Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

A Phase 1 Clinical Trial of Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

Sponsors

Lead Sponsor: C. Babis Andreadis

Collaborator: University of California, Davis

Source University of California, San Francisco
Brief Summary

This study will assess safety and feasibility of infusing genetically modified autologous T cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen Cluster of Differentiation 19 (CD19)

Detailed Description

This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19 CAR-T cell infusion in participants with R/R B-cell NHL. The dose-finding cohorts in this study will evaluate and define the safe dose of anti-CD19 CAR-T cells. Using a "3+3" design, participants will be enrolled sequentially to each dose level. A dose expansion will then occur at the maximum tolerated dose (MTD) and dose levels that have not exceeded the MTD.

Up to 36 participants will be enrolled and treated. Each subject will provide consent and be evaluated for study eligibility. Eligible subjects will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. The CAR T cells will be produced using the Miltenyi Prodigy and an FDA compliant Lentigen CD19 targeted lentiviral vector. After successful generation of the anti-CD19 CAR-T cells (drug product (DP)), subjects will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-CD19 CAR-T cells at the starting dose of 5 x 105 cells/kg will be given on Day=0. Following treatment with DP, subjects will be followed on this study for 12 months for safety, disease status, and survival. For long term follow-up, participants will be followed for 15 years.

PRIMARY OBJECTIVES

1. To evaluate the safety of administering chimeric antigen receptor T cells targeting CD-19 to patients with relapsed or refractory CD19+ B-cell nonHodgkin lymphoma (NHL).

2. To determine the recommended phase 2 dose (RP2D) for this cellular therapy.

SECONDARY OBJECTIVES

1. To assess the safety and toxicity of cell collection and infusion of CAR-T cells targeting CD19 in patients with relapsed or refractory CD19+ B cell NHL.

2. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in patients with relapsed or refractory CD19+ B cell NHL.

3. To evaluate the feasibility of CD19 CAR T cell manufacturing for patients with relapsed or refractory CD19+ B cell NHL of local manufacturing and ability to produce adequate quantities of vector positive T-cells

Overall Status Recruiting
Start Date September 11, 2020
Completion Date October 31, 2023
Primary Completion Date October 31, 2023
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Proportion of participants with treatment-emergent adverse events (AEs) From initiation of study treatment to 12 months following CAR-T infusion, approximately 15 months
Proportion of participants who experience a dose-limiting toxicity (DLT) From initiation of study treatment to 30 days following CAR-T infusion
Secondary Outcome
Measure Time Frame
Proportion of participants with delayed infusion due to study-related adverse events From T-cell collection to end of infusion, approximately 18 days
Table of adverse events related to collection and infusion of CAR-T cells From T-cell collection to end of infusion, approximately 18 days
Response rates over time From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Best response rates From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Duration of response From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Progression-free survival (PFS) From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Overall Survival Up to 15 years
Proportion of subjects for whom CD19 CAR T-cell therapy is manufactured From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
Proportion of participants who complete study treatment From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
Enrollment 36
Condition
Intervention

Intervention Type: Drug

Intervention Name: Fludarabine

Description: Given intravenously (IV)

Arm Group Label: Treatment Regimen

Intervention Type: Drug

Intervention Name: Cyclophosphamide

Description: Given intravenously (IV)

Arm Group Label: Treatment Regimen

Intervention Type: Biological

Intervention Name: anti-CD19 CAR-T cells

Description: Single infusion

Arm Group Label: Treatment Regimen

Eligibility

Criteria:

Inclusion Criteria:

1. Patients must have a diagnosis of relapsed or refractory B-cell NHL:

- DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma, transformed lymphoma.

- Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax.

- Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to >= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.

- Subjects with indolent lymphomas (follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to >=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents.

- For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy.

- Positron Emission Tomography (PET) -positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"

- At least one of the following:

- Primary refractory or early relapse (first remission < 12 months) and not eligible for stem cell transplant

- Relapsed or refractory disease after two or more lines of systemic therapy

- No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.

2. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy.

3. Age >=18 years at the time of consent

4. Absolute lymphocyte count > 100/ (microliter)

5. Eastern Cooperative Oncology Group (ECOG) performance status < 2

6. Adequate organ function, defined as:

- Adequate bone marrow function for apheresis and lymphodepleting chemotherapy

- Hemoglobin (Hgb) >8 grams per deciliter (gm/dl) (transfusions allowed)

- Platelets >50,000/microliter (uL) (transfusions allowed)

- Absolute Neutrophil Count (ANC) > 500/uL

- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome

- Serum Creatinine < 2 x the institutional ULN

- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA)

7. Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).

8. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of antiCD19 CAR-T cells

9. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method

10. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

1. Autologous transplant within 6 weeks of planned CAR-T cell infusion

2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol

3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).

4. HIV seropositivity

5. 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.)

6. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.

7. 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. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.

8. Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.

9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.

10. Body weight <40 kilograms(kg)

Eligibility for Infusion of Investigational Product:

Subjects will undergo a second evaluation of eligibility on day -2 or -1 prior to infusion of antiCD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions

Inclusion criteria exceptions:

1. Hematologic function parameters will not be included as a pre-infusion eligibility criterion (because lymphodepletive chemotherapy is expected to cause pancytopenia).

2. Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.

Exclusion criteria additions:

1. Use of corticosteroids within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).

2. Neurologic symptoms suggestive of an active central nervous system condition.

3. Signs or laboratory markers of active infection or systemic inflammatory response.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
C. Babis Andreadis, MD Principal Investigator University of California, San Francisco
Overall Contact

Last Name: Julie McCluggage, RN

Phone: 877-827-3222

Email: [email protected]

Location
Facility: Status: Contact: Investigator: University of California, San Francisco Julie McCluggage 877-827-3222 [email protected] C. Babis Andreadis, MD Principal Investigator
Location Countries

United States

Verification Date

September 2020

Responsible Party

Type: Sponsor-Investigator

Investigator Affiliation: University of California, San Francisco

Investigator Full Name: C. Babis Andreadis

Investigator Title: Principal Investigator

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment Regimen

Type: Experimental

Description: Apheresis (1 day): Autologous lymphocytes/ mononuclear cell collection will be collected through standard apheresis procedures as per University of California, San Francisco (UCSF) institutional practices CAR-T cell manufacturing (estimated ~13-14 days) Lymphodepleting chemotherapy: 3 days of immunosuppressive chemotherapy. Cyclophosphamide given at a dose of 300 mg/m2/IV and fludarabine given at 30 mg/m2 /IV on days -5, -4, and -3. CAR-T cell infusion (1 day): The infusion of CAR-T cells targeting CD19 will occur over 5-30 minutes.

Patient Data No
Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov