to determine the safety and efficacy of CTL019 in adults with relapsed or refractory DLBCL and to monitor all patients exposed to CTL019 for 5 years following CTL019 infusion
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the efficacy of CTL019 therapy, defined as overall response rate
(ORR), which includes complete response (CR) and partial response (PR) based on
Cheson 2007 response criteria modified by Novartis version 1 as determined by a
central independent review committee. (Cheson et al 2007)
Secondary outcome
To evaluate the safety of CTL019, time to response (TTR), duration of overall
response (DOR), event free survival (EFS), progression free survival (PFS),
overall survival (OS), safety and efficacy in histological and molecular
subtypes. Characterize the in vivo cellular PK profile (levels, persistence,
trafficking) of CTL019 transduced cells into target tissues (blood, bone
marrow, cerebral spinal fluid and other tissue if available). Describe the
incidence of immunogenicity to CTL019 and describe the presence of Replication
competent lentivirus (RCL)
Background summary
DLBCL is the most frequent lymphoma subtype, representing 30-35% of all non-
Hodgkin lymphomas (NHL). Two-thirds of patients are cured by a combination of
chemotherapy agents ± radiotherapy in addition to rituximab, but one-third of
patients
have disease that is either refractory to initial therapy or relapses after
standard
therapy. Relapsed and refractory patients have a poor prognosis, particularly
those who do not respond to 2nd
line chemotherapy. The median survival of patients non-responding to 2nd line
chemotherapy is 4 months and. For patients relapsing with
chemotherapy-sensitive disease, high-dose chemotherapy followed by autologous
hematopoetic stem cell transplantation (HSCT) provides the best chance
of cure. However due to advanced age and comorbidities, only half of all
patients are
eligible for such an intensive approach. Yet, only a modest minority of patients
undergoing HSCT are cured. In summary treatment options for patients who do not
respond to 2nd line chemotherapy or who relapse after autologous HSCT are
generally considered palliative. Novel therapies are urgently needed for this
patient
population.
CTL019 is a novel adoptive cancer immunotherapy whereby autologous T cells are
genetically
modified/transduced by replication-deficient lentiviral vector (rdLVV) to
express anti CD19
antibody based receptors on the surface of T cells (the GMO) to target CD19
antigens on the
surface of malignant B cells (i.e., tumour cells).
Study objective
to determine the safety and efficacy of CTL019 in adults with relapsed or
refractory DLBCL and to monitor all patients exposed to CTL019 for 5 years
following CTL019 infusion
Study design
Patients will be treated with chemotherapie: Fludarabine and Cyclophosphamide,
during this phase autologous T-cells, from afaresis, will be genetically
modified. After chemotherapie the modified T-cells are infused. The patient
will be monitored for 5 years on regular basis and adverse events will be
monitored for 15 years after infusion.
Intervention
Leucopheresis, 3 days chemotherapie (Fludarabine and Cyclophosphamide) and
CTL019 infusion
Study burden and risks
Risk: adverse events of the CTL019 treatment after infusiion. Risk of
assessments e.g. bone marrow aspirate/biopsy, tumor biopsy and blood draw.
Burden: CTL019 infusion 1 time, possible hospitalization after infusion
(d1-d21) (dependant of medical condition), 8 controls in the first 28 days, 15
visites afterwards (m2-m60)
Physical examination: 6 times first 28 days after infusion, from there every
month (till m6) and from there every 3 months (m9-m12 and everry 6 months
(m18-m60)
Blood tests: every visit, maximal 50 ml per visit, depending on requierd
tests: 2-6 tubes
Lymphodepleting chemo: 1 time (2-3 weeks for infusion)
Leukafresis (B2206 protocol): 1 time
CT/MRI: D28 and from there every 3 months
PET-CT: only M3
Beenmerg biopt en of aspiraat: SCR, M3 and when CR occurs
Pregnancy check: every 3 months, testing only at SCR and prior infusion
Tumor biopsy: SCR and M3
Questionaires: Scr, M3, M6, M12, M18 en M24
optional use of remaining blood, bone marrow and tissue for future research
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1) Written informed consent must be obtained prior to any screening
procedures
2) Histologically confirmed DLBCL at last relapse (by central pathology review
before enrolment)
3) Relapsed or refractory disease after *2 lines of chemotherapy, including
rituximab and anthracycline, and
either having failed autologous HSCT, or being ineligible for or not
consenting to autologous HSCT
4) Measurable disease at time of enrollment
5) Life expectancy *12 weeks
6) ECOG performance status that is either 0 or 1 at screening
7) Adequate organ function:
- Renal function defined as: A serum creatinine of *1.5 x ULN OR eGFR
* 60 mL/min/1.73 m2
- Liver function defined as:
* ALT * 5 times the 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 LVEF * 45% confirmed by echocardiogram or
MUGA .
- Adequate bone marrow reserve without transfusions defined as:
* Absolute neutrophil count (ANC) > 1.000/mm3
* Absolute lymphocyte count (ALC) * 300/mm3
* Platelets * 50.000//mm3
* Hemoglobin > 8.0 mg/dl .
8) Must have an apheresis product of non-mobilized cells accepted for
manufacturing .
9) 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 CD19 CART infusion and untill CAR-T cells are no longer present by
PCR on two consecutive tests.
Exclusion criteria
1) Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any
other anti-CD19 therapy
2) Treatment with any prior gene therapy product
3) Active CNS involvement by malignancy
4) Prior allogeneic HSCT
5) Eligible for and concenting to autologus HSCT
6) Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of
infusion.
7) Investigational medicinal product within the last 30 days prior to screening
Note: Investigational therapies must not be used at any time while on study
until the first
progression following CTL019 infusion.
8) The following medications are excluded:
* Steroids: Therapeutic doses of steroids must be stopped > 72 hours
prior to prior to leukapheresis and > 72 hours CTL019 infusion. However, the
following physiological
replacement doses of steroids are allowed: <6 * 12 mg/m2/day
hydrocortisone or equivalent
* Immunosuppression: Any immunosuppressive medication must be
stopped * 2 weeks prior to leukapheresis and * 2 weeks prior to CTL019 infusion.
* Antiproliferative therapies other than lymphodepleting chemotherapy within 2
weeks of leukapheresis and 2 weeks prior to infusion
* Antibody use including anti-CD20 therapy within 4 weeks prior to
enrollment or 5 halflives of the respected antibody, whichever is longer
* CNS disease prophylaxis must be stopped > 1 week prior to
CTL019 infusion (e.g. intrathecal methotrexate)
9) Prior radiation therapy within 2 weeks of enrollment
10) Active replication of or prior infection with latent hepatitis B or active
hepatitis C
11) HIV positive patients
12) Uncontrolled acute life threatening bacterial, viral or fungal infection
(e.g. blood culture positive * 72 hours prior to infusion)
13) Unstable angina and/or myocardial infarction within 6
months prior to screening
14) 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 more than 5 years
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003060-20-NL |
| ClinicalTrials.gov | NCT02445248 |
| CCMO | NL54154.000.15 |