RECRUITING

Preliminary Safety and Tolerability of CD19x22 CAR T Cells in Adolescent and Adult R/R B-NHL Patients

Conditions

Non-Hodgkin Lymphoma B-cell Non-Hodgkin Lymphoma (B-NHL)Mantle Cell Lymphoma (MCL)CNS Lymphoma Relapsed Refractory

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

This open-label, single arm phase 1 trial aims to determine the safety and tolerability of anti-CD19 and anti-CD22 chimeric antigen receptor-expressing (CAR) T cells (CD19x22 CAR T) in adolescents and adults with relapsed/refractory (R/R) B-cell Non-Hodgkin Lymphoma (B-NHL). This trial will determine the maximum tolerated dose of CD19x22 CAR T cells using a standard 3+3 trial design.

Official Title

Phase 1 Study of Bispecific CD19 and CD22 Chimeric Antigen Receptor Co-Expressing T Cells (CD19x22 CAR T) in Adolescent and Adult Patients With Relapsed and/or Refractory B-Non-Hodgkin's Lymphoma (B-NHL)

Quick Facts

Study Start:2021-12-21

Study Completion:2027-12

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05098613

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:16 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Histologically confirmed aggressive B-cell NHL including the following types defined by World Health Organization (WHO) 2008: 2. Subjects must not have any signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at screening; subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible for this cohort. 3. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least two lines of therapy. 4. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. 1. Mantle Cell Lymphoma (MCL). 2. Subjects must have relapsed and/or refractory MCL confirmed by either flow cytometry or immunohistochemistry (ICH), disease stabilization, or disease recurrence after at least two lines of therapy including any combination of the agents below: 3. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. MCL patients without measurable nodal or extranodal disease by IWG criteria are eligible if they have bone marrow involvement of MCL at relapse 1. Subjects with relapsed and/or refractory primary CNS lymphoma (PCNSL) OR secondary CNS lymphoma (SCNSL), as defined by the following: 2. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least one line of therapy. 1. Subjects who have undergone autologous stem cell transplantation (SCT) with disease progression or relapse are eligible. 2. Subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, are: 1. At least 100 days post-transplant, 2. Do not have active graft versus host disease (GVHD) 3. Any standard of care systemic therapy prior to leukapheresis must follow the washout period. 4. Any steroid use (dexamethasone or prednisone) prior to apheresis must follow the washout period. Physiological replacement doses are allowable with no washout period. Topical or inhaled steroids for localized GVHD is allowable. 5. Peripheral blood CD3 count must be \>0.15 x 10 (to the 6th) cells/mL within 14 days prior to proceeding with apheresis. 6. Toxicities from prior therapy must be stable and recovered to ≤ grade 1 (exceptions include non-clinically significant toxicities such as alopecia and the organ function definitions provided in inclusion criteria 12). 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or Karnofsky ≥ 80%. 8. Adequate organ function as defined by: 1. Absolute neutrophil count (ANC) ≥ 500/μL 2. Platelet count ≥ 50,000/ μL. 3. Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min. 4. Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN). 5. Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin \<4.0 will be acceptable. 6. Cardiac: Ejection fraction ≥ 40%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings within 6 weeks of apheresis. 7. Pulmonary: No clinically significant pleural effusion and; 9. Females of childbearing potential must have a negative serum pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 6 months are not considered to be of childbearing potential). 10. Subjects of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after receiving the CD19x22 infusion; females of childbearing potential must have a negative pregnancy test.	1. Age \< 16 years of age. 2. Patient who is intolerant of contrast-enhanced MRI due to allergic reactions to contrast agents. Only applicable to Cohort 3. 3. History of other malignancies, unless they have been disease free for at least 3 years. Exceptions include non-melanoma skin cancer or carcinoma in situ and localized prostate cancer not on active treatment. 4. Uncontrolled fungal, bacterial, viral, or other infection requiring antimicrobials for management; uncomplicated infections are permitted if responding to active treatment. 5. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen \[HBsAg\] positive) or hepatitis C. 6. History of known myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment or have cardiac atrial or cardiac ventricular lymphoma involvement. 7. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation. 8. Any medical condition that in the judgement of the sponsor is likely to interfere with assessment of safety or efficacy of study treatment. 9. History of severe immediate hypersensitivity reaction to any of the agents used in this study. 10. Pregnancy (serum pregnancy test must be obtained at time of enrollment for females of childbearing potential and to be repeated 72 hours prior to lymphodepleting chemotherapy regimen); females who have undergone surgical sterilization or who have been postmenopausal for at least 6 months are not considered to be childbearing potential. 11. Lactating. 12. 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. 13. Unwilling to participate in long-term follow-up protocol that is required if CAR T cell therapy is administered at CU Anschutz. * If the participant received bridging therapy after apheresis, confirmation of disease reevaluation is required. It must be within 6 weeks of initiation of LD chemotherapy. * Confirmation that the participant has met the washout period for bridging therapy. * Negative serum pregnancy test (for women of childbearing potential) * Adequate organ function as defined by: * Absolute neutrophil count (ANC) ≥ 500/μL. * Platelet count ≥ 50,000/ μL. * Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min. * Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN). * Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin \<3.0 will be acceptable. * Pulmonary: No clinically significant pleural effusion and; Baseline oxygen saturation must be \> 92% on room air. * Cardiac: Ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO) (only if subject received bridging anthracycline or developed a significant illness prior to LD-chemo per investigator assessment.) If clinically indicated, ECHO must be performed within 2 weeks prior to LD-chemotherapy. * CD19x22 CAR T cells must have met manufacturing release criteria (unless prospectively approved by IND Sponsor, Gates Institute Medical Lead, and FDA). * Confirmation that the site has Anakinra and Ruxolitinib in stock and available (should IEC-HS treatment be required). * ECOG ≤2 or Karnofsky≥ 50%. * Clinically stable without evidence of vital sign instability, including the lack of supportive vasoactive drugs or intensive care unit support. * Oxygen saturation \> 92% on room air; cannot be on supplemental oxygen. * No evidence of uncontrolled, significant tumor lysis syndrome prior to cell infusion per investigator assessment. * No evidence of rapidly progressive NHL per investigator determination. * Participants' temperature is \<38.0 °C within 48 hours prior to cell infusion. (If the source of fever cannot be identified \[after thorough infectious disease work-up\], and the suspected cause is underlying malignancy, discussion and approval by the Gates Institute Medical Lead may allow continued infusion of CD19x22 cells. This should be appropriately documented in the patient's medical record. * Liver transaminase (ALT and AST) \< 5 x institutional ULN (\< grade 3) based on age- and laboratory- specific normal ranges. * Adequate renal function as defined by creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by the Cockcroft- Gault equation) ≥ 60 mL/min.

