Principal Investigator: Michael Boyer
Keywords: lymphoblastic , luekemia Department: Hematology
IRB Number: 00078083
Specialty: Pediatric Hematology and Oncology, Pediatric Hematology and Oncology
Sub Specialties: Blood and Marrow Transplantation
Recruitment Status: Recruiting

Contact Information

Diana Hernandez

Brief Summary

Study rationale and purpose
Outcome remains poor for patients with r/r pediatric B-cell lineage acute lymphoblastic leukemia (B-cell ALL). Treatment options for r/r B-cell ALL include further treatment with salvage chemotherapy, second allogeneic stem cell transplantation (SCT) or supportive care. Therapy in this population is not curative with an overall survival of 3 to 6 months. As an example, clofarabine was approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients with r/r ALL after at least 2 prior therapeutic regiments. The overall remission rates were 30% for ALL and 38% for Acute Myeloid Leukemia (AML) in Phase I studies (Jeha et al 2004); 30% (20% CR or complete remission with incomplete platelet recovery [CRp] and 10% Partial Remission [PR]) for ALL and 26% for AML in Phase II studies (Jeha et al 2006). The median duration of remission for patients with ALL who achieved at least a partial remission was 9.7 weeks (range 7 to 335 days) in the Phase II study.

CD19 has emerged as an attractive therapeutic target because it is widely expressed on normal and malignant B-cells throughout B-cell maturation but not on pluripotent stem cells or non– B-cell tissues. The development of CAR T cells to target CD19+ cells (CART19 or CTL019) provides an innovative new approach to these malignancies. This approach involves recipient- derived T cells that are genetically modified ex vivo via lentiviral transduction to express a CD19 antigen recognition domain attached to intracellular signaling domains that mediate T- cell activation in an MHC independent manner. Encouraging anti-tumor efficacy has been seen in r/r adult and pediatric ALL and in r/r CLL.

Rationale for the study design
This is a single arm, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with relapsed or refractory B-cell ALL. A single arm study design is supported by the absence of effective therapies in this setting, and high unmet medical needs. This study will enroll approximately 95 patients to allow 50 patients treated. Approximately 14 patients will be enrolled to ensure at least 10 patients are infused with CTL019 manufactured by the Fraunhofer Institute. Approximately, 5 additional Japanese patients will be screened to allow at least 3 additional patients infused with CTL019 manufactured from the US facility (total 5 Japanese patients infused). Sponsor approval will be required to screen more than 5 patients, based on target number of infused patients.After assessment of eligibility, patients qualifying for the study will be enrolled and start lymphodepleting chemotherapy as indicated per protocol, followed by a single dose of CTL019 transduced cells.

Previous clinical data with CTL019 therapy has been generated using cell product manufactured at the Cell and Vaccine Production Facility (CVPF) at the University of Pennsylvania. The current trial will utilize product manufactured by Novartis or designee. In vitro studies assessing the comparability of these two products will have been completed prior to initiation of this protocol. A limited safety run-in stage will be conducted at the beginning of this trial. These patients will be included in the total targeted patient population. The efficacy of CTL019 will be evaluated through the primary endpoint of ORR (ORR = CR + CRi) as determined by Independent Review Committee (IRC) assessment, including CR and CRi. The choice of ORR as the primary endpoint is based on evidence that ORR: 1) Is a standard outcome measurement in ALL; and 2) the established correlation with long-term outcome (Cheson 2003, Appelbaum 2007, NCCN v1 2013).

Rationale for lymphodepletion
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell proliferation (Dummer et al 2002), a recent finding that naive T cells begin to proliferate and differentiate into memory-like T cells when total numbers of naive T cells are reduced below a certain threshold Goldrath 1999, Surh 2000). Host lymphodepletion may enhance the effectiveness of adoptively transferred T cells (Dummer et al 2002). Homeostatic T cell proliferation can lead to activation of certain immune cell subsets (King et al 2004), providing a clue to improved anti-tumor responses. T cells can undergo up to seven rounds of cell division after being deprived of contact with antigen presenting cells (Kaech 2001, van Stipdonk 2001). Lymphodepletion eliminates regulatory T-cells and other competing elements of the immune system that act as “cytokine sinks”, enhancing the availability of cytokines such as IL-7 and IL-15 (Klebanoff et al 2005). This hypothesis has been tested clinically in patients with metastatic melanoma refractory to conventional treatments
(Dudley et al 2002). The patients received a lymphodepleting conditioning regimen consisting of cyclophosphamide (60 mg/kg x 2 days) and fludarabine (25 mg/m2 x 5 days) prior to adoptive transfer of T cells. Patients with myeloma have been treated with CARs and lymphopenia after lymphodepleting chemotherapy, and observed improved engraftment (Laport 2003, Rapoport 2005). In this protocol, it is proposed to infuse CTL019 T cells into patients that are rendered lymphopenic as a result of cytotoxic chemotherapy. Recent data indicates that the increased antitumor efficacy of adoptive transfer following host conditioning is more than simply “making room” because the quantitative recovery of adoptively transferred T cells in mice reveals that in vivo proliferation following adoptive transfer is identical in mice with or without previous irradiation (Palmer et al 2004).

