Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Follicular

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Follicular Lymphoma

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Patients will receive a lymphodepletion chemotherapy with fludarabine plus cyclophosphamide for three consecutive days(Day -5 to Day -3) before infusion of CD19-targeted chimeric antigen receptor T-cell (CD19 CAR-T). Patients will receive the CD19 CAR-T(also known as PL001) infusion on Day 0.

Drug: Fludarabine

patients will receive a lymphodepletion chemotherapy with Fludarabine 25 mg/m2/day IV for 3 days on Day-5 to Day-3(a safe window for a small subset of patients will be D -7 to D -3).

Drug: Cyclophosphamide

patients will receive a lymphodepletion chemotherapy with cyclophosphamide 300 mg/m2/day IV for 3 dys Day-5 to Day-3(a safe window for a small subset of patients will be D -7 to D -3).

Biological: CD19 CAR-T

CD19 CAR-T cells will be administered using as a single dose at 0.1-9\*10\^6 cells/kg on Day 0 after completion of the lymphodepletion chemotherapy. The body weight calculated for PL001 dose is the actual body weight on the day of leukapheresis.

CD19-targeted chimeric antigen receptor T-cell

Cherry Lo, MSC

Shyh-Shin Chiou

Jyh-Pyng Gau

Shang-Ju Wu

Liang-Tsai Hsiao

Chen-Lung Lin, MD

This is a multiple center, non-randomized, open-label, phase 1/2 study. The primary objective of Phase 1 is to evaluate the safety of PL001 and find the recommended Phase 2 dose (RP2D). The objective of Phase 2 is to evaluate the safety and efficacy of CD19 CAR-T(known as PL001).

Cluster of differentiation (CD) 19 chimeric antigen receptor T-cell (CAR-T) has been a very promising treatment option for multiple types of B-cell lymphoma. Kymriah® (tisagenlecleucel, Novartis) and Yescarta® (axicabtagene ciloleucel, Gilead) were licensed by the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) in 2017 to treat relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and High-grade B-cell lymphoma (HGBCL). A third anti-CD19 CAR-T product, Tecartus (brexucabtagene autoleucel, Gilead) was approved by the US FDA for relapsed and refractory mantle cell lymphoma (MCL) in July 2020. In February 2021, another product, Breyanzi® (lisocabtagene maraleucel, Juno Therapeutics, Inc.), was approved by the US FDA for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, Primary mediastinal large B cell lymphoma (PMLBCL), and Gr. 3b FL.

Currently, in Taiwan, no CD19 CAR-T therapies are available commercially.This Phase 1/Phase 2 study will test PL001, a CD19 CAR-T therapy manufactured by Pell Bio-Med Technology Co., Ltd., as a monotherapy for relapsed or refractory B-cell lymphoma. The Phase 1 of the study will be conducted to establish a dose range that is well tolerated by the majority of patients and to provide a safety profile of PL001 in the target patient population. The results of the Phase 1 of the study will recommend the dose selection for the Phase 2 of the study. Phase 2 of the study will assess the efficacy and safety of PL001 in patients with relapsed or refractory B cell lymphoma.

This study is a multiple-center, non-randomized, open-label, phase 1/2 study. Lymphodepletion chemotherapy (intravenous infusion of fludarabine plus cyclophosphamide will be administered for 3 consecutive days before the day of PL001 dosing (Day 0) and should take place within Day -5 to Day -3 (a safe window for a small subset of patients will be D -7 to D -3). This study will test two dose levels of PL001, dose level 1 and dose level 2. In Phase 1, doses will be tested in the modified "3 + 3" design initiating with dose level 1. The primary objective of Phase 1 is to assess the safety of PL001 and find the recommended phase 2 dose. Phase 2 expansion cohort will receive PL001 at the recommended dose determined in Phase 1. Efficacy evaluations using computed tomography (CT) and positron emission tomography (PET) will be performed at 1, 3, 6, 9, and 12 months.

Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) for Relapsed or Refractory B-cell Lymphoma

A Phase 1/2 Multicenter, Open-label, Single-arm Study to Evaluate the Safety and Efficacy of CD19-targeted Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) Therapy in Patients With Relapsed or Refractory B-cell Lymphoma

Persistence of PL001 in peripheral blood using flow cytometry

PL001 transgene levels by qPCR (quantitative polymerase chain reaction) in peripheral blood

Rates for successful production and infused patients

Cytokine concentrations in peripheral blood

Dose-limiting toxicities through 30 days after PL001 infusion

The BOR comprising of patients with partial and complete responses according to Lugano criteria assessed by the Independent Central Review.

Treatment-related adverse events assessed by CTCAE v 5.0. Overall grading of Cytokine Release Syndrome, immune effector cell associated neurotoxicity syndrome, based on the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.