Inclusion Criteria

Exclusion Criteria

1. Histologically confirmed aggressive B-cell NHL including the following types defined by World Health Organization (WHO) 2008:
2. Subjects must not have any signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at screening; subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible for this cohort.
3. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least two lines of therapy.
4. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
1. Mantle Cell Lymphoma (MCL).
2. Subjects must have relapsed and/or refractory MCL confirmed by either flow cytometry or immunohistochemistry (ICH), disease stabilization, or disease recurrence after at least two lines of therapy including any combination of the agents below:
3. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. MCL patients without measurable nodal or extranodal disease by IWG criteria are eligible if they have bone marrow involvement of MCL at relapse
1. Subjects with relapsed and/or refractory primary CNS lymphoma (PCNSL) OR secondary CNS lymphoma (SCNSL), as defined by the following:
2. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least one line of therapy.
1. Subjects who have undergone autologous stem cell transplantation (SCT) with disease progression or relapse are eligible.
2. Subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, are:
1. At least 100 days post-transplant,
2. Do not have active graft versus host disease (GVHD)
3. Any standard of care systemic therapy prior to leukapheresis must follow the washout period.
4. Any steroid use (dexamethasone or prednisone) prior to apheresis must follow the washout period. Physiological replacement doses are allowable with no washout period. Topical or inhaled steroids for localized GVHD is allowable.
5. Peripheral blood CD3 count must be \>0.15 x 10 (to the 6th) cells/mL within 14 days prior to proceeding with apheresis.
6. Toxicities from prior therapy must be stable and recovered to ≤ grade 1 (exceptions include non-clinically significant toxicities such as alopecia and the organ function definitions provided in inclusion criteria 12).
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or Karnofsky ≥ 80%.
8. Adequate organ function as defined by:
1. Absolute neutrophil count (ANC) ≥ 500/μL
2. Platelet count ≥ 50,000/ μL.
3. Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min.
4. Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN).
5. Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin \<4.0 will be acceptable.
6. Cardiac: Ejection fraction ≥ 40%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings within 6 weeks of apheresis.
7. Pulmonary: No clinically significant pleural effusion and;
9. Females of childbearing potential must have a negative serum pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 6 months are not considered to be of childbearing potential).
10. Subjects of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after receiving the CD19x22 infusion; females of childbearing potential must have a negative pregnancy test.

