CCTL019B2205J for Pediatric Patients with ALL

Principal Investigator: Michael Boyer
Keywords: Leukemia Department: Hematology
IRB Number: 00076874 Co Investigator:  
Specialty: Pediatric Hematology and Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Diana Hernandez
diana.hernandez@hsc.utah.edu
801-662-5352

Brief Summary

Primary 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, CSF, and other tissues if available)

Objective 8: To describe the prevalence and incidence of immunogenicity to CTL019

 

 

Inclusion Criteria

1. [Retired from UPenn protocol version 2.0]

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:

i. Calculated creatinine clearance or radioisotope GFR > 60 mL/min/1.73 m2 OR

ii. A serum creatinine based on age/gender as listed in Section 5.2

          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 within 7 days of screening

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

5.  Life expectancy > 12 weeks

6.  [Retired from UPenn protocol version 2.0]

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

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

9.  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 Note: Leukapheresis product will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other eligibility criteria is received

10. Relapsed or refractory pediatric B-cell Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

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 relapse 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
 2. Other contraindications to allogeneic SCT conditioning regimen
 3. Lack of suitable donor
 4. Prior SCT
 5. Declines allogeneic SCT as a therapeutic option after documented discussion, including expected outcomes, about the role of SCT with a BMT physician not part of the study team
 
11. Age 3 at the time of screening to age 21 at the time of initial diagnosis.
12. 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

1. Isolated extra-medullary disease relapse

 

2. Patients with concomitant genetic syndromes associated with bone marrow failure states: 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. Prior treatment with gene therapy product

 

6. Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy

 

7. [Retired from UPenn protocol version 2.0]

 

8. [Retired from UPenn protocol version 2.0]

 

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

 

10. [Retired from UPenn protocol version 2.0]

 

11. [Retired from Amended Protocol Version 02]

 

12. Patient has participated in an investigational research study using an investigational agent 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 UPenn protocol version 2.0]

 

15.  Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening

 
16. HIV positive test within 8 weeks of screening
 
17. [Retired from Amended Protocol Version 02]
 
18. [Retired from Amended Protocol Version 02]
 
19. 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-tumor necrosis factor [anti-TNF], anti-interleukin 6 [anti-IL6] or antiinterleukin
6 receptor [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
 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

20. 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:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation
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
a. 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 c. 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
d. Use of intrauterine devices (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
e. 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:
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