MT2017-45: CAR-T Cell Therapy for Heme Malignancies

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT03642626

Collaborator

(none)

120

Enrollment

Location

114.4

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia Large B-cell Lymphoma	Drug: KYMRIAH Drug: YESCARTA Drug: Fludarabine 30mg/m2 4 doses Drug: Cyclophosphamide 500 mg/m2; 2 doses Drug: Fludarabine 30mg/m2 3 doses Drug: Cyclophosphamide 500 mg/m2; 3 doses Drug: Fludarabine 25mg/m2 3 days Drug: Cyclophosphamide 250 mg/m2; 3 days Drug: Tecartus

Study Design

Study Type:

Observational

Anticipated Enrollment :

120 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Chimeric Antigen Receptor (CAR)-T Cell Therapy for Patients With Hematologic Malignancies

Actual Study Start Date :

Dec 18, 2018

Anticipated Primary Completion Date :

Jul 1, 2028

Anticipated Study Completion Date :

Jul 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
ARM A: Refractory/relapsed B-cell acute lymphoblastic leukemia (ALL)	Drug: KYMRIAH FDA approved CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells Other Names: tisagenlecleucel Drug: Fludarabine 30mg/m2 4 doses 30 mg/m2 IV daily for 4 doses Drug: Cyclophosphamide 500 mg/m2; 2 doses 500 mg/m2 IV daily for 2 doses starting with the first dose of fludarabine
ARM B: Yescarta for Refractory diffuse large B cell lymphoma (DLBCL)	Drug: YESCARTA CD19-directed genetically modified autologous T cell immunotherapy Drug: Fludarabine 30mg/m2 3 doses 30 mg/m2 IV daily for 3 doses Drug: Cyclophosphamide 500 mg/m2; 3 doses 500 mg/m2 IV daily for 3 doses starting with the first dose of fludarabine
ARM C: Kymriah for Refractory diffuse large B cell lymphoma (DLBCL)	Drug: KYMRIAH FDA approved CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells Other Names: tisagenlecleucel Drug: Fludarabine 25mg/m2 3 days 25 mg/m2 i.v. daily for 3 days Drug: Cyclophosphamide 250 mg/m2; 3 days 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine
Arm D: Tecartus CAR-T product for Mantle Cell Leukemia (MCL)	Drug: Fludarabine 30mg/m2 3 doses 30 mg/m2 IV daily for 3 doses Drug: Cyclophosphamide 500 mg/m2; 3 doses 500 mg/m2 IV daily for 3 doses starting with the first dose of fludarabine Drug: Tecartus TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells Other Names: Brexucabtagene Autoleucel

Outcome Measures

Primary Outcome Measures

Arm A: Complete Remission (CR) [Day 28]
Incidence of CR
Arm A: CRi (complete remission without count recovery) [Day 28]
Incidence of CRi
Arms B & C&D: Overall Response Rate (ORR) [Week 8]
ORR defined by complete response + partial response by Lugano