1. Age \< 16 years of age.
2. Patient who is intolerant of contrast-enhanced MRI due to allergic reactions to contrast agents. Only applicable to Cohort 3.
3. History of other malignancies, unless they have been disease free for at least 3 years. Exceptions include non-melanoma skin cancer or carcinoma in situ and localized prostate cancer not on active treatment.
4. Uncontrolled fungal, bacterial, viral, or other infection requiring antimicrobials for management; uncomplicated infections are permitted if responding to active treatment.
5. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen \[HBsAg\] positive) or hepatitis C.
6. History of known myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment or have cardiac atrial or cardiac ventricular lymphoma involvement.
7. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation.
8. Any medical condition that in the judgement of the sponsor is likely to interfere with assessment of safety or efficacy of study treatment.
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
10. Pregnancy (serum pregnancy test must be obtained at time of enrollment for females of childbearing potential and to be repeated 72 hours prior to lymphodepleting chemotherapy regimen); females who have undergone surgical sterilization or who have been postmenopausal for at least 6 months are not considered to be childbearing potential.
11. Lactating.
12. 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.
13. Unwilling to participate in long-term follow-up protocol that is required if CAR T cell therapy is administered at CU Anschutz.
* If the participant received bridging therapy after apheresis, confirmation of disease reevaluation is required. It must be within 6 weeks of initiation of LD chemotherapy.
* Confirmation that the participant has met the washout period for bridging therapy.
* Negative serum pregnancy test (for women of childbearing potential)
* Adequate organ function as defined by:
* Absolute neutrophil count (ANC) ≥ 500/μL.
* Platelet count ≥ 50,000/ μL.
* Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min.
* Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN).
* Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin \<3.0 will be acceptable.
* Pulmonary: No clinically significant pleural effusion and; Baseline oxygen saturation must be \> 92% on room air.
* Cardiac: Ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO) (only if subject received bridging anthracycline or developed a significant illness prior to LD-chemo per investigator assessment.) If clinically indicated, ECHO must be performed within 2 weeks prior to LD-chemotherapy.
* CD19x22 CAR T cells must have met manufacturing release criteria (unless prospectively approved by IND Sponsor, Gates Institute Medical Lead, and FDA).
* Confirmation that the site has Anakinra and Ruxolitinib in stock and available (should IEC-HS treatment be required).
* ECOG ≤2 or Karnofsky≥ 50%.
* Clinically stable without evidence of vital sign instability, including the lack of supportive vasoactive drugs or intensive care unit support.
* Oxygen saturation \> 92% on room air; cannot be on supplemental oxygen.
* No evidence of uncontrolled, significant tumor lysis syndrome prior to cell infusion per investigator assessment.
* No evidence of rapidly progressive NHL per investigator determination.
* Participants' temperature is \<38.0 °C within 48 hours prior to cell infusion. (If the source of fever cannot be identified \[after thorough infectious disease work-up\], and the suspected cause is underlying malignancy, discussion and approval by the Gates Institute Medical Lead may allow continued infusion of CD19x22 cells. This should be appropriately documented in the patient's medical record.
* Liver transaminase (ALT and AST) \< 5 x institutional ULN (\< grade 3) based on age- and laboratory- specific normal ranges.
* Adequate renal function as defined by creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by the Cockcroft- Gault equation) ≥ 60 mL/min.

Contacts and Locations

Study Contact

Derek Schatz

CONTACT

7208480628

derek.schatz@cuanschutz.edu

Principal Investigator

Manali Kamdar, MD

PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Study Locations (Sites)

University of Colorado Hospital

Aurora, Colorado, 80045

United States

Collaborators and Investigators

Sponsor: University of Colorado, Denver

Manali Kamdar, MD, PRINCIPAL_INVESTIGATOR, University of Colorado, Denver

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2021-12-21

Study Completion Date2027-12

Study Record Updates

Study Start Date2021-12-21

Study Completion Date2027-12

Terms related to this study

Keywords Provided by Researchers

Relapsed
Refractory

Additional Relevant MeSH Terms

Non-Hodgkin Lymphoma
B-cell Non-Hodgkin Lymphoma (B-NHL)
Mantle Cell Lymphoma (MCL)
CNS Lymphoma