In  ongoing  CTL019  pediatric  ALL studies,  13  out  of  the  first  16  patients  infused  with CTL019 cells received a lymphodepleting conditioning regimen prior to adoptive transfer of T cells.   Six   patients   received   a   lymphodepleting   conditioning   regimen   consisting   of cyclophosphamide and fludarabine, five patients received cyclophosphamide and etoposide, one patient received etoposide and cytarabine and one patient received cyclophosphamide alone. Of the three patients who did not receive a lymphodepleting conditioning regimen, two patients presented with Absolute Lymphocyte Count (ALC) < 1000 at the time of infusion.

Rationale for dose and regimen selection
Animal studies support a threshold dose of CTL019 cells and therefore the initial clinical dose selection was within the range of 1 x 107 to 1 x109 CTL019 transduced cells (Milone et al 2009). Please see IB for further information on preclinical studies. For safety reasons, initial phase I cell dosing was divided among three split infusions (10%, 30% and 60% of the total cell dose). Of the 26 pediatric ALL patients that had a complete remission, 13 patients received a single infusion due to the onset of fevers, yet CRs were observed with either 1 to 3 infusions. In phase I CLL studies, patients have shown responses after a single infusion or multiple infusions. In the phase II CLL trial, the dose has been given as a single infusion of 1 to 5 x 107 or 1 to 5 x 108 CTL019 transduced cells to study dose optimization. This single infusion was clinically well tolerated. No significant differences have been seen in responses or toxicity between these two doses. In responding CLL patients with CR or lasting PR, the CTL019 transduced cell numbers infused have ranged from 1.4 x 107 to 1.1 x 109 cells. From the data collected to date in patients with CLL and ALL, there does not appear to be a discernible dose-response relationship with CTL019 transduced cell numbers infused. This is likely the result of CTL019 transduced cells ability to proliferate and expand extensively (e.g. 1000 to >10,000 fold) in vivo. Thus, the administered dose may underestimate the number of CTL019 cells in vivo following engraftment and expansion and will vary from patient to patient. Additional considerations in this dose selection take into account the manufacturing feasibility of producing adequate numbers of CTL019 transduced cells.

In pediatric ALL patients treated in the CHP959 study, patients received once, two or three CTL019 infusions. Tumor responses were seen with each of these dosing schedules. Nineteen patients received only a single infusion of CTL019 due to the onset of fever with a cell range of 1.1 x 106 to 6.3 x106 CTL019 cells per kg. Therefore this dose range, given s a single infusion of CTL019 cells, is considered safe in paediatric patients, as defined in the protocol. Several patients received total CTL019 cell dose of over 5 x 108 cells (e.g. 6.8, 7.8 and 9.1 x 108 total CTL019 cells). Since the experience with these higher doses is more limited, a cut off of 2.5 x 108 cells as a maximum dose, based upon a weight ≥50 kg, is proposed. At the lower end of this dose range there is concern that doses less than 2 x 106 CTL019 cells/kg have been associated with a lack of response or CR with an early relapse. Therefore based upon safety experience and efficacy
results a dose range of 2 to 5 x106 CTL019 cells/kg was chosen. Manufacturing consideration and practicality were also considered in the dosing selection. Toxicity as assessed by severity of CRS appears to correlate with pre-infusion tumor burden in pediatric ALL but not with transduced CTL019 cell numbers within the range of cell doses studied.
Therefore, the targeted CTL019 cell dose for pediatric ALL patients is 2 to 5 x 106 CTL019 transduced cells per kg body weight with a maximum dose of 2.5 x 108 CTL019 transduced cells (non-weight adjusted). Dose reductions per se are not recommended.

Primary Objective(s) and Key Secondary Objective

To evaluate the efficacy of CTL019 therapy as measured by overall remission rate (ORR), which includes Complete Remission (CR) and CR with incomplete blood count recovery (CRi) as determined by independent review committee (IRC) assessment.

