Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

Inclusion criteria

• Relapsed or refractory pediatric B-cell ALL and lymphoblastic lymphoma:

• 2nd or greater Bone Marrow (BM) relapse OR
• Any BM relapse after allogeneic SCT and must be > 6 months from SCT at the time of CTL019 infusion OR
• 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
• 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
• 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:

• 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
• Alanine Aminotransferase (ALT) <= 5 times the upper limit of normal (ULN) for age;
• Bilirubin < 2.0 mg/dL;
• Must have a minimum level of pulmonary reserve defined as ≤Grade 1 dyspnea and pulse oxygenation > 91% on room air
• 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:

• 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
• Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CTL019 infusion
• 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)
• 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:

• 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
• 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
• 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
• 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
• 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
• 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:

• Demographics show age < 11
• Physical examination indicates Tanner Stage 1
• Physician report/letter
• Operative report or other source documentation in the patient record
• Discharge summary
• Follicle stimulating hormone measurement elevated into the menopausal range