Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

NCT02228096 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: CCTL019B2205J2015-003736-13
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 13

Brief Summary

This was a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of an experimental therapy called CTL019 T-cells in pediatric patients with B-cell acute lymphoblastic leukemia, who were refractory to standard chemotherapy regimen or relapsed after allogeneic stem cell transplant.

Conditions

B-cell Acute Lymphoblastic Leukemia; Relapsed B-cell Acute Lymphoblastic Leukemia; Refractory B-cell Acute Lymphoblastic Leukemia

Keywords

relapsed/refractory; Philadelphia chromosome positive acute lymphoblastic leukemia; Pharmaceuticals; Philadelphia chromosome positive; Acute Lymphoid Leukemia (ALL); Acute Lymphocytic Leukemia (ALL); CTL019; tisagenlecleucel

Outcome Measures

Primary Outcomes (2)

• Overall Remission Rate (ORR) Per Independent Review Committee (IRC) (for ALL Participants)

  ORR is defined as the percentage of participants with a best overall disease response of complete remission (CR) or Complete remission with incomplete blood count recovery (CRi), where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until the start of new anticancer therapy. Best response was assigned in the following order: CR, CRi, CR or CRi with residual mediastinal disease, No response and Unknown.

  within 6 months after CTL019 infusion

• Overall Remission Rate (ORR) Per Local Investigator Assessment (for Lymphoblastic Lymphoma Patients Only)

  Overall Remission Rate (ORR), which includes Complete Remission (CR) and Complete Remission with Incomplete Blood Count Recovery (CRi), as determined by assessments of peripheral blood, bone marrow, CNS symptoms, physical exam (PE) and cerebrospinal fluid (CSF). This primary endpoint was based on the local investigator assessment. No participants with lymphoblastic lymphoma were infused in this study.

  6 months after CTL019

Secondary Outcomes (38)

• Percentage of Participants With Clinical Response Without Stem Cell Transplantation (SCT) at Month 6 - Per IRC Assessment

  Month 6

• Percentage of Subjects Who Achieved CR or CRi and Then Proceeded to SCT While in Remission Prior to Month 6 Response - Per IRC Assessment

  prior to Month 6

• Duration of Remission (DOR) Per Local and IRC Assessment

  From CR or CRi to relapse or death up to 60 months

• Percentage of Participants With CR or CRi With Minimum Residual Disease (MRD) Negative Bone Marrow 6 Months After CTL019 Infusion

  within 6 months

• Relapse-free Survival (RFS) for Responders Per Local and IRC Assessment

  60 Months

Study Arms (1)

tisagenlecleucel (CTL019)

EXPERIMENTAL

Pediatric patients with relapsed/refractory B-cell ALL

Biological: CTL019 T-cells

Interventions

CTL019 T-cells BIOLOGICAL

A target dose of CTL019 transduced cells will consist of a single infusion of 2.0 to 5.0 x 10\^6 CTL019 transduced cells per kg body weight (for patients ≤ 50 kg) and 1.0 to 2.5 x 10\^8 CTL019 transduced viable T cells (for patients \> 50 kg). The following cell dose ranges may be infused if all other safety release criteria are met: 0.2 to 5.0 x 10\^6 CTL019 transduced viable T cells per kg body weight (for patient ≤ 50 kg) and 0.1 to 2.5 x 10\^8 CTL019 transduced viable T cells (for patients \> 50 kg).

Also known as: tisagenlecleucel

tisagenlecleucel (CTL019)

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Relapsed or refractory pediatric B-cell ALL and lymphoblastic lymphoma:
• nd or greater Bone Marrow (BM) relapse OR
• Any BM relapse after allogeneic SCT and must be \> 6 months from SCT at the time of CTL019 infusion OR
• Refractory as defined by not achieving a CR after 2 cycles of a standard chemotherapy regimen chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapse leukemia OR
• Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated OR
• Ineligible for allogeneic SCT
• For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry
• Adequate organ function defined as:
• Renal function defined as (Calculated creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) \> 60 mL/min/1.73 m2 OR serum creatinine based on age/gender
• Alanine Aminotransferase (ALT) \<= 5 times the upper limit of normal (ULN) for age;
• Bilirubin \< 2.0 mg/dL;
• Must have a minimum level of pulmonary reserve defined as ≤Grade 1 dyspnea and pulse oxygenation \> 91% on room air
• Left Ventricular Shortening Fraction (LVSF) ≥ 28% confirmed by echocardiogram, or Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or MUGA within 7 days of screening
• Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening
• Life expectancy \> 12 weeks