Secondary Objectives

  • Objective 1: To evaluate the percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment.
  • Objective 2: To evaluate the percentage of patients who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment.
  • Objective 3: To evaluate the duration of remission (DOR).
  • Objective 4: To evaluate the percentage of patients who achieve CR or CRi with minimal residual disease (MRD) negative bone marrow.
  • Objective 5: To evaluate the relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS).
  • Objective 6: To evaluate the safety of CTL019 therapy as measured by type, frequency and severity of adverse events and laboratory abnormalities.
  • Objective 7: To characterize the in vivo cellular pharmacokinetic (PK) profile (levels, persistence, trafficking) of CTL019 cells in target tissues (blood, bone marrow, Cerebral Spinal Fluid (CSF), and other tissues if available).
  • Objective 8: To describe the prevalence and incidence of immunogenicity to CTL019




Inclusion Criteria

1.  Relapsed or refractory pediatric B-cell ALL

a.   2nd or greater BM relapse OR

b.  Any BM relapse after allogeneic SCT and must be ≥ 6 months from SCT at the time of CTL019
infusion OR

c.   Primary refractory as defined by not achieving a CR after 2 cycles of a standard chemotherapy regimen  or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapsed leukemia OR

d.  Patients with Ph+ ALL are eligible if they are intolerant to or have failed two lines of TKI
therapy, or if TKI therapy is contraindicated OR

e.   Ineligible for allogeneic SCT because of:

  • Comorbid disease
  • Other contraindications to allogeneic SCT conditioning regimen
  • Lack of suitable donor
  • Prior SCT
  • Declines allogeneic SCT as a therapeutic option after documented discussion about the role of SCT with a BMT physician not part of the study team

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

3.  Adequate organ function defined as:

a.   Renal function defined as:
•    A serum creatinine based on age/gender as follows:
Maximum Serum Creatinine (mg/dL)
Age                                           Male                                                 Female
1 to < 2 years                            0.6                                                   0.6
2 to < 6 years                            0.8                                                   0.8
6 to < 10 years                          1.0                                                   1.0
10 to < 13 years                        1.2                                                   1.2
13 to < 16 years                        1.5                                                    1.4
≥ 16 years                                 1.7                                                   1.4


b.  ALT ≤ 5 times the ULN for age

c.   Bilirubin < 2.0 mg/dl

d.  Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse
oxygenation > 91% on room air

e.   LVSF ≥ 28% confirmed by echocardiogram, or LVEF ≥ 45% confirmed by echocardiogram or MUGA

4.  Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening

5.  Life expectancy > 12 weeks

6.  Age 3 years at the time of screening to age 21 years at the time of initial diagnosis

7.  Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at

8.  Signed written informed consent and assent forms if applicable must be obtained prior to
any study procedures

9.  Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored
apheresis product

10. 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

Pregnant Partners: The consent document indicates that if a female partner of a male participant becomes pregnant while her partner is in this study, the doctor will ask to monitor the pregnancy.  If a pregnant partner needs to be enrolled in this study so that her pregnancy can be followed by the researchers, an Amendment will be submitted to add a "Pregnant Partner Consent & Authorization Document".  The partner will not be enrolled until after the Amendment has been approved by the IRB.”

Exclusion Criteria

  1. Isolated extra-medullary disease relapse
  2. 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.
  3. Patients with Burkitt’s lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)
  4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
  5. Treatment with any prior gene therapy product
  6. Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti- CD19 therapy
  7. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
  8. Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
  9. Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD):
  10. [Retired from Amended Protocol Version 01]
  11. Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible
  12. Patient has an investigational medicinal product within the last 30 days prior to screening
  13. 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
  14. [Retired from Amended Protocol Version 02]
  15. [Retired from Amended Protocol Version 02]
  16. [Retired from Amended Protocol Version 04]
  17. The following medications are excluded:
    a. 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
    b. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CTL019 infusion
    c. 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, mycophenolyate, rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R, systemic steroids)
    d. 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
  • radiation must be completed > 8 weeks prior to CTL019 infusion CNS directed r

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.

18. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using effective methods of contraception for a period of 1 year after the CTL019 infusion. Sexually active women must continue to use contraception for greater than 12 months after the CTL019 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests. Sexually active males must use a condom during intercourse for 12 months after CTL019 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests, as they should not father a child in this period. A condom is required to be used also by vasectomized men (as well as during intercourse with a male partner) as WBCs are a normal part of semen and transmission of CTL019 transduced cells may occur. Effective contraception methods include:

a. 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

b. 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

c. 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.

d. BOTH of the following forms of contraception must be utilized:

i. 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 hormonal vaginal ring or transdermal hormone contraception

ii. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/fil/cream/vaginal suppository

e. 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. Additionally, drugs that induce cytochrome P450 (CYP) enzymes can increase the clearance of sex hormones that are eluted by the IUD and reduce contraceptive efficacy, given the poly-pharmacy for these patients this presents a real risk of IUD failure and resultant contraception.

f. 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 documentationcommunicated by clinician or clinician’s staff of one of the following:

a. Demographics show age <11

b. Physical examination indicates Tanner Stage 1

c. Physician report/letter

d. Operative report or other source documentation in the patient record

e. Discharge summary

f. Follicle stimulating hormone measurement elevated into the menopausal range