The BOR of patients with partial and complete responses according to Lugano criteria assessed by the Investigator.

Median duration of response (mDOR) measured from the time of initial documented response (complete response or partial response) until documented disease progression or death.

Progression-free survival (PFS) defined as the time from the infusion of PL001 until objective disease progression or death, whichever occurs first.

Overall survival (OS) defined as the time from the infusion of PL001 until death from any cause.

Change in the health-related quality of life (HRQoL) by FACT-Lym (the Functional Assessment of Cancer Therapy-Lymphoma)® version 4

Pell Bio-Med Technology Co., Ltd.

Ofatumumab

Patients who had negative baseline Bcl-2 in PB and BM will not undergo further treatment after radiotherapy; they will not repeat Bcl-2 during subsequent follow-up visits.

Patients who had positive baseline Bcl-2 in PB and / or BM and become negative after local radiotherapy will not undergo further treatment.

Patients who had positive baseline Bcl-2 in PB and / or BM and remain positive after local radiotherapy get Ofatumumab (8 weekly infusion of 1000 mg total dose).

Patients Bcl-2 negativized either after radiotherapy or after Ofatumumab, who became Bcl-2 positive during the follow-up monitoring will be treated/retreated with Ofatumumab 8 weekly infusions at the conventional dose of 1000 mg; Bcl-2 monitoring will be continued subsequently according to the program.In case of persistent positive PCR after Ofatumumab the treatment will not be repeated.

OFATUMUMAB

Alessandro Pulsoni, MD

Phase II prospective multicenter study for stage I/II Follicular Lymphoma treated with involved-field radiotherapy (IFRT) at doses of 24 Gy) with or without Ofatumumab for 8 weekly doses on molecular basis. Patients with positive basal Bcl-2 will be followed every 3 months and with Bcl-2 detection every 6 months for 3 years. Patient with negative basal Bcl-2 will be followed every 3 months without further Bcl-2 detection.

Ofatumumab treatment will be administered to:

1. Patients with positive basal PCR for Bcl-2-IgH rearrangement in BM and/or PB, resulting still positive after IFRT;
2. Patients with positive basal PCR for Bcl-2-IgH in

Stage I/IIA follicular lymphoma (FL) is considered a localized disease that can be adequately treated with radiotherapy alone. This strategy is recommended by the guidelines of the "Società Italiana di Ematologia" (SIE) and of the "European Society for Medical Oncology" (ESMO) The accurate definition of the truly localised forms represents a crucial issue in order to ensure an appropriate treatment design for such patients. The characteristic t(14;18) translocation, which leads to the over-expression of the Bcl-2 gene, is found in approximately 85% of FL; cells bearing this translocation can be detected in the peripheral blood (PB) or bone marrow (BM) by polymerase chain reaction (PCR).

PCR for the t(14;18) translocation provides a sensitive device to identify the presence of minimal non-Hodgkin lymphoma (NHL) cell contamination. Previous experiences have demonstrated that despite the limited stage, Bcl-2/IgH+ cells can be found at diagnosis in PB and/or BM of the majority of the patients. After treatment with local radiotherapy confined to the involved lymph node(s) only, disappearance of circulating Bcl-2/IgH+ cells in PB and/or BM was demonstrated in approximately 60% of positive patients. Quantitative PCR demonstrated the feasibility of clearing PB and BM Bcl-2+ cells after local irradiation of the primary site of the disease only when the basal number of lymphoma cells was \<1:100 000.

Anti-CD20 monoclonal antibody treatment has clearly demonstrated, both alone and in combination with chemotherapy and radiotherapy, a high therapeutic potential in FL. A significant impact of treatment with the anti CD20 monoclonal antibody in reducing the minimal residual disease in FL has been demonstrated in several studies when used as consolidation or during the maintenance phase.

No data are currently available concerning the ability of anti-CD20 antibody treatment in reducing the proportion of Bcl-2 positive residual cells after radiotherapy in localized FL. The objective of this study is to take advantage of the therapeutic potential of anti-CD20 monoclonal antibody to reduce or eliminate minimal residual disease in patients with FL in localized stage (I/II) after conventional treatment with local radiotherapy of the involved site(s). The effectiveness of anti-CD20 monoclonal antibody treatment will be determined by the proportion of negativization of residual Bcl-2 positive cells after radiotherapy, evaluated by qualitative and quantitative PCR detection of viable Bcl-2/IgH rearranged cells in PB and/or BM.

