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CAR T-cell Therapy

CAR T-Cell Therapy for Leukemia

Phase 1

Waitlist Available

Led By David Miklos

Research Sponsored by Crystal Mackall, MD

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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; 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; Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL) subjects are eligible if they progressed after receiving a tyrosine kinase inhibitor (TKI); 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; 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; 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; 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; 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; 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: There is no time restriction with regard to prior intrathecal chemotherapy (incl. steroids) provided there is complete recovery from any acute toxic effects; 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; 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; 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; Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia); Age 18 or older; Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or Karnofsky ≥ 60%; Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion); ANC ≥ 1000/uL*; Platelet count ≥ 50,000/uL*; Absolute lymphocyte count ≥ 300/uL*; Adequate renal, hepatic, pulmonary and cardiac function defined as: Creatinine ≤ 2 mg/dL or creatinine clearance ≥ 60 mL/min; 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); Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome; 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)]; No clinically significant ECG findings; No clinically significant pleural effusion; 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; 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; 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); 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; 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

- Received a CD19/CD22 CAR-T infusion

Must not have

- HIV

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 15 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new cancer treatment involving genetically-engineered immune cells and chemotherapy. The goal is to see if the treatment is effective and has manageable side effects.

Who is the study for?

Adults with recurrent or resistant B-cell acute lymphoblastic leukemia (B-ALL), including those with Philadelphia Chromosome positive ALL who've failed tyrosine kinase inhibitor therapy. Participants must have CD19 expression, be at least 18 years old, and have adequate organ function. They should not have received certain treatments recently and must agree to contraception.

What is being tested?

The trial is testing the effectiveness of combining CAR T-cell therapy targeting CD19/CD22 with chemotherapy drugs cyclophosphamide and fludarabine phosphate, alongside NKTR-255, a drug designed to enhance the immune system's cancer-fighting abilities.

What are the potential side effects?

Potential side effects include reactions related to immune cell infusion such as fever and fatigue, organ inflammation due to autoimmune responses, blood count changes leading to increased infection risk, neurological issues like confusion or seizures, and general discomfort from chemotherapy.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have received a CD19/CD22 CAR-T cell therapy infusion.

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My leukemia is a type of B-cell ALL that has come back or didn't respond to treatment.

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I am on maintenance chemo for ALL but can stop it 1 week or 5 half-lives before apheresis.

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I am on a low dose of steroids (≤5 mg/day of prednisone or equivalent) and haven't increased the dose in the last 2 weeks.

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I can take care of myself but may not be able to do heavy physical work.

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My kidney function is normal or only slightly impaired.

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I haven't had a fever or severe side effects in the last 12 hours.

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My leukemia has worsened despite taking a TKI medication.

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My B-ALL cancer did not respond to my first chemotherapy treatment.

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My cancer has come back after it was completely gone.

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I am 18 years old or older.

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I do not have ongoing severe nerve damage.

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I do not have any serious or uncontrolled infections.

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I have never had severe nerve damage symptoms for more than 48 hours before.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am HIV positive.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 15 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 15 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 15 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells

Maximum tolerated dose of CD19/CD22 chimeric antigen receptor (CAR) T cells defined as the dose level immediately below the level at which the enrollment is stopped due to a dose limiting toxicity

Rate of successful manufacture and expansion of the CD19/CD22 chimeric antigen receptor (CAR) T cells to satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis

Secondary study objectives

Overall survival

Progression free survival

The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells

Other study objectives

Alterations in early B cell development induced by immune pressure exerted via CD19/CD22 chimeric antigen receptor (CAR) T cells

CD19/CD22 chimeric antigen receptor (CAR) T cell properties

Establish the utility of chromatin structure and epigenomic technology to characterize chimeric antigen receptor (CAR) T cell therapies

+4 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)Experimental Treatment6 Interventions

Patients receive cyclophosphamide IV over 60 minutes and fludarabine phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22 CAR T cells IV over 10-20 minutes on day 0. On Day 14 after CAR-T, eligible patients will be given NKTR-255 IV over 30 minutes, and it will be repeated every 28 days for up to 6 cycles. Patients that benefited from the first dose of CD19/CD22 CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22 CAR T cells.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cyclophosphamide

2010

Completed Phase 4

~2310

NKTR-255

2020

Completed Phase 2

~60