A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

• ClinicalTrials.gov Identifier: NCT03277729
• Recruitment Status: Recruiting
• First Posted: September 11, 2017
• Last Update Posted: July 13, 2021
• Sponsor: Fred Hutchinson Cancer Research Center
• Collaborators: National Cancer Institute (NCI); Mustang Bio
• Information provided by (Responsible Party): Fred Hutchinson Cancer Research Center

Tracking Information

• First Submitted Date: September 7, 2017
• First Posted Date: September 11, 2017
• Last Update Posted Date: July 13, 2021
• Actual Study Start Date: December 5, 2017
• Estimated Primary Completion Date: November 16, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 7, 2017)

Dose-limiting toxicity [ Time Frame: Up to 28 days ]

Will be graded by Common Terminology Criteria for Adverse Events version 4.0.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 1, 2019)

• Complete remission [ Time Frame: Up to 15 years ]
  Will be assessed based on the Lugano criteria.
• Progression-free survival (PFS) [ Time Frame: Duration from study enrollment to progression or death due to any cause (whichever comes first), assessed up to 15 years ]
  A Cox proportional hazards model will be used to evaluate PFS.
• Overall survival (OS) [ Time Frame: Duration from study enrollment to death due to any cause, assessed up to 15 years ]
  A Cox proportional hazards model will be used to evaluate OS.
• Incidence of adverse events [ Time Frame: Up to 15 years ]
  Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Original Secondary Outcome Measures (submitted: September 7, 2017)

• Complete remission [ Time Frame: Up to 15 years ]
  Will be assessed based on the Lugano criteria.
• Incidence of adverse events [ Time Frame: Up to 15 years ]
  Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
• Overall survival [ Time Frame: Duration from study registration to death due to any cause, assessed up to 15 years ]
• Progression-free survival [ Time Frame: Duration from study registration to progression or death due to any cause (whichever comes first), assessed up to 15 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas
• Official Title: A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas
• Brief Summary: The purpose of this research is to find the best dose of genetically modified T-cells, to study the safety of this treatment, and to see how well it works in treating patients with B cell non-Hodgkin lymphoma that has come back (relapsed) or did not respond to previous treatment (refractory).

Detailed Description

OUTLINE:

This is a phase I/II dose-escalation study of CD20-specific CAR T cell therapy.

Patients undergo leukapheresis and may receive treatment after if needed for disease control. Patients then receive cyclophosphamide intravenously (IV). Patients may also receive fludarabine IV. After 36-96 hours, patients receive CD20-specific CAR T cell infusion IV over 20-30 minutes.

Patients will be actively participating in the study for approximately 15 months. The total time includes the time for the T cells to be made, the T cell infusion, and for approximately 12 months after the T cell infusion is given. After completion of study treatment, patients are followed up for a minimum of 15 years.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent B-Cell Non-Hodgkin Lymphoma
• Recurrent Chronic Lymphocytic Leukemia
• Recurrent Diffuse Large B-Cell Lymphoma
• Recurrent Follicular Lymphoma
• Recurrent Lymphoplasmacytic Lymphoma
• Recurrent Mantle Cell Lymphoma
• Recurrent Marginal Zone Lymphoma
• Refractory B-Cell Non-Hodgkin Lymphoma
• Refractory Diffuse Large B-Cell Lymphoma
• Refractory Follicular Lymphoma
• Refractory Lymphoplasmacytic Lymphoma
• Refractory Mantle Cell Lymphoma
• Refractory Transformed Non-Hodgkin Lymphoma
• Recurrent Transformed B-Cell Non-Hodgkin Lymphoma
• Recurrent Transformed Chronic Lymphocytic Leukemia
• Refractory Marginal Zone Lymphoma
• Refractory Transformed B-Cell Non-Hodgkin Lymphoma
• Refractory Transformed Chronic Lymphocytic Leukemia
• Recurrent Small Lymphocytic Lymphoma
• Refractory Chronic Lymphocytic Leukemia
• Refractory Small Lymphocytic Lymphoma

Intervention

• Biological: Chimeric Antigen Receptor T-Cell Therapy
  Given CD20 CAR T cell IV
  Other Names:

  • CAR T-cell therapy
  • CAR T Infusion
  • CAR T Therapy
• Drug: Cyclophosphamide
  Given IV
  Other Names:

  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Procedure: Leukapheresis
  Undergo leukapheresis
  Other Names:

  • Leukocytopheresis
  • Therapeutic Leukopheresis
• Drug: Fludarabine Phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • Beneflur
  • Fludara
  • Fludarabine-5''-Monophosphate
  • SH T 586

Study Arms

Experimental: Treatment (CD20-specific CAR T cell, chemotherapy)

Patients undergo leukapheresis and may receive treatment after if needed for disease control. Patients then receive cyclophosphamide IV. Patients may also receive fludarabine IV. After 36-96 hours, patients receive CD20-specific CAR T cell infusion IV over 20-30 minutes.

