Primary Objective- To determine if axicabtagene ciloleucel is superior to SOC as measured by event-free survival (EFS), as determined by blinded central reviewSecondary Objectives- To evaluate the effect of axicabtagene ciloleucel compared to SOC on…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
Event Free Survival (EFS): EFS is defined as the time from randomization to the
earliest date of disease progression per the Lugano Classification (Cheson et
al, 2014), commencement of new lymphoma therapy, or death from any cause.
Subjects not meeting the criteria for these events by the analysis data cutoff
date will be censored.
For the primary analysis of EFS, disease progression events and censoring times
will be determined by blinded central review. Events of new therapy and death
will be based on the clinical trial database.
Secondary outcome
Key secondary endpoints (in order of hierarchical testing):
- Objective response rate
- Overall survival
Secondary endpoints:
- EFS based on investigator disease assessments
- Modified EFS based on blinded central review and on investigator disease
assessments
- Progression-free survival
- Duration of response and complete response
- Incidence of adverse events and clinically significant changes in safety lab
values including antibodies to axicabtagene ciloleucel
- Changes from screening to post baseline in the global health status QoL scale
and the physical functioning domain of the European Organisation for Research
and Treatment of Cancer Quality of Life Questionnaire Cancer-30 (EORTC QLQ-C30)
- Changes from screening to post baseline in the Euro-QOL, Five Dimensions,
Five Levels (EQ-5D-5L) index and visual analog scale (VAS) scores
Exploratory endpoints:
For axicabtagene ciloleucel treatment arm only:
• Levels of anti CD19 chimeric antigen receptor (CAR) T cells in blood
• Levels of cytokines in serum
For both treatment arms:
• Tumor molecular and histological characteristics by levels of PD-L1 and
molecular and cytogenetic subclassifications
• Changes in the work productivity and activity impairment (WPAI) from
screening to post baseline
• Time to next therapy
Background summary
Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of cancers
originating primarily in B lymphocytes, and to a lesser extent, in T
lymphocytes and natural killer cells. NHL is the most prevalent hematological
malignancy and is the seventh most common new cancer among men and women,
accounting for 4% of all new cancer cases and 3% of cancer-related deaths
(Howlader et al, 2015).
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL,
accounting for approximately 30% to 40% of all cases (Morton et al, 2006; Sehn
and Gascoyne, 2015; Chaganti et al, 2016). In the past two decades, progress
has been made in understanding the biological heterogeneity of DLBCL and in
improving survival with combinations of CHOP and immunotherapy. The addition of
ritixumab into combination therapies for DLBCL have greatly improved patient
outcomes. However, patients with chemotherapy-refractory DLBCL following
treatment under the current standards of care still have a particularly dire
prognosis, with no curative treatment options (Flowers 2010). Patients with r/r
DLBCL especially primary refractory and early relapse within 1 year after
first-line rituximab-based chemoimmunotherapy have poor prognosis even with
HDT-ASCT. Because these patients are resistant to chemotherapy, they may
benefit from therapies with different mechanisms of action. Immunotherapy,
which is based on the enhancement of an immune response against the tumor, is a
promising approach to treating many cancer types. T cells play an important
role in destroying diseased cells throughout the body. Studies with immune
checkpoint inhibitors and bi-specific T-cell engagers have demonstrated the
potential of T cells to treat cancer. T cells need to possess the appropriate
specificity for a tumor, be present in sufficient numbers, and overcome any
local immunosuppressive factors to be effective. The ability to genetically
engineer human T cells and use them to mediate cancer regression in patients
has been demonstrated in a number of studies and has opened possibilities for
the treatment of patients with a wide variety of cancer types including B cell
malignancies expressing the CD19 antigen. CD19 is a 95 kDa transmembrane
protein expressed only in the B cell lineage. It is expressed in all normal B
cells starting at the pre-B cell stage until the final differentiation stage
and is not expressed in pluripotent hematopoietic stem cells or most plasma
cells. The pattern of CD19 expression is maintained in B cell malignancies
including all subtypes of B cell NHL, chronic lymphocytic leukemia (CLL) and
non T cell acute lymphoblastic leukemia (ALL) (Blanc et al 2011) with the
exception of multiple myeloma. Although there have recent advances in novel
therapies for these B cell malignancies (Wang et al 2013; Byrd et al 2013; and
Furman et al 2014); most patients eventually develop resistance to approved
therapies. Chimeric antigen receptor (CAR) engineered + T cell therapy may
circumvent mechanisms of resistance and potentially address the unmet medical
need for these patients.
