Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells With or Without NKTR-255 in Adults With Recurrent or Refractory B Cell Malignancies
Brief Summary: This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy and NKTR-255, and to see how well they work in treating patients with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. Giving CD19/CD22-CAR T cells and chemotherapy in combination with NKTR-255 may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.


Options:
A: Inclusion Criteria:

* Metastatic Melanoma patients failing to prior chemo and immunotherapy with good performance status.

Exclusion Criteria:

* Brain mets
B: 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
C: Inclusion Criteria:

1. Age 18-70.
2. Patients with B-cell lymphoma who are candidates to autologous stem-cell transplantation, including: 1. Primary refractory or relapsed diffuse large B-cell lymphoma in response to salvage treatment. 2. Primary refractory or relapsed follicular lymphoma or other indolent B-cell histology in response to salvage treatment. 3. Chemosensitive mantle-cell lymphoma in first or later line of treatment. 4. Patients with B cell lymphoma (all CD19+ NHL) with progressive or refractory disease who would otherwise not be candidates for autologous stem cell transplantation.
3. Adequate organ function: Renal: Creatinine clearance (as estimated by Cockcroft Gault) \>/= 60 cc/min. Hepatic: ALT/AST \</= 2.5 x ULN or \</= 5 x ULN if documented liver metastases, Total bilirubin \</= 1.5 mg/dL, except in subjects with Gilbert's Syndrome in whom total bilirubin must be \</= 3.0 mg/dL. Cardiac: Cardiac ejection fraction \>/= 50%, no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings. Pulmonary: No clinically significant pleural effusion, Baseline oxygen saturation \> 92% on room air.
4. Patients must have a cord blood unit available which is matched with the patient at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens.
5. Availability of autologous peripheral blood stem cell graft, containing at least 6.0 x 10\^6 CD34+ cells/kg.
6. Performance status \< 2 (ECOG).
7. Negative Beta HCG in woman with child-bearing potential.
8. All participants who are able to have children must practice effective birth control while on study. Acceptable forms of birth control for female patients include: hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor.
9. Signed consent to long-term follow-up protocol PA17-0483.

Exclusion Criteria:

1. Primary CNS lymphoma.
2. Grade \>/= 3 non-hematologic toxicity from prior therapy that has not resolved to \</= G1.
3. Prior whole brain irradiation.
4. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA \>/= 10,000 copies/mL, or \>/= 2,000 IU/mL).
5. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
6. Active infection requiring parenteral antibiotics.
7. HIV infection.
8. Radiation therapy in the month prior to enroll.
9. Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management. Note: Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
10. Concomitant use of other investigational agents.
D: Inclusion Criteria:

* Patient´s written informed consent
* ≥ 18 years of age; male and female
* Confirmed CLL, low grade NHL or high grade NHL on standard histological or immunophenotypical criteria described in the WHO classification of lymphoid malignancies
* CD20 positivity (if not already confirmed)
* Adequate haematological, liver and kidney functions
* Platelet count ≥25,000mm³ (=25 x 10\^9/l)
* Patients with active disease (relapsed/refractory) that survived at least 60 days after allogeneic transplantation
* Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (Appendix IV)
* Negative pregnancy test (no more than 2 days before enrolment) and adequate contraception during the study in women of child bearing potential (pre- menopausal, \<2 years post-menopausal or not surgically sterile)

Exclusion Criteria:

* Any anti-CD20 and / or any other anti-T cell directed antibody treatments \< 3 months before application of FBTA05
* Positivity for human anti-mouse antibodies (HAMAs)
* History of GvHD ° III or IV, or GvHD requiring steroid therapy with more than 10 mg/day
* Known or suspected hypersensitivity to recombinant, murine or rat proteins
* AST/SGOT greater than 10 x ULN (grade 3, CTCAE)
* Bilirubin greater than 5 x ULN (grade 3, CTCAE)
* Creatinine greater than 3.5 mg/dl (grade 3, CTCAE)
* Acute or uncontrolled chronic infections, viral infections at risk of reactivation (e.g.HCV, HBV, HIV)
* Unable or unwilling to comply fully with the protocol
* Any condition which in the judgement of the Investigator would place the subject at undue risk or interfere with the results of the study

Answer: B