Fludarabine and Cyclophosphamide With or Without Rituximab Before CD19 Chimeric Antigen Receptor T Cells for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma

NCT05052528 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: UCDCC#299NCI-2021-07396P30CA093373
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial evaluates the best dose, possible benefits and/or side effects of fludarabine and cyclophosphamide with or without rituximab before CD19 chimeric antigen receptor T cells in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or has not responded to previous treatment (refractory). T-cells are a normal part of the immune system. To make the T-cell medication, T-cells are taken from the blood and altered in a laboratory. They are then returned to the body. The altered T-cells will latch on to a specific part of the cancer cells and hopefully kill them. Once the T-cells have been altered in the laboratory, they are called "CAR T-cells." CAR is short for "chimeric antigen receptors." These are structures on the surface of cells that allow the altered T-Cells to find and destroy the cancer cells. Another part of the T-Cell medication is called "CD19." This part is called a "biomarker." Biomarkers help doctors determine whether a cancer is getting worse and whether medications are working to stop it. The chemotherapy drugs that are given before the T-Cell therapy are cyclophosphamide, fludarabine and rituximab. Rituximab is an immunotherapy drug. These chemotherapy drugs will reduce the number of normal (unaltered) T-Cells in the body to make room for the altered T-cells to kill the cancer cells. Giving fludarabine and cyclophosphamide with or without rituximab before CD19 CAR T cell therapy may help improve response to CD19 CAR T cell therapy in patients with diffuse large B-cell lymphoma.

Conditions

Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (5)

• Proportion of products successfully manufactured meeting the established release criteria with a goal of at least 1.0 x 10^6 cells/kilogram

  Up to 15 years

• Incidence and severity of adverse events related to lymphodepleting chemotherapy and or CD19 chimeric antigen receptor (CAR) T cells

  Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.

  2 months

• Dose limiting toxicities (DLTs) related to lymphodepleting chemotherapy and or CD19 CAR T cells

  Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.

  2 months

• Maximum tolerated dose

  2 months

• Incidence and severity of DLT associated with infusion of CD19 CAR T cells (infusion reactions)

  Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate and the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.

  2 months

Secondary Outcomes (6)

• Incidence of toxicities related to CD19 CAR T cells

  Up to 15 years

• Overall response rate

  At 3 months after completion of CAR-T therapy

• Complete response rate

  At 3 months after completion of CAR T therapy

• Overall survival

  From the start of the conditioning lymphodepletion chemotherapy on day -6 until death, assessed at 1 year

• Progression free survival

  From the start of the conditioning lymphodepletion chemotherapy regimen until the documentation of disease progression or death due to any cause, whichever occurs first, assessed at 1 year

Study Arms (6)

Dose level 1 (fludarabine, cyclophosphamide, CD19 CAR T)

EXPERIMENTAL

Patients receive fludarabine phosphate IV over 30 minutes daily and cyclophosphamide IV over 60 minutes daily on days -5 to -3. Patients also receive CD19 CAR T cells IV on day 0.

Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate

Dose level 2 (rituximab, fludarabine, cyclophosphamide, CAR T)

EXPERIMENTAL

Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -3, and cyclophosphamide IV over 60 minutes on days -5 to -3. Patients also receive CD19 CAR T cells IV on day 0.

Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Biological: Rituximab

Dose level 3 (fludarabine, cyclophosphamide, CD19 CAR T)

EXPERIMENTAL

Patients receive fludarabine phosphate IV over 30 minutes daily on days -3 to -5 and cyclophosphamide IV over 60 minutes daily on day -5. Patients also receive CD19 CAR T cells IV on day 0.

Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate

Dose level 4 (rituximab, fludarabine, cyclophosphamide, CAR T)

EXPERIMENTAL

Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -3, and cyclophosphamide IV over 60 minutes on day -5. Patients also receive CD19 CAR T cells IV on day 0.

Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Biological: Rituximab

Dose level 5 (fludarabine, cyclophosphamide, CD19 CAR T)

EXPERIMENTAL

Patients receive fludarabine phosphate IV over 30 minutes daily on days -5 to -1 and cyclophosphamide IV over 60 minutes daily on days -5 and -4. Patients also receive CD19 CAR T cells IV on day 0.

Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate

Dose level 6 (rituximab, fludarabine, cyclophosphamide, CAR T)

EXPERIMENTAL

Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -1, and cyclophosphamide IV over 60 minutes on days -5 and -4. Patients also receive CD19 CAR T cells IV on day 0.

Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Biological: Rituximab

Interventions

Chimeric Antigen Receptor T-Cell Therapy BIOLOGICAL

Given CD19 CAR T cells IV

Also known as: CAR T Infusion, CAR T Therapy, CAR T-cell Therapy, Chimeric Antigen Receptor T-cell Infusion

Dose level 1 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 2 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 3 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 4 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 5 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 6 (rituximab, fludarabine, cyclophosphamide, CAR T)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Dose level 1 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 2 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 3 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 4 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 5 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 6 (rituximab, fludarabine, cyclophosphamide, CAR T)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Dose level 1 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 2 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 3 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 4 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 5 (fludarabine, cyclophosphamide, CD19 CAR T); Dose level 6 (rituximab, fludarabine, cyclophosphamide, CAR T)

Rituximab BIOLOGICAL

Given IV

Also known as: ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima

Dose level 2 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 4 (rituximab, fludarabine, cyclophosphamide, CAR T); Dose level 6 (rituximab, fludarabine, cyclophosphamide, CAR T)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Commercial CD19 CAR T cell product not available for the patient
• Male or female, aged \>= 18
• In good general health as evidenced by medical history or as determined by the principal investigator (PI)
• Ability to swallow oral medication and willingness to adhere to the study intervention and any required medications
• For females of reproductive potential: use of highly effective contraception (oral contraceptives, intrauterine device) during screening confirmed with serum pregnancy test, and agreement to use such a method during study participation and for an additional 4 weeks after the end of CD19 CAR T cell infusion
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner
• Agreement to adhere to lifestyle considerations throughout study duration including abstaining from tobacco and drug use
• Subjects must have relapsed or refractory diffuse large B cell lymphoma treated with at least two lines of therapy Subjects must have failed to have a complete response, or have recurrent disease after the last treatment regimen. Subjects must have previously been treated with a regimen that includes an anthracycline and an anti-CD20 monoclonal antibody. Autologous transplant will be counted as one line of therapy
• The patient's disease must be CD19 positive, either by immunohistochemistry or flow cytometry analysis on the last biopsy available
• Age \>= 18 years
• Performance status: Adult Subjects: Eastern Cooperative Oncology Group (ECOG) \>= 1; Subjects \> 10 years of age: Karnofsky \>= 80%
• Absolute neutrophil count (ANC) \>= 1000
• Platelets \>= 100/mm\^3

You may not qualify if:

• Presence of supplemental oxygen, cardiac pacemaker
• Known allergic reactions to components of the anti-CD19 CAR T cell product as evidenced by prior documented anaphylactic reaction or other clinical signs and/or symptoms of an allergic reaction as determined by the PI
• Febrile illness within 3 days of admission for lymphodepleting conditioning therapy
• Treatment with another investigational drug or other investigational intervention within 2 weeks of apheresis
• Primary immunodeficiency
• History of autoimmune diseases (ex: Crohn's, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's) resulting in end organ damage or requiring systemic immunosuppressive or systemic disease modifying agents within the last two years prior to enrollment
• Autologous transplant within 6 weeks and allogeneic transplant within 3 months of planned CAR T cell infusion
• Recipient of CD19 CAR T cell therapy outside of this protocol
• Active central nervous system or meningeal involvement by tumor. Subjects with untreated brain metastases/central nervous system (CNS) disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) for at least 30 days prior to study enrollment
• History of active malignancy other than non-melanoma skin cancer, carcinoma in situ (e.g. cervix, bladder, breast)
• Active human immunodeficiency virus (HIV) infection documented by positive viral load
• Subjects with uncontrolled concurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements
• Pregnant or breastfeeding women are excluded from this study because CAR T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) weeks after receiving the CAR-T cell infusion
• Diagnosis of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
• Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded)

Sponsors & Collaborators

• Mehrdad Abedi, MD: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

RECRUITING

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

Immunotherapy, Adoptive; Cyclophosphamide; fludarabine phosphate; Rituximab; CT-P10

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Adoptive Transfer; Immunization, Passive; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Mehrdad Abedi

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 13, 2021
• First Posted: September 22, 2021
• Study Start: September 17, 2021
• Primary Completion: May 15, 2025
• Study Completion: December 15, 2025
• Last Updated: May 13, 2024

Record last verified: 2024-05

Locations

US (1)