Clinical trial NCT02445248: Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients
Official title: A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Large B-cell Lymphoma (DLBCL)
Keywords: Diffuse large B-cell lymphoma
DLBCL
Relapsed/refractory
CTL019
CART19
CART
CAR T cells
Chimeric antigen receptor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-05-15
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.

Detailed description: This was a single arm, open-label, multi-center, Phase II study conducted to determine the efficacy and safety of tisagenlecleucel in adult patients with r/r DLBCL. The study consisted of the following sequential periods: Screening, Pre-Treatment, Treatment and Primary follow-up, Secondary follow-up, Survival follow-up.

Patients were enrolled in 2 cohorts to receive one tisagenlecleucel infusion as follows:

* Main Cohort (patients treated with tisagenlecleucel manufactured at the Novartis manufacturing facility in Morris Plains, US, referred to as "US manufacturing facility") and
* Cohort A (patients treated with tisagenlecleucel manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany, referred to as "EU manufacturing facility").

The study enrolled adult patients ≥ 18 years with histologically confirmed relapsed or refractory (r/r) DLBCL after ≥ 2 lines of chemotherapy, with a life expectancy of ≥ 12 weeks and not eligible or not consenting to stem cell transplantation (SCT).

Patients had measurable disease at time of enrollment, adequate organ function and zero or one Eastern Cooperative Oncology Group performance status at screening. For each patient, the apheresis product of non-mobilized cells was received and accepted by the manufacturing site.

Eligibility criteria: Inclusion Criteria:

* Written informed consent must be obtained prior to any screening procedures
* Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment.

  .- Relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT
* Measurable disease at time of enrollment
* Life expectancy ≥12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening
* Adequate organ function:

  * Renal function defined as:

    * A serum creatinine of ≤1.5 x Upper Limit of Normal ULN OR
    * Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m\^2
  * Liver function defined as:

    * Alanine Aminotransferase (ALT) ≤ 5 times the Upper Limit of Normal (ULN) for age
    * Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
  * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation \> 91% on room air
  * Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
  * Adequate bone marrow reserve without transfusions defined as:

    * Absolute neutrophil count (ANC) \> 1.000/mm\^3
    * Absolute lymphocyte count (ALC) ≥ 300/mm\^3 and absolute number of CD3+ T cells \> 150/mm\^3
    * Platelets ≥ 50.000//mm\^3
    * Hemoglobin \> 8.0 g/dl
  * Must have an apheresis product of non-mobilized cells accepted for manufacturing
  * Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests

Exclusion Criteria:

* Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
* Treatment with any prior gene therapy product
* Active Central Nervous System (CNS) involvement by malignancy
* Prior allogeneic HSCT
* Eligible for and consenting to HSCT
* Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
* Investigational medicinal product within the last 30 days prior to screening
* The following medications are excluded:

  * Steroids: Therapeutic doses of steroids must be stopped \>72 hours prior to leukapheresis and \>72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: \< 12 mg/m\^2/day hydrocortisone or equivalent
  * Immunosuppression: Any other immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators)
  * Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
* Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyurea) must be stopped \> 72 hour prior to leukapheresis and \> 72 hours prior to CTL019 infusion
* Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion
* Fludarabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis collection.

  * Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer
  * CNS disease prophylaxis must be stopped \> 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
* Prior radiation therapy within 2 weeks of infusion
* Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive )
* HIV positive patients
* Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
* Unstable angina and/or myocardial infarction within 6 months prior to screening
* Previous or concurrent malignancy with the following exceptions:

  * Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
  * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
  * A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
* Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before lymphodepletion
* Intolerance to the excipients of the CTL019 cell product
* Cardiac arrhythmia not controlled with medical management
* Prior treatment with any adoptive T cell therapy
* Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter's transformation, and Burkitt lymphoma
* Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)