Interventions:

• Biological: Chimeric Antigen Receptor T-Cell Therapy
• Drug: Cyclophosphamide
• Other: Laboratory Biomarker Analysis
• Procedure: Leukapheresis
• Drug: Fludarabine Phosphate

• Publications *: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9:CD013365. doi: 10.1002/14651858.CD013365.pub2. Review.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 4, 2020): 35
• Original Estimated Enrollment (submitted: September 7, 2017): 30
• Estimated Study Completion Date: November 16, 2037
• Estimated Primary Completion Date: November 16, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible lymphoma subtypes include (but not limited to): mantle cell, follicular, lymphoplasmacytic, marginal zone, transformed indolent B cell lymphoma (including transformed chronic lymphoid leukemia [CLL]), or diffuse large B cell lymphoma that has relapsed after a response to at least one prior therapy regimen or is refractory to prior therapy; patients with mantle cell lymphoma must have previously been treated with a Bruton tyrosine kinase (BTK) inhibitor and have either had disease progression, intolerance, or exposure to the drug for at least 3 months; patients with CLL/SLL are eligible if they had disease progression or intolerance to BTKis and/or venetoclax; they are also required to have been treated with the other agent for at least 3 months (i.e. patients with progression/intolerance to BTKi need to be treated with venetoclax for at least 3 months, and patients with progression/intolerance to venetoclax need at least 3 months of exposure to a BTKi); patients with de novo diffuse large B-cell lymphoma (DLBCL) must meet one of the following criteria:

  • Biopsy-proven refractory disease after a frontline regimen containing both an anthracycline and rituximab or other anti-CD20 antibody (i.e. "primary refractory"), where any disease recurring within 6 months of completion of the regimen is considered refractory

  • Relapsed or refractory disease after at least one of the following:

    • At least 2 lines of therapy (including at least one with an anthracycline and anti-CD20 antibody)
    • Autologous stem cell transplant
    • Allogeneic stem cell transplant
• Patients of any gender, race or ethnicity
• Patients must be capable of understanding and providing a written informed consent
• Negative serum pregnancy test within 2 weeks before enrollment for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
• Fertile male and female patients must be willing to use an effective contraceptive method before, during, and for at least 4 months after the CAR T cell infusion
• Patients must have a Karnofsky performance status of >= 60%
• Confirmation of diagnosis by internal pathology review of initial or subsequent biopsy or other pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA)/University of Washington (UW)/Harborview Medical Center (HMC)
• Evidence of CD20 expression by immunohistochemistry or flow cytometry on the tumor specimen obtained with the biopsy performed with screening; if the CD20 expression on the screening tumor biopsy is unclear or could not be assessed due to technical reasons, CD20 expression on a concomitant tumor specimen (such as marrow biopsy or circulating tumor cells) may be used to satisfy this requirement
• Serum creatinine =< 2.5
• Total bilirubin =< 3.0 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x the upper limit of normal
• Adequate pulmonary function, defined as =< grade 1 dyspnea and saturated oxygen (SaO2) >= 92% on room air; if pulmonary function test (PFT)s are performed based on the clinical judgment of the treating physician, patients with forced expiratory volume in 1 second (FEV1) >= 50% of predicted and carbon monoxide diffusing capability (DLCO) (corrected) of >= 40% of predicted will be eligible
• Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of >= 50% as assessed by echocardiogram or multigated acquisition (MUGA) scan, or LVEF of 45-49% and clearance by a cardiologist
• Measurable disease that can be accurately measured in at least one dimension as >= 2.0 cm with computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI) techniques; extranodal disease that is measurable by fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) imaging only will also be allowed; note that if an excisional biopsy was performed that removed the sole site of measurable disease, the patient will not be eligible for leukapheresis and generation of CAR T cell product
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Absence of uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding to treatment with antibiotics, antiviral agents, or antifungal agents
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Absence of active autoimmune disease requiring ongoing systemic immunosuppressive therapy
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Negative serum pregnancy test within 2 weeks before lymphodepletion chemotherapy for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: No treatment with any investigational agent on a different clinical trial between enrollment and lymphodepleting chemotherapy
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Serum creatinine =< 2.5
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Total bilirubin =< 3.0 mg/dL
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: AST and ALT =< 5 x the upper limit of normal
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Adequate pulmonary function, defined as =< grade 1 dyspnea and SaO2 >= 92% on room air; if PFTs are performed based on the clinical judgment of the treating physician, patients with FEV1 >= 50% of predicted and DLCO (corrected) of >= 40% of predicted will be eligible
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of >= 50% as assessed by echocardiogram or MUGA scan, or LVEF of 45-49% and clearance by a cardiologist; if subject receives cardiotoxic chemotherapy after enrollment, repeat echocardiogram or MUGA is required to reestablish eligible LVEF
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must have a Karnofsky performance status of >= 60%
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Measurable disease that can be accurately measured in at least one dimension as >= 2.0 cm with CT, ultrasound, or MRI techniques; extranodal disease that is measurable by FDG-PET imaging only will also be allowed; note that if an excisional biopsy was performed that removed the sole site of measurable disease, the patient is not be eligible for lymphodepletion and CAR T cell infusion; measurable disease can be based on the imaging study done during the screening unless the patient received treatment in the interim, in which case imaging should be repeated
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must require no corticosteroid therapy or dose of less than 15 mg per day of prednisone or the equivalent; pulsed corticosteroid dose for disease control is acceptable until the day before the start of lymphodepletion
• ELIGIBILITY FOR LYMPHODEPLETION CHEMOTHERAPY: Patients must have no active acute or chronic GVHD