Secondary Outcome Measures

Arm A: MRD-negative CR (or CRi) [Day 28]
Proportion of patients with MRD-negative CR (or CRi)
Arm A: Proportion of patients who are alive but not in remission [Day 28]
Proportion of patients who are alive but not in remission
Arm A: Treatment Related Mortality (TRM) [Day 28]
Incidence of treatment related mortality (in absence of disease relapse/progression)
Arm A: Treatment Related Mortality (TRM) [Day 100]
Incidence of treatment related mortality (in absence of disease relapse/progression)
Arm A: Treatment Related Mortality (TRM) [1 Year]
Incidence of treatment related mortality (in absence of disease relapse/progression)
Arm A: Relapse-free Survival (RFS) [At complete remission, relapse, death]
Incidence of Relapse-free Survival (RFS)
Arm A: 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
Arm A: Overall Survival (OS) [Date of Death]
Incidence of Overall Survival (OS) from the date of the CAR-T infusion through the date of patient death for any reason.
Arm A: Toxicity [Day 28]
Proportion of patients with grade 3 or 4 targeted toxicity of CRS and/or neurotoxicity
Arms B/C/D: Complete Remission (CR) [Day 28]
Proportion of patients with Complete Remission by Lugano criteria
Arms B/C/D: Treatment Related Mortality (TRM) [Day 28]
Incidence of treatment related mortality
Arms B/C/D: Treatment Related Mortality (TRM) [Day 100]
Incidence of treatment related mortality
Arms B/C/D: Treatment Related Mortality (TRM) [1 Year]
Incidence of treatment related mortality
Arms B/C/D: Relapse-free Survival (RFS) [At complete remission, relapse, or death]
Incidence of Relapse-free Survival (RFS)
Arms B/C: Event-free Survival (EFS) [1 Year post treatment]
Event-free survival (EFS) from the date of the CAR-T infusion through 1 year post treatment
Arms B/C/D: Overall Survival (OS) [Date of Death]
Incidence of Overall Survival (OS) from the date of the CAR-T infusion through the date of patient death for any reason
Arms B/C/D: Toxicity [Day 28]
Proportion of patients developing grade 3, 4 targeted toxicity of CRS and/or neurotoxicity

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

ARM A: Kymriah for Refractory/relapsed B-cell acute lymphoblastic leukemia expressing CD19

Inclusion Criteria:

Age and Disease Status
Must be age 0-25 years
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
Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50% at screening
ALC >500/uL at screening (prior to apheresis) and absolute lymphocyte count >/= 150/uL
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.

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.
Active CNS involvement by malignancy (no evidence of disease in CSF by flow cytometry) 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 (controlled HIV is permissible)
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 apheresis.
Patient has taken one of the prohibited concomitant medications within the timeframe.

ARM C: Kymriah for rRelapsed or rRefractory diffuse large B cell lymphoma

Inclusion Criteria:

Age and Disease Status
Adult patients (age ≥ 18 years)
with relapsed or refractory (r/r) large B-cell lymphoma, including
diffuse large B-cell lymphoma (DLBCL) not otherwise specified,
high grade B-cell lymphoma
and DLBCL arising from follicular lymphoma.
Disease status:
after two or more lines of systemic therapy or
relapse after autologous HCT
Performance Status
ECOG performance status 0-2
ALC >/=100/uL at screening (prior to apheresis)
Organ Function
Renal function defined as:
A serum creatinine of ≤1.5 x ULN OR
eGFR ≥ 50 mL/min/1.73 m^2
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)
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.
Active CNS involvement by malignancy (no evidence of disease in CSF by flow cytometry) 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 or inactive 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 apheresis.
Patient has taken one of the prohibited concomitant medications within the timeframe

ARM D: Tecartus (Brexucabtagene Autoleucel) for relapsed or refractory mantle cell lymphoma

Inclusion Criteria:

Age and Disease Status

with relapsed or refractory (r/r) mantle cell lymphoma, including

prior anthracycline or Bendamustine containing therapy
prior Rituximab or other CD20 directed antibody (or inability to treat with CD20 MoAb)
not a candidate or relapse after autologous HCT
active disease at enrollment
Performance Status

*ECOG performance status 0-1

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
Adequate bone marrow reserve (unless marrow infiltrated by disease) defined as:
Absolute neutrophil count (ANC) > 1,000/mm^3 (only for NHL)
Platelets ≥ 50,000/mm^3 (transfusion support can be provided)
Hemoglobin >8.0 mg/dl (transfusion support can be provided)

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. See section 4.5 for definitions of child bearing potential and section 4.6 for definitions of adequate birth control.
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.
Active CNS involvement by malignancy (no evidence of disease in CSF by flow cytometry) 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 apheresis (steroids must be stopped >72 hours prior to apheresis).
Patient has taken one of the prohibited concomitant medications within the timeframe