Acute Lymphoblastic Leukemia, Large B-cell Lymphoma
Conditions
Keywords
ALL, CAR-T, CAR19-T, chimeric antigen receptor T cells
Brief summary
This is a phase II study of FDA-approved CAR-T products for patients with hematologic malignancies. Patients will be assigned to Arm A and B based on age and diagnosis. Overall remission rate, safety events and other endpoints will be calculated for Arm A and B separately.
Interventions
DRUGYESCARTA
CD19-directed genetically modified autologous T cell immunotherapy
DRUGFludarabine 30mg/m2 4 doses
30 mg/m2 IV daily for 4 doses
DRUGCyclophosphamide 500 mg/m2; 2 doses
500 mg/m2 IV daily for 2 doses starting with the first dose of fludarabine
DRUGKYMRIAH
FDA approved CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells
DRUGFludarabine 30mg/m2 3 doses
30 mg/m2 IV daily for 3 doses
DRUGCyclophosphamide 500 mg/m2; 3 doses
500 mg/m2 IV daily for 3 doses starting with the first dose of fludarabine
DRUGFludarabine 25mg/m2 3 days
25 mg/m2 i.v. daily for 3 days
DRUGCyclophosphamide 250 mg/m2; 3 days
250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine
DRUGTecartus
TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells
DRUGAbecma, Intravenous Suspension
Infuse ABECMA 2 days after completion of lymphodepleting chemotherapy.
DRUGCyclophosphamide 900 mg/m2; 1 day
Administer cyclophosphamide 900 mg/m2 over 60 minutes on the second day before infusion of TECARTUS
DRUGBreyanzi Injectable Product
Infuse BREYANZI 2 to 7 days after completion of lymphodepleting chemotherapy.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
ARM A (Kymriah) and Arm G (Tecartus) :Refractory/relapsed B-cell acute lymphoblastic leukemia expressing CD19 Inclusion Criteria: * Age and Disease Status * Must be age 0-25 years (for Arm A Kymriah) or \>18 years (Arm G Tecartus) * Disease status: Relapsed and refractory pediatric B-cell ALL defined by one of these: * Primary induction failure with no complete remission after ≥2 cycles of induction chemotherapy, or * Patients with persistent minimal residual disease (MRD \>0.01% by flow cytometry or persistent by cytogenetic or molecular assays) after ≥2 cycles of consolidation chemotherapy, or * Patients in 2nd or greater relapse of B-ALL or * Patients with persistent CNS leukemia, or * Down Syndrome or other congenital diseases assuming that they fit the criteria for second or greater relapse or refractory leukemia, or * Patients with Ph+ ALL are eligible if theywho have failed or are intolerant to two lines of TKI assuming they fit the criteria for second or greater relapse or are considered refractory. * Performance Status \* Arm A: Karnofsky (age ≥16 years) or Lansky (age \< 16 years) performance status ≥ 50% at screening; Arm G: ECOG 0, 1 or 2 * Organ Function * Renal function defined as: * A serum creatinine of ≤1.5 x ULN OR * eGFR ≥ 50 mL/min/1.73 m2 * Liver function defined as: \*\* ALT ≤ 5 times the ULN for age (unless due to disease) \*\* Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation SpO2 \> 91% on room air * Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA * Other Inclusion Criteria * Life expectancy ≥12 weeks * Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use adequate birth control for the duration of treatment. * Written voluntary consent (adults) or parental/guardian consent (minors or adults with diminished capacity) prior to the performance of any research related tests or procedures.
Exclusion criteria
* Pregnant or breastfeeding - Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. * 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) * CNS 2A * CAR-T is not indicated for the treatment of patients with primary central nervous system lymphoma. * Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 2 weeks prior to apheresis. * Uncontrolled active hepatitis B or hepatitis C * Active HIV infection * Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion) * Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion * Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion * Intolerance to the excipients of the CAR-T cell product * Any immunosuppressive medication must be stopped ≥ 2 weeks prior to enrollment. * Patient has taken one of the prohibited concomitant medications within the timeframe outlined in section 6.1 ARM B: Yescarta for Relapsed or Refractory diffuse large B cell lymphoma Inclusion Criteria: * Age and Disease Status * Adult patients (age ≥ 18 years)Patients must be ≥18 years of age * One of the following histologies and expression of CD19 by tumor cells: \*\* diffuse large B-cell lymphoma (DLBCL) not otherwise specified, or \*\* primary mediastinal large B-cell lymphoma, or \*\* high grade B-cell lymphoma, or \*\* DLBCL arising from follicular lymphoma * Disease status: \*\* Chemotherapy refractory disease after ≥2 lines of chemotherapy, or \*\* Relapsed with no remission after ≥1 lines of salvage chemotherapy, or \*\* Relapsed following autologous HCT (and failed at least 2 prior lines of therapy including high dose chemotherapy). If salvage therapy is given post autoHCT, the subject must have no response or relapse after the last line of therapy * Measurable disease at time of apheresis: Nodal lesions or extranodal lesion * ECOG performance status 0-2 * ALC \>/=100/uL at screening (prior to apheresis) * Renal function defined as: \*\* A serum creatinine of ≤1.5 x ULN OR \*\* eGFR ≥ 50 mL/min/1.73 m2 * Liver function defined as: * ALT ≤ 5 times the ULN for age (unless due to disease) * Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation SpO2 \> 91% on room air * Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA * Adequate bone marrow reserve (unless marrow infiltrated by disease) defined as : * Absolute neutrophil count (ANC) \> 1.000/mm3 (only for NHL) * Platelets ≥ 50.000/mm3 (transfusion support can be provided) * Hemoglobin \>8.0 mg/dl (transfusion support can be provided) * Life expectancy ≥12 weeks * Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use adequate birth control for the duration of treatment. * Written voluntary consent (adults) or parental/guardian consent (minors or adults with diminished capacity) prior to the performance of any research related tests or procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arms B & C&D& E&F: Overall Response Rate (ORR) | Day 100 | ORR defined by complete response + partial response by Lugano |
| Arm A & E: MRD-negative CR (or CRi) | Day 28 | Percentage of patients with MRD-negative Complete Response CR (or CRi) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Developing Grade 3 or 4 ICANS | Day 28 | Percentage of patients developing grade 3 or 4 ICANS |
| Treatment Related Mortality (TRM) | Day 28 | Incidence of treatment related mortality (in absence of disease relapse/progression) |
| Relapse-free Survival (RFS) | 1 year | Incidence of Relapse-free Survival (RFS) |
| Event-Free Survival (EFS) | 1 Year post treatment | Incidence of event-free survival (EFS) from the date of the CAR-T infusion through 1 year post treatment |
| Overall Survival (OS) | 1 year | Incidence of Overall Survival (OS) from the date of the CAR-T infusion through the date of patient death for any reason. |
| Overall Toxicity | Day 28 | Percentage of patients with grade 3 or 4 targeted toxicity of CRS and/or neurotoxicity |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORVeronika Bachanova, MD, PhD
Masonic Cancer Center, University of Minnesota
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 57 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) White | 133 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 3 / 44 | 0 / 30 | 1 / 7 | 2 / 13 | 0 / 20 | 0 / 10 |
| other Total, other adverse events | 0 / 26 | 0 / 44 | 0 / 30 | 0 / 7 | 0 / 13 | 0 / 20 | 0 / 10 |
| serious Total, serious adverse events | 0 / 26 | 1 / 44 | 0 / 30 | 0 / 7 | 0 / 13 | 0 / 20 | 0 / 10 |
Outcome results
None listed