Exclusion Criteria:

• Active autoimmune disease requiring systemic immunosuppressive therapy
• Patients requiring corticosteroid therapy at a dose of 15 mg or more per day of prednisone or the equivalent; pulsed corticosteroid dose for disease control is acceptable
• Patients who are human immunodeficiency virus (HIV) seropositive
• Women who are pregnant or breastfeeding
• Significant cardiovascular diseases within the past 6 months including uncontrolled congestive heart failure (> New York Heart Association [NYHA] class II), myocardial infarction, unstable angina, or uncontrolled arrhythmia
• History of severe immediate hypersensitivity reaction to cyclophosphamide or fludarabine
• History or presence of clinically relevant non-lymphoma central nervous system pathology, including seizures that are uncontrolled on anticonvulsant therapy (>= 1 seizure in the last year), paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson disease, cerebellar disease, or psychosis
• Treatment with any investigational agent on a different clinical trial within 4 weeks prior to enrollment, unless the patient is documented to be unresponsive to the therapy and at least 3 half-lives have elapsed prior to enrollment
• Treatment with any anti-CD19 or anti-CD20 antibody or antibody-drug conjugate therapy within 4 weeks before enrollment
• Previous treatment with CD19-targeted CAR T cells that has resulted in ongoing B cell aplasia at the time of enrollment; patients that demonstrate recovery of normal B cells (>= 20 B cells/ul) by flow cytometry at any point 28 days or later after CD19 CAR T cell infusion will be considered to have functional loss of CD19 CAR T cells and are potentially eligible
• Known active central nervous system metastases and/or lymphomatous meningitis; patients with isolated cerebrospinal fluid (CSF) involvement detectable by flow cytometry are eligible if clinically asymptomatic and if abnormal B cells are reported to be less than 3% by flow cytometry; subjects with previously treated central nervous system (CNS) disease may participate provided: 1) any CNS-directed treatment was completed at least 1 month prior to enrollment, 2) imaging studies and CSF evaluation show no evidence of disease progression, and 3) any neurologic symptoms have returned to baseline
• Presence of active acute or chronic graft versus host disease (GVHD)
• Uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding to treatment with intravenous antibiotics, antiviral or antifungal agents
• Patients with concurrent known additional malignancy that is progressing and/or requires active treatment; exceptions include squamous or basal cell carcinoma of the skin and low grade prostate carcinoma (Gleason grade =< 6)
• Patients with blood or platelet transfusion within 1 week prior to signing Consent A, or with platelets < 50,000/mm^3, neutrophils < 750/mm^3, or hemoglobin < 8.5 g/dL, unless the cytopenias are considered by the treating physician to be largely due to marrow involvement by lymphoma

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: SCCA Immunotherapy Intake; 206-606-4668; immunotherapy@seattlecca.org

Contact: SCCA Immunotherapy Intake; 855-557-0555

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03277729
• Other Study ID Numbers: 9738; NCI-2017-01595 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 9738 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); RG9217017 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Fred Hutchinson Cancer Research Center
• Study Sponsor: Fred Hutchinson Cancer Research Center

Collaborators

• National Cancer Institute (NCI)
• Mustang Bio

Investigators

• Principal Investigator: Mazyar Shadman; Fred Hutch/University of Washington Cancer Consortium

• PRS Account: Fred Hutchinson Cancer Research Center
• Verification Date: July 2021