients must have no acute/ongoing neurologic toxicity > Grade 1 with the
             exception of a history of controlled seizures or fixed neurologic deficits that have
             been stable/improving over the past 3 months.

        Exclusion Criteria:

          -  Isolated extra-medullary disease relapse

          -  Patients with concomitant genetic syndrome: such as patients with Fanconi anemia,
             Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome.
             Patients with Down Syndrome will not be excluded.

          -  Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL,
             leukemia with B-cell [surface Immunoglobulin (sIg) positive and kappa or lambda
             restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)

          -  Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative
             intent and with no evidence of active disease

          -  Prior treatment with gene therapy product

          -  Treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy

          -  Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)

          -  Patient has participated in an investigational research study using an investigational
             agent within the last 30 days prior to screening

          -  Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive
             potential must have a negative serum or urine pregnancy test performed within 48 hours
             before infusion

          -  Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening),
             or any uncontrolled infection at screening

          -  HIV positive test within 8 weeks of screening

          -  The following medications are excluded:

               1. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior
                  to CTL019 infusion. However, the following physiological replacement doses of
                  steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent

               2. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be
                  completed > 6 weeks prior to CTL019 infusion

               3. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks prior
                  to CTL019 infusion to confirm that GVHD recurrence is not observed (e.g.
                  calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolate,
                  rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20
                  (rituximab), anti-tumor necrosis factor [anti-TNF], anti-interleukin 6 [anti-IL6]
                  or anti-interleukin 6 receptor [anti-IL6R], systemic steroids)

               4. Chemotherapy:

          -  Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to CTL019
             infusion

          -  The following drugs must be stopped > 1 week prior to CTL019 infusion and should not
             be administered concomitantly or following lymphodepleting chemotherapy: vincristine,
             6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg/m2, cytosine arabinoside < 100
             mg/m2/day, asparaginase (non-pegylated)

          -  The following drugs must be stopped >2 weeks prior to CTL019 infusion: salvage
             chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines,
             cyclophosphamide, methotrexate ≥ 25 mg/m2), excluding the required lymphodepleting
             chemotherapy drugs

          -  Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion e. CNS
             disease prophylaxis:

          -  CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion (e.g.
             intrathecal methotrexate) f. Radiotherapy:

          -  Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 infusion

          -  CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion g. Anti
             T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g.
             alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic levels
             may destroy the infused CTL019 cells and/or prevent their in vivo expansion. If such
             an agent has been administered within 8 weeks prior to CTL019, contact the Sponsor,
             consider consultation with an pharmacology expert, and consider measuring residual
             drug levels, if feasible, prior to CTL019 infusion Women of child-bearing potential
             (defined as all women physiologically capable of becoming pregnant) and all male
             participants, unless they are using highly effective methods of contraception for a
             period of 1 year after the CTL019 infusion. Highly effective contraception methods
             include:

               1. Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are NOT acceptable methods of
                  contraception

               2. Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
                  taking study treatment. In case of oophorectomy alone, only when the reproductive
                  status of the woman has been confirmed by follow up hormone level assessment

               3. Male sterilization (at least 6 months prior to screening). For female patients on
                  the study the vasectomized male partner should be the sole partner for that
                  patient

               4. Use of oral, injected or implanted hormonal methods of contraception or other
                  forms of hormonal contraception that have comparable efficacy (failure rate <1%),
                  for example hormone vaginal ring or transdermal hormone contraception

               5. Use of IUDs are excluded due to increased risks of infection and bleeding in this
                  population. However, IUD inserted prior to consent may remain in place, and a
                  second method of contraception is mandated

               6. In case of use of oral contraception, women must be stable on the same pill for a
                  minimum of 3 months before taking study treatment.

        Women who are not of reproductive potential (defined as either <11 years of age, Tanner
        Stage 1, post-menopausal for at least 24 consecutive months (i.e. have had no menses) or
        have undergone hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) are
        eligible without requiring the use of contraception. Women who are not yet of reproductive
        potential are to agree to use acceptable forms of contraception when they reach
        reproductive potential if within 1 year of CTL019 or if CAR cells are present in the blood
        by PCR. Acceptable documentation includes written or oral documentation communicated by
        clinician or clinician's staff of one of the following:

          1. Demographics show age < 11

          2. Physical examination indicates Tanner Stage 1

          3. Physician report/letter

          4. Operative report or other source documentation in the patient record

          5. Discharge summary

          6. Follicle stimulating hormone measurement elevated into the menopausal range