| Eligibility |
For B acute lymphoblastic leukemia (ALL)
1. Confirmed diagnosis of relapsed or refractory B-cell ALL of one of the following
types:
- Chemotherapy refractory disease in subjects with B-ALL, defined as progression or
stable disease after one line of therapy.
- Recurrence of disease after achieving CR.
2. Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
cytometry, PCR, FISH, or next generation sequencing) require verification of MRD
positivity on two occasions at least 4 weeks apart.
3. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL)
subjects are eligible if they progressed after receiving a tyrosine kinase inhibitor
(TKI).
4. Subjects with recurrence of isolated CNS relapse after achieving complete remission
(CR); if relapsed with MRD, will require verification of MRD positivity on two
occasions at least 4 weeks apart.
5. CD19 positive expression- CD19 expression is required at any time since diagnosis. If
patient has received anti-CD19 targeted therapy (i.e. Blinatumomab or CD19-CAR T
cells), then CD19 expression must be subsequently demonstrated. CD19 expression may be
detected by immunohistochemistry or by flow cytometry. The choice of whether to use
flow cytometry or immunohistochemistry will be determined by what is the most easily
available tissue sample in each subject. In general, immunohistochemistry will be used
for lymph node biopsies, flow cytometry will be used for peripheral blood and bone
marrow samples.
6. Subjects who have undergone autologous SCT with disease progression or relapse
following SCT are eligible. Subjects who have undergone allogeneic SCT will be
eligible if, in addition to meeting other eligibility criteria, they have elelino
evidence of GVHD and have been without immunosuppressive agents for at least 30 days.
7. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy must be at least
30 days post CAR infusion and may not have eficence of persistnce of CAR T cells in
blood smples (circulating levels of genetically modified cels of >/= 5% by flow
cytometry.
8. Must have evaluable or measurable disease. Lesions that have been previously
irradiated will be considered measurable only if progression has been documented
following completion of radiation therapy.
9. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any
prior systemic therapy at the time the subject is planned for leukapheresis, except
for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5
half-lives.
Exceptions:
1. There is no time restriction with regard to prior intrathecal chemotherapy (incl.
steroids) provided there is complete recovery from any acute toxic effects;
2. Subjects who are on standard ALL maintenance type chemotherapy (vincristine,
6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy
is discontinued at least 1 week or 5 half-lives (whichever is shorter) prior to
apheresis.
3. Subjects receiving steroid therapy at physiologic replacement doses (=5 mg/day of
prednisone or equivalent doses of other corticosteroids) only are allowed
provided there has been no increase in dose for at least 2 weeks prior to
starting apheresis;
4. For radiation therapy: Radiation therapy must have been completed at least 3
weeks prior to apheresis, with the exception that there is no time restriction if
the volume of bone marrow treated is less than 10% and also the subject has
measurable/evaluable disease outside the radiation port.
10. Toxicities due to prior therapy must be stable and recovered to = Grade 1 (except for
clinically non-significant toxicities such as alopecia)
11. Age 18 or older
12. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or
Karnofsky = 60%
13. Normal Organ and Marrow Function (supportive care is allowed per institutional
standards, i.e. filgrastim, transfusion)
1. ANC = 1000/uL*
2. Platelet count = 50,000/uL*
3. Absolute lymphocyte count = 300/uL*
4. Adequate renal, hepatic, pulmonary and cardiac function defined as:
5. Creatinine = 2 mg/dL or creatinine clearance = 60 mL/min
6. Serum ALT or AST = 5x ULN (Elevated ALT/AST associated with leukemia or lymphoma
involvement of the liver will not disqualify a subject; only one value required
for eligibility).
7. Total bilirubin = 1.5 mg/dl, except in subjects with Gilbert's syndrome.
8. Cardiac ejection fraction = 45%, no evidence of physiologically significant
pericardial effusion as determined by an ECHO, MUGA or Cardiac MRI [performed
within 180 days or after most recent anthracycline based treatment or mediastinal
radiation therapy (whichever is most recent)]
9. No clinically significant ECG findings
10. No clinically significant pleural effusion
11. Baseline oxygen saturation > 92% on room air * A subject will not be excluded
because of cytopenia if it is felt by the investigator to be due to underlying
leukemia/lymphoma.
14. Subjects with CNS involvement are eligible as long as there are no overt signs or
symptoms that in the evaluation of the investigator would mask or interfere with the
neurological assessment of toxicity.
15. Females of childbearing potential must have a negative serum or urine pregnancy test
(females who have undergone surgical sterilization or who have been postmenopausal for
at least 2 years are not considered to be of childbearing potential)
16. Subjects of child-bearing or child-fathering potential must be willing to practice
birth control from the time of enrollment on this study and for four (4) months after
receiving the preparative lymphodepletion regimen or 1 month after the last dose of
NKTR_255, whichever is later.
17. Ability to give informed consent. Must be able to give informed consent. Subjects
unable to give informed consent will not be eligible for this study.
=ELIGIBILITY TO RECEIVE NKTR-255=
- Received a CD19/CD22 CAR-T infusion
- No persisting grade =1 CRS or greater than grade 1 fever within 12 hours preceding
NKTR-255 infusion
- No grade 4 CRS within 96 hours preceding NKTR-255 infusion
- No persisting grade = 2 neurotoxicity on the day of NKTR-255 infusion
- No previous grade = 3 neurotoxicity of > 48 hours duration at any time preceding
NKTR-255 infusion
- ANC = 1000/µL
- No intervention with tocilizumab and/or dexamethasone within 48 hours preceding
NKTR-255 infusion
- No active, serious, and uncontrolled infection(s)
- No contraindications according to the PI's assessment
- Life expectancy > 30 days
Exclusion Criteria:
1. History of other malignancy, unless disease free for at least 3 years. At the
discretion of the Principal Investigator, subjects in remission for 1-2 years prior to
enrollment may be deemed eligible after considering the nature of other malignancy,
likelihood of recurrence during one year following CAR therapy, and impact of prior
treatment on risk of CD19/CD22-CAR T cells. Subjects in remission <1 year are not
eligible.
- Exception: Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder,
breast) is eligible.
- Hormonal therapy in subjects in remission >1 year will be allowed.
2. Presence of fungal, bacterial, viral, or other infection that is uncontrolled. Simple
UTI and uncomplicated bacterial pharyngitis are permitted if responding to active
treatment.
3. Known history of infection with any of the following:
- HIV
- Hepatitis B (HBsAg positive)
- Hepatitis C virus (anti-HCV positive) A history of hepatitis B or hepatitis C is
permitted if the viral load is undetectable per quantitative PCR and/or nucleic
acid testing.
4. Presence of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,
cerebellar disease, or any autoimmune disease with CNS involvement that in the
judgment of the investigator may impair the ability to evaluate neurotoxicity.
5. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
other clinically significant cardiac disease within 12 months of enrollment
6. Any medical condition that in the judgement of the investigator is likely to interfere
with assessment of safety or efficacy of study treatment
7. History of severe immediate hypersensitivity reaction to any of the agents used in
this study
8. Women who are pregnant or breastfeeding
9. In the investigator's judgment, the subject is unlikely to complete all
protocol-required study visits or procedures, including follow-up visits, or comply
with the study requirements for participation.
10. Previous treatment with interleukin-2 or interleukin-15.
11. Confirmed diagnosis of relapsed/refractory biphenotypic BT cell ALL
12. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid
arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease
modifying agents within the last 2 years
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