Clinical Trials /

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

NCT03642626

Description:

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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Mediastinal Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Trial Eligibility

Document

Title

  • Brief Title: MT2017-45 :CAR-T Cell Therapy for Heme Malignancies
  • Official Title: Chimeric Antigen Receptor (CAR)-T Cell Therapy for Patients With Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2017LS118
  • SECONDARY ID: MT2017-45
  • NCT ID: NCT03642626

Conditions

  • Acute Lymphoblastic Leukemia
  • Large B-cell Lymphoma

Interventions

DrugSynonymsArms
KYMRIAHtisagenlecleucelARM A: Refractory/relapsed B-cell acute lymphoblastic leuk
YESCARTAARM B: Yescarta for Refractory diffuse large B cell lymphom
FludarabineARM A: Refractory/relapsed B-cell acute lymphoblastic leuk
CyclophosphamideARM A: Refractory/relapsed B-cell acute lymphoblastic leuk
FludarabineARM B: Yescarta for Refractory diffuse large B cell lymphom
CyclophosphamideARM B: Yescarta for Refractory diffuse large B cell lymphom
FludarabineARM C: Kymriah for Refractory diffuse large B cell lymphom
CyclophosphamideARM C: Kymriah for Refractory diffuse large B cell lymphom

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
ARM A: Refractory/relapsed B-cell acute lymphoblastic leukExperimental
  • KYMRIAH
  • Fludarabine
  • Cyclophosphamide
ARM B: Yescarta for Refractory diffuse large B cell lymphomExperimental
  • YESCARTA
  • Fludarabine
  • Cyclophosphamide
ARM C: Kymriah for Refractory diffuse large B cell lymphomExperimental
  • KYMRIAH
  • Fludarabine
  • Cyclophosphamide

Eligibility Criteria

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

          -  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. 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.

               -  See sections 4.4 and 4.5 for additional criteria involving pregnancy and
                  contraception.

          -  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

          -  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 0-1

               -  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 June
                  6ly 10, 2018 Page 20 of 69 2017LS118

               -  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. 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.

               -  See sections 4.4 and 4.5 for additional criteria involving pregnancy and
                  contraception.

          -  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 outlined in section 6.1

        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 0-1

               -  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 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 June 6ly 10, 2018 Page 22 of 69
                  2017LS118

               -  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. 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.

               -  See sections 4.4 and 4.5 for additional criteria involving pregnancy and
                  contraception.

          -  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 outlined in section 6.1
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Arm A: Complete Remission (CR)
Time Frame:Day 28
Safety Issue:
Description:Incidence of CR

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Masonic Cancer Center, University of Minnesota

Trial Keywords

  • ALL

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