"MIRO" Molecularly Oriented Immuno-radio-therapy

"MIRO" (Molecularly Oriented Immuno - Radio -Therapy): Multicenter Phase II Study for the Treatment of the Molecular Basis of Stage I / II Follicular Lymphoma With Local Radiotherapy With / Without Ofatumumab

The proportion of Bcl-2 negativization after Ofatumumab treatment will be estimated by the proportion, and its confidence interval, of residual Bcl-2 positive cases after radiotherapy, which will became negative after Ofatumumab treatment

Clinical response rate will be evaluated by the proportion and its confidence interval of patients achieving overall response (OR) complete response (CR) and partial response (PR).

Progression Free Survival (PFS) is defined as the length of time between the date of registration and the earliest date of disease progression or death due to any cause; If the patients doesn't not have a documented date of progression or death, the PFS will be censored at the date of last adequate assessment. Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease

Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease

Fondazione Italiana Linfomi - ETS

After completion or early withdraw from the treatment protocol, patients will be enrolled into this long-term follow-up study. If patients do not enter this study right after leaving the treatment protocol, they may have the option to enter this study at any time within 15 years after the last lentiviral-based gene-edited immune cell infusion.

Some patients may require joining other Pell's gene-edited immune cell therapy study during participating in this long-term follow-up study. For such case, the patient could be enrolled into the new treatment protocol. Meanwhile, the patient can be remaining in this long-term follow-up protocol as an inactive participant.

No study drug or other planned treatment will be administered. Subjects who previously received Pell's lentiviral-based gene-edited immune cell therapy will be evaluated the safety and efficacy.

Pell's lentiviral-based gene-edited immune cell therapy

According to health authorities guidances (FDA 2006, EMA(European Medicines Agency) 2009) for gene therapy clinical trials, observing subjects for delayed adverse events for 15 years is recommended. This purpose of this long-term follow-up study is to evaluate the safety and efficacy in patients who have ever received lentiviral-based gene-edited immune cells which are manufactured by Pell Bio-Med Technology Co. Ltd.

After completion or early withdraw from the other treatment protocol, patients should be enrolled into this long-term follow-up study. If patients do not enter this study right after leaving the treatment protocol, they may have the option to enter this long-term follow-up study at any time within 15 years after the last lentiviral-based gene-edited immune cell infusion.

Long-term Follow-up Study of Lentiviral-based Gene-edited Immune Cell Therapy

Long-term Follow-up Study to Evaluate the Safety and Efficacy in Patients Who Have Ever Received Lentiviral-based Gene-edited Immune Cell Therapy

• Proportion of patients with any events of the following items which are suspected related to previous gene-edited immune cell therapy.

1. New malignancies
2. New incidence or exacerbation of a pre-existing neurologic disorder
3. New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder
4. New incidence of a hematologic disorder, including hypogammaglobulinemia
5. New incidence of infection (potentially product-related)
6. Other than the above adverse events, which are suspected related to gene-edited immune cell therapy judged by the investigator

Proportion of patients with detectable RCL in peripheral blood by VSV-G(Vesicular stomatitis virus G) qPCR

Proportion of patients with detectable transgene level in peripheral blood by qPCR

Persistence of gene-edited immune cells in peripheral blood using flow cytometry

1. Proportion of patients with relapse or progress among patients who didn't progress or relapse at study entry/reentry
2. Incidence of death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) for Relapsed or Refractory B-cell Lymphoma	NCT05326243	Diffuse Large B... Primary Mediast... Large B-cell Ly... Follicular Lymp... Follicular Lymp...	CD19-targeted c...	14 Years - 70 Years	Pell Bio-Med Technology Co., Ltd.
Phase 1/2 Study of CD19 Chimeric Antigen Receptor T-cell (CD19 CAR-T; PL001) for Relapsed or Refractory B-cell Lymphoma	NCT05326243	Diffuse Large B... Primary Mediast... Large B-cell Ly... Follicular Lymp... Follicular Lymp...	CD19-targeted c...	14 Years - 70 Years	Pell Bio-Med Technology Co., Ltd.
"MIRO" Molecularly Oriented Immuno-radio-therapy	NCT02710643	Follicular Lymp... Follicular Lymp... Follicular Lymp...	OFATUMUMAB	18 Years -	Fondazione Italiana Linfomi - ETS
Long-term Follow-up Study of Lentiviral-based Gene-edited Immune Cell Therapy	NCT05377307	Diffuse Large B... Large B-cell Ly... Primary Mediast... Follicular Lymp... Follicular Lymp...	Pell's lentivir...	-	Pell Bio-Med Technology Co., Ltd.
"MIRO" Molecularly Oriented Immuno-radio-therapy	NCT02710643	Follicular Lymp... Follicular Lymp... Follicular Lymp...	OFATUMUMAB	18 Years -	Fondazione Italiana Linfomi - ETS

Spots Global Cancer Trial Database for follicular lymphoma grade 3a