Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients

Novartis Pharmaceuticals34 enrolled

Overview

The purpose of the study was to assess the efficacy and safety of tisagenlecleucel in pediatric, adolescent and young adult patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL) including Burkitt Lymphoma and Burkitt Leukemia. For pediatric patients who have r/r B-NHL including Burkitt Lymphoma and Burkitt Leukemia, survival rates are dismal, only \~20-50% subjects are alive at 2 years with overall response rate (ORR) of 20-30% after conventional salvage chemotherapy.

This study was part of an agreed Pediatric Investigation Plan (PIP). The single-arm study design included r/r B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia subject population with poor prognosis, lack of approved effective therapies in this setting. Subject population included aggressive subtypes of B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia who were allowed to receive "bridging therapy" of investigator's choice. After assessment of eligibility, subjects qualifying for the study were enrolled and were allowed to start lymphodepleting chemotherapy as recommended in protocol after which a single dose of tisagenlecleucel product was infused. The efficacy of tisagenlecleucel was evaluated through the primary endpoint of Overall Response Rate (ORR) which included complete response (CR) and partial response (PR) as determined by local assessment. Safety assessments were conducted until study completion.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-Hodgkin Lymphoma

Interventions

TisagenlecleucelBIOLOGICAL

Tisagenlecleucel was infused once as an intravenous infustion at a dose of either 0.2 to 5 x 106 CAR-positive viable T cells per kg body weight for subjects ≤ 50 kg or 0.1 to 2.5 x 108 CAR-positive viable T cells for subjects \> 50 kg.

lymphodepleting chemotherapyDRUG

Prior to tisagenlecleucel infusion, each subject underwent lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)

Bridging TherapyDRUG

Pre-treatment phase could also include bridging therapy of investigator's choice

Eligibility

Sex: ALLMax age: 25 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt lymphoma/ Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with B-cell NHL associated with Nijmegen breakage syndrome will be allowed. * Patients \<25 years of age and weighing at least 6 kg at the time of screening * Patients who have relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic stem cell transplant) or are primary refractory (have not achieved a CR or PR after the first line of therapy) * Measurable disease by radiological criteria in all patients at the time of screening. Patients with Burkitt leukemia who don't meet radiological criteria must have bone marrow involvement of \>25% by local assessment of bone marrow aspirate and/or biopsy. * Karnofsky (age ≥16 years) or Lansky (age \<16 years) performance status ≥60. * Adequate bone marrow reserve without transfusions (transfusion \>2 weeks prior to laboratory assessment is allowed) defined as: 1. Absolute neutrophil count (ANC) \>1000/mm3 2. Platelets ≥50000//mm3 3. Hemoglobin ≥8.0 g/dl * Adequate organ function defined as: 1. a serum creatinine (sCR) based on gender/age as follows: Maximum Serum Creatinine (mg/dL) Age Male Female 1 to \<2 years 0.6 0.6 2 to \<6 years 0.8 0.8 6 to \<10 years 1.0 1.0 10 to \<13 years 1.2 1.2 13 to \<16 years 1.5 1.4 ≥16 years 1.7 1.4 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age 3. Total bilirubin \<2 mg/dL (for Gilbert's Syndrome patients total bilirubin \<4 mg/dL) 4. Adequate pulmonary function i. Oxygen saturation of \>91% on room air ii. No or mild dyspnea (≤Grade 1) * Must have a leukapheresis material of non-mobilized cells accepted for manufacturing. Exclusion Criteria: * Prior gene therapy or engineered T cell therapy. * Prior treatment with any anti-CD19 therapy. * Allogeneic hematopoietic stem cell transplant (HSCT) \<3 months prior to screening and ≤4 months prior to infusion. * Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT. * Prior diagnosis of malignancy other than study indication, and not disease free for 5 years. * Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.) * Presence of active hepatitis B or C as indicated by serology. * Human Immunodeficiency Virus (HIV) positive test. * Active neurological autoimmune or inflammatory disorders not related to B cell NHL (eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis) * Active central nervous system (CNS) involvement by malignancy. * Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders (PTLD) associated lymphomas.

Locations (26)

Childrens Hospital Los Angeles

Los Angeles, California, United States

Outcomes

Primary Outcomes

Overall Response Rate (ORR) as Determined by Local Investigator

The overall response rate (ORR) is defined as the percentage of subjects with a best overall disease response of complete response (CR) or partial response (PR), where the best overall disease response is defined as the best disease response recorded from tisagenlecleucel infusion until progressive disease or start of new anticancer therapy, whichever comes first.

Time frame: 6 months post-tisagenlecleucel infusion

Secondary Outcomes

Duration of Response (DOR)

Duration of response (DOR) is defined as the time from the date of first documented disease response (CR or PR) as determined by local investigator assessments to the date of first documented progression or death due to underlying cancer.

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Event Free Survival (EFS)

Event free survival (EFS) is defined as the time from date of first tisagenlecleucel infusion to the earliest date of death from any cause, disease progression as determined by local investigator assessments, or starting new anticancer therapy for underlying cancer, excluding hematopoietic stem cell transplant (HSCT).

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Relapse Free Survival (RFS)

Relapse free survival (RFS) is defined as the time from the date of first documented disease response (CR or PR) as determined by local investigator assessments to the date of first documented disease progression or death due to any cause.

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Progression Free Survival (PFS)

Progression free survival (PFS) is defined as the time from the date of first tisagenlecleucel infusion to the date of first documented disease progression as determined by local investigator assessments or death due to any cause. Progression is defined using the International non-Hodgkin Lymphoma Response Criteria. For a PET-based response, progressive disease is defined as a 4 or 5 on the 5 point scale with increased uptake compared to the nadir or new FDG-avid foci consistent with lymphoma. For a CT/MRI based response progressive disease is defined as a 25% increase in the SPD (sum of the products of two largest perpendicular diameters) of index lesions, or unequivocal progression in either non-index lesions or the spleen. Any new disease attributable to lymphoma would also constitute progressive disease.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.