Clinical trial NCT04553393: Decitabine-primed Tandem CD19/CD20 CAR T Cells Plus Epigenetic Agents in Aggressive r/r B-NHL With Huge Tumor Burden
Official title: Treatment of Decitabine-primed Tandem Targeting CD19 and CD20 Chimeric Antigen Receptor T Cells Plus Epigenetic Agents in Aggressive Relapsed and/or Refractory Non-Hodgkin's Lymphoma Patients With Huge Tumor Burden
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Refractory or Relapsed Aggressive r/r B-NHL With Huge Tumor Burden
Lead sponsor: Chinese PLA General Hospital
Sponsor class: OTHER
First posted: 2020-09-17
Enrollment: 80
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This open-label, multi-cohorts, phase 1/2 study has the primary objective of comparing decitabine-primed tandem CART 19/20 solo, with decitabine-primed tandem CART 19/20 plus chidamide, decitabine-primed tandem CART 19/20 plus decitabine, and decitabine-primed tandem CART 19/20 plus decitabine+chidamide in patients with aggressive B-NHL who were confirmed as Relapsed and/or Refractory B cell Non-Hodgkin's Lymphoma with hugh tumor burden (Sum of the Product of the perpendicular Diameters for multiple lesions, SPD ≥ 100cm\^2 or the largest-diameter of tumor ≥ 10 cm.).


Eligibility criteria: Inclusion Criteria:

1. Age ≥16 and ≤ 65 years.
2. Sum of the Product of the perpendicular Diameters for multiple lesions, SPD ≥ 100cm\^2 or the largest-diameter of tumor ≥ 10cm.
3. Histologically confirmed CD20+ and/or CD19+ aggressive B-cell non-Hodgkin lymphoma (NHL), including the following types defined by the World Health Organization (WHO) 2016:

   * Diffuse large B-cell lymphoma (DLBCL).
   * High grade B-cell lymphoma(HGBL).
   * Other aggressive B-cell lymphoma.
4. Refractory disease or relapse after treatment with ≥2 lines of chemotherapy, including rituximab and anthracycline and either having failed autologous hematopoietic stem cell transplantation (HSCT), being ineligible for autologous HSCT or not consenting to autologous HSCT.

   We defined chemotherapy-refractory disease as meeting one or more of the following criteria:
   * No response to first-line therapy (primary refractory disease).
   * No response to second-line or later therapy.
   * Progressive disease (PD) as the best response to the most recent therapy regimen.
   * Stable disease (SD) as the best response after at least 2 cycles of the most recent line of therapy with an SD duration of no longer than 6 months from the last dose of therapy.

   Failure following autologous HSCT was defined as follows:
   * PD or relapsed disease ≤12 months after autologous stem cell transplantation (ASCT) (requires biopsy-proven recurrence in relapsed subjects).
   * No response or relapse after salvage therapy is given post-ASCT.
5. PD or relapse ≥3 months after treatment with targeted CD19 therapy, including CD19 CAR T cells or anti-CD19/anti-CD3.
6. Successful leukapheresis assessment and preculture of T cells.
7. Life expectancy \> 3 months.
8. Adequate organ function:

   * Creatinine \< 1.6 mg/dL (140 µmol/L) or creatinine clearance ≥60 mL/min.
   * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 3× upper limit of the normal range.
   * Bilirubin \<2.0 mg/dL unless the subject had Gilbert's syndrome (\<3.0 mg/dL).
   * A minimum level of pulmonary reserve defined as ≤ grade 1 dyspnoea and pulse oxygenation \> 91% with room air.
   * Cardiac ejection fraction ≥50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings.
9. An adequate bone marrow reserve defined as:

   * Absolute neutrophil count (ANC)\>1,000/mm3.
   * Absolute lymphocyte count (ALC)≥300/mm3.
   * Platelet count ≥ 50,000/mm3.
   * Haemoglobin \> 7.0 mg/dL.
10. Measurable or assessable disease according to the "IWG Response Criteria for Malignant Lymphoma" (Cheson 2014). Patients in complete remission (CR) with no evidence of disease were not eligible.
11. Informed consent/assent requiring that all patients have the ability to understand and the willingness to provide written informed consent.

Exclusion Criteria:

1. Patients with definite involvement of the gastrointestinal tract. Endoscopy should be performed to confirm gastrointestinal involvement in suspected patients. However, patients with central nervous system (CNS) involvement were cautiously enrolled in this clinical study.
2. Detection of a clear HAMA effect in patients with prior CD19 CAR T cell treatment failure or recurrence, or negative tumour puncture detection of CD19 and CD20.
3. Pregnant or lactating women.
4. Uncontrolled active bacterial or viral infection (active hepatitis B or hepatitis C infection, HIV infection) or treponema pallidum infection.
5. Class III/IV cardiovascular disability according to the New York Heart Association Classification and a cardiac ejection fraction ≥50%.
6. History of allo-HSCT.
7. Requirement for urgent therapy due to tumour mass effects such as respiratory obstruction or blood vessel compression.
8. Current or expected need for systemic corticosteroid therapy.
9. Any organ failure.
10. Patients with a second tumour requiring therapy or intervention.
11. Eastern Cooperative Oncology Group (ECOG) performance status score between 0 and 2.
12. Subjects considered unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation according to the investigator's judgement.

Primary outcomes:
measure: Adverse events after intervention
timeFrame: 12 months
measure: Progression Free Survival
timeFrame: 2 years
measure: Duration of Response
timeFrame: 2 years
measure: Overall Survival
timeFrame: 2 years
Secondary outcomes:
measure: Objective Response Rate Outcome Measure
timeFrame: 2 years
measure: Intervention treatment-related adverse events (AEs)
timeFrame: 12 months
Other outcomes:
measure: Exploratory research
timeFrame: 12 months
Locations:
city: Beijing
country: China
facility: Biotherapeutic Department of Chinese PLA General Hospital
state: Beijing
Study officials:
affiliation: Chinese PLA Hospital
name: Weidong Han, M.D.
role: PRINCIPAL_INVESTIGATOR
References: