A Phase I/IIa Multicenter Study Evaluating the Safety and Efficacy of CAR20(NAP)-T in Patients With Relapsed/Refractory B Cell Lymphoma (CARMA-01 Study)
Overview
- Phase
- Phase 1
- Intervention
- CAR20(NAP)-T
- Conditions
- B-cell Lymphoma
- Sponsor
- Uppsala University
- Enrollment
- 18
- Locations
- 2
- Primary Endpoint
- Incidence of dose limiting toxicity
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
The purpose is to study the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of CAR20(NAP)-T for patients with B-cell malignancies.
Detailed Description
A cancer patient's T cells can be isolated and engineered to express a chimeric antigen receptor (CAR), which re-directs the T cells to recognize and kill tumor cells expressing that particular antigen. CD19-targeted CAR-T cell therapy has shown good effects for B cell malignancies, even cure, in otherwise therapy refractory patients. Antigen escape, i.e., the downregulation of the antigen targeted by the CAR due to the selective pressure caused by the CAR-T cell therapy is a challenge. For patients treated with CD19 CAR-T cell therapy, about 30% of the patients are resistant to treatment and about 20% of patients relapse after an initial response. CAR20(NAP)-T cells target CD20 and upon target recognition secrete a bacterial-derived pluripotent immune-stimulating factor named NAP (Helicobacter pylori Neutrophil-activating protein). Secretion of NAP in the tumor microenvironment can induce an endogenous bystander immune response, that counteracts antigen escape and thereby improves the therapeutic outcome. CAR20(NAP)-T is an investigational agent not yet approved by authorities. Design: The study is designed as 3+3 dose escalation phase I, and a dose expansion Phase IIa. The safety, tolerability, PK/PD, and efficacy will be evaluated.Dose escalation is to be based on the incidence of dose-limiting toxicity (DLTs). The investigator or sub-investigator will decide if the AE is related to IMP-treatment on a case-by-case basis depending on the character of the DLT symptoms. Investigator or sub-investigator has a possibility to classify various toxicity observed in patient as DLT.The Recommended phase II dose (RP2D) is decided based on safety, PK/PD data as well as preliminary clinical activity data from the Phase I dose escalation. After setting the RP2D, additional patients will be treated at RP2D to make sure at least 6 patients will be treated at RP2D dose level already at the phase I part. Protocol treatment: The enrolled patient will undergo a leukapheresis procedure to harvest enough T cells for IMP production. During CAR20(NAP)-T manufacturing, the patient may receive bridging therapy to control tumor burden. All patients will receive pre-conditioning chemotherapy (cyclophosphamide and fludarabine) followed by one dose of CAR20(NAP)-T cell infusion intravenously. The patient will then be followed by doctor/study nurse for evaluation of the health status and side effects. At follow-up visits, blood samples will be obtained and CT imaging will be performed. Patient will actively participate in the study for about 24 months when the final follow-up visit will be scheduled.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed informed consent.
- •Relapsed or refractory CD20+ diffuse large B-cell lymphoma, mantle cell lymphoma or indolent lymphoma.
- •The patient should have been treated with at least two lines of therapy and have no curative treatment option, specifically
- •Relapsed or refractory CD20+ B-cell lymphoma that are not eligible to receive clinically approved CD19-directed CAR T cell treatment.
- •Relapsed or refractory CD20+ B-cell lymphoma who are CD19 negative.
- •Relapsed or refractory B-cell lymphoma who relapse after CD19 CAR T cell treatment.
- •In phase I age \>18 years, in phase II all ages
- •Measurable disease per Lugano classification.
- •Performance status ECOG 0-
- •Adequate bone marrow function as evidenced by:
Exclusion Criteria
- •Other CD20-positive lymphomas i.e Burkitt lymphoma, primary CNS lymphoma, plasmablastic lymphoma or CLL transformed to DLBCL/HGBL (Richter transformation)
- •Any significant medical or psychiatric illness that would prevent the subject from giving informed consent or from following the study procedures.
- •Known human immunodeficiency virus (HIV) infection.
- •Impending organ-compromising disease.
- •Rapidly progressing disease
- •Active and/or severe infection (e.g., tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
- •Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the subject to perform the treatment.
- •Treatment with an investigational product within 30 days prior to enrolment
- •Potential sign of hypersensitivity reaction to tocilizumab or any of the agents used in this study
- •Systemic corticosteroid treatment (\>10mg/day) \<5 days prior to IMP treatment or \<7 days prior leukapheresis.
Arms & Interventions
Treatment
CAR20(NAP)-T treatment
Intervention: CAR20(NAP)-T
Treatment
CAR20(NAP)-T treatment
Intervention: Cyclophosphamide
Treatment
CAR20(NAP)-T treatment
Intervention: Fludarabine
Outcomes
Primary Outcomes
Incidence of dose limiting toxicity
Time Frame: First infusion up to 30 days
The incidence of dose limiting toxicity (DLT). Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
Adverse events
Time Frame: 24 months
The nature, frequency, severity, and tolerability of adverse events (AEs) including clinically significant laboratory data, and their relation to dosage.
Pharmacodynamic (PD) and pharmacokinetic (PK)
Time Frame: Either 24 month or 15 years during long-term follow up if clinically indicated
PD is assessed by determine circulating B cell level; PK is assessed by determine circulating CAR20(NAP)-T cells.
Secondary Outcomes
- Progression free survival [PFS](24 months)
- Objective response rate [ORR](24 months)
- Best Objective Response(24 months)
- Duration of Response (DOR)(24 months)
- Overall Survival (OS)(either 24 months or 15 years during long-term follow up if clinically indicated)