Primary outcomes:
measure: Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort
timeFrame: 60 months
Secondary outcomes:
measure: Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients
timeFrame: 5 years
measure: Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)
timeFrame: up to approx. 3.3 months
measure: Duration of Overall Response (DOR) Per IRC
timeFrame: up to approx. 60.1 months
measure: Event Free Survival (EFS) Per Independent Review Committee
timeFrame: up to approx. 61 months
measure: Progression Free Survival (PFS) Per Independent Review Committee
timeFrame: up to approx. 61 months
measure: Overall Survival (OS) Per Independent Review Committee
timeFrame: 60 months
measure: Pharmacokinetics (Pk): Cmax
timeFrame: 60 months
measure: Pharmacokinetics (Pk): Tmax
timeFrame: 60 months
measure: Pharmacokinetics (Pk): AUC0-28d and AUC0-84d
timeFrame: 0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d
measure: Pharmacokinetics (Pk): T1/2
timeFrame: 60 months
measure: Pharmacokinetics (Pk): Clast
timeFrame: 60 months
measure: Pharmacokinetics (Pk): Tlast
timeFrame: 60 months
measure: Incidence of Immunogenicity to CTL019
timeFrame: pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center .
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine/Winship Cancer Institute SC CTL019
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center Hematology and Oncology SC - CTL019B2207J
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center SC - CTL019C2201
state: Kansas
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center SC-2
state: Maryland
city: Ann Arbor
country: United States
facility: Uni of Michigan Health System SC CTL019
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Columbus
country: United States
facility: The Ohio State University James Cancer Hospital &
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University Oregon Health & Sci Uni
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Perelman School of Medicine
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center SC
state: Texas
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Camperdown
country: Australia
facility: Novartis Investigative Site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Cartron G, Fox CP, Liu FF, Kostic A, Hasskarl J, Li D, Bonner A, Zhang Y, Maloney DG, Kuruvilla J. Matching-adjusted indirect treatment comparison of chimeric antigen receptor T-cell therapies for third-line or later treatment of relapsed or refractory large B-cell lymphoma: lisocabtagene maraleucel versus tisagenlecleucel. Exp Hematol Oncol. 2022 Mar 25;11(1):17. doi: 10.1186/s40164-022-00268-z.
citation: Frigault MJ, Dietrich J, Gallagher K, Roschewski M, Jordan JT, Forst D, Plotkin SR, Cook D, Casey KS, Lindell KA, Depinho GD, Katsis K, Elder EL, Leick MB, Choi B, Horick N, Preffer F, Saylor M, McAfee S, O'Donnell PV, Spitzer TR, Dey B, DeFilipp Z, El-Jawahri A, Batchelor TT, Maus MV, Chen YB. Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial. Blood. 2022 Apr 14;139(15):2306-2315. doi: 10.1182/blood.2021014738.
citation: Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Bishop MR, Damon LE, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu JM, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradini P, Martinez-Prieto M, Han X, Tiwari R, Salles G, Maziarz RT. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1403-1415. doi: 10.1016/S1470-2045(21)00375-2. Epub 2021 Sep 10.
citation: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
citation: Westin JR, Kersten MJ, Salles G, Abramson JS, Schuster SJ, Locke FL, Andreadis C. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am J Hematol. 2021 Oct 1;96(10):1295-1312. doi: 10.1002/ajh.26301. Epub 2021 Aug 13.
citation: Schuster SJ, Maziarz RT, Rusch ES, Li J, Signorovitch JE, Romanov VV, Locke FL, Maloney DG. Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv. 2020 Apr 14;4(7):1432-1439. doi: 10.1182/bloodadvances.2019001304.
citation: Maziarz RT, Schuster SJ, Romanov VV, Rusch ES, Li J, Signorovitch JE, Maloney DG, Locke FL. Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv. 2020 Apr 14;4(7):1440-1447. doi: 10.1182/bloodadvances.2019001305.
citation: Maziarz RT, Waller EK, Jaeger U, Fleury I, McGuirk J, Holte H, Jaglowski S, Schuster SJ, Bishop MR, Westin JR, Mielke S, Teshima T, Bachanova V, Foley SR, Borchmann P, Salles GA, Zhang J, Tiwari R, Pacaud LB, Ma Q, Tam CS. Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020 Feb 25;4(4):629-637. doi: 10.1182/bloodadvances.2019001026.
citation: Awasthi R, Pacaud L, Waldron E, Tam CS, Jager U, Borchmann P, Jaglowski S, Foley SR, van Besien K, Wagner-Johnston ND, Kersten MJ, Schuster SJ, Salles G, Maziarz RT, Anak O, Del Corral C, Chu J, Gershgorin I, Pruteanu-Malinici I, Chakraborty A, Mueller KT, Waller EK. Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL. Blood Adv. 2020 Feb 11;4(3):560-572. doi: 10.1182/bloodadvances.2019000525.
citation: Bishop MR, Maziarz RT, Waller EK, Jager U, Westin JR, McGuirk JP, Fleury I, Holte H, Borchmann P, Del Corral C, Tiwari R, Anak O, Awasthi R, Pacaud L, Romanov VV, Schuster SJ. Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion. Blood Adv. 2019 Jul 23;3(14):2230-2236. doi: 10.1182/bloodadvances.2019000151.
citation: Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jager U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak O, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1.