You may not qualify if:

• Isolated extra-medullary disease relapse
• Patients with concomitant genetic syndrome: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.
• Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell \[surface Immunoglobulin (sIg) positive and kappa or lambda restricted positivity\] ALL, with FAB L3 morphology and /or a MYC translocation)
• Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
• Prior treatment with gene therapy product
• Treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
• Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
• Patient has participated in an investigational research study using an investigational agent within the last 30 days prior to screening
• Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
• Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
• HIV positive test within 8 weeks of screening
• The following medications are excluded:
• Steroids: Therapeutic systemic doses of steroids must be stopped \> 72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: \< 12 mg/m2/day hydrocortisone or equivalent
• Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be completed \> 6 weeks prior to CTL019 infusion
• GVHD therapies: Any systemic drug used for GVHD must be stopped \> 4 weeks prior to CTL019 infusion to confirm that GVHD recurrence is not observed (e.g. calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolate, rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-tumor necrosis factor \[anti-TNF\], anti-interleukin 6 \[anti-IL6\] or anti-interleukin 6 receptor \[anti-IL6R\], systemic steroids)

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (13)

Childrens Hospital Los Angeles SC

Los Angeles, California, 90027, United States

Location

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Children's Healthcare of Atlanta SC-2

Atlanta, Georgia, 30342, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-5941, United States

Location

University of Minnesota Medical Center

Minneapolis, Minnesota, 55455, United States

Location

Mercy Children's Kansas University

Kansas City, Missouri, 64108, United States

Location

Duke University Medical Center

Durham, North Carolina, 27708, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45230, United States

Location

Oregon Health and Science University SC

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Texas Southwestern Medical Center SC

Dallas, Texas, 75390-9034, United States

Location

University of Utah

Salt Lake City, Utah, 84113, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53705, United States

Location

Related Publications (4)

• Laetsch TW, Maude SL, Balduzzi A, Rives S, Bittencourt H, Boyer MW, Buechner J, De Moerloose B, Qayed M, Phillips CL, Pulsipher MA, Hiramatsu H, Tiwari R, Grupp SA. Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2022 Jun;36(6):1508-1515. doi: 10.1038/s41375-022-01550-z. Epub 2022 Apr 14.

  PMID: 35422096 DERIVED

• Thudium Mueller K, Grupp SA, Maude SL, Levine JE, Pulsipher MA, Boyer MW, August KJ, Myers GD, Tam CS, Jaeger U, Foley SR, Borchmann P, Schuster SJ, Waller EK, Awasthi R, Potthoff B, Warren A, Waldron ER, McBlane F, Chassot-Agostinho A, Laetsch TW. Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Blood Adv. 2021 Dec 14;5(23):4980-4991. doi: 10.1182/bloodadvances.2020003844.

  PMID: 34432863 DERIVED

• Levine JE, Grupp SA, Pulsipher MA, Dietz AC, Rives S, Myers GD, August KJ, Verneris MR, Buechner J, Laetsch TW, Bittencourt H, Baruchel A, Boyer MW, De Moerloose B, Qayed M, Davies SM, Phillips CL, Driscoll TA, Bader P, Schlis K, Wood PA, Mody R, Yi L, Leung M, Eldjerou LK, June CH, Maude SL. Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J Immunother Cancer. 2021 Aug;9(8):e002287. doi: 10.1136/jitc-2020-002287.

  PMID: 34353848 DERIVED

• Buechner J, Grupp SA, Hiramatsu H, Teachey DT, Rives S, Laetsch TW, Yanik GA, Wood P, Awasthi R, Yi L, Chassot-Agostinho A, Eldjerou LK, De Moerloose B. Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy. Blood Adv. 2021 Jan 26;5(2):593-601. doi: 10.1182/bloodadvances.2020002757.

  PMID: 33496754 DERIVED

MeSH Terms

Conditions

Burkitt Lymphoma; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

tisagenlecleucel

Condition Hierarchy (Ancestors)

Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Leukemia; Hematologic Diseases

Limitations and Caveats

Safety data reported is based on all the 64 infused patients with data cutoff of 24May2019.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2014
• First Posted: August 28, 2014
• Study Start: August 14, 2014
• Primary Completion: May 29, 2018
• Study Completion: May 24, 2019
• Last Updated: November 23, 2020
• Results First Posted: November 23, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share

Locations

US (13)