Anti-CD19 CAR T cells are autologous human T cells that have been engineered to
express an extracellular single-chain variable fragment (scFv) with specificity
for CD19 linked to an intracellular signaling part comprised of signaling
domains from CD28 and CD3* molecules arranged in tandem.
An anti-CD19 CAR vector construct has been designed, optimized and initially
tested at the Surgery Branch of the National Cancer Institute (NCI) (refer to
Figure 1); (Kochenderfer et al, 2009; Kochenderfer et al, 2010). The scFv is
derived from the variable region of the anti-CD19 monoclonal antibody FMC63
(Nicholson et al, 1997). A portion of the CD28 costimulatory molecule is
added, as murine models suggest this is important for the anti-tumor effect and
expansion of anti*CD19 CAR T cells (Kowolik et al, 2006). The signaling domain
of the CD3* chain is essential for T-cell activation. These fragments were
cloned into the murine stem cell virus-based (MSGV1) vector, utilized to
genetically engineer the autologous T cells. The safety and efficacy of anti
CD19 CAR T cells has been evaluated in subjects with CD19+ B cell malignancies
at the NCI (Kochenderfer et al, 2012; Kochenderfer et al, 2015; Kochenderfer et
al, 2017). The same anti*CD19 CAR vector construct used in the NCI protocol,
and ZUMA-1 will be used in this study.
Axicabtagene ciloleucel is an engineered autologous T cell immunotherapy by
which a patient*s own T cells are collected and subsequently genetically
altered to recognize CD19. CD19 is expressed on the cell surface of B-cell
malignancies. In ZUMA-1, which investigated the safety and efficacy of
axicabtagene ciloleucel in subjects with refractory aggressive NHL,
axicabtagene ciloleucel significantly improved ORR (P < 0.0001). The ORR was
82% with a complete response (CR) rate of 54%. At the primary analysis, 44% of
subjects had ongoing responses (39% in CR).
Axicabtagene ciloleucel may have an improved efficacy and tolerability in
patients with less chemo-refractory disease and lower disease burden.
Therefore ZUMA-7 will recruit patients with r/r DLBCL after first-line
rituximab and anthracycline-based chemotherapy. Axicabtagene ciloleucel will be
compared to standard of care (SOC) to determine if axicabtagene ciloleucel is
superior to SOC as measured by event-free survival (EFS), as determined by
blinded central review.
Study objective
Primary Objective
- To determine if axicabtagene ciloleucel is superior to SOC as measured by
event-free survival (EFS), as determined by blinded central review
Secondary Objectives
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on
objective response rate (ORR), as determined by blinded central review
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on overall
survival (OS)
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on
progression-free survival (PFS)
- To evaluate the effect of axicabtagene ciloleucel compared to SOC on duration
of response (DOR) and duration of complete response among responding subjects,
as determined by blinded central review
- To evaluate the safety of axicabtagene ciloleucel compared to SOC
- To evaluate the effect of axicabtagene ciloleucel on patient reported
outcomes (PROs) and quality of life (QoL) compared to SOC
Exploratory Objectives
- Explore mechanisms of resistance to treatment with axicabtagene ciloleucel
- Evaluate mechanistic aspects and reversibility of toxicities with
axicabtagene ciloleucel
- Explore molecular and histologic characteristics of the tumor microenvironment
- Evaluate impact of disease and treatment on work productivity and activity
- Estimate time to next therapy
Study design
This is a Phase 3 randomized, open-label, multicenter study evaluating the
efficacy of axicabtagene ciloleucel versus standard of care therapy (SOC) in
subjects with r/r DLBCL. Adult subjects with r/r DLBCL after first-line
rituximab and anthracycline-based chemotherapy will be randomized in a 1:1
ratio to receive axicabtagene ciloleucel or SOC. Randomization will be
stratified by response to first-line therapy (primary refractory, vs relapse <=6
months of first-line therapy vs relapse > 6 and <= 12 months of first line
therapy) and second line age-adjusted IPI (International Prognostic Index) (0
to 1 vs. 2 to 3) as assessed at the time of screening.
For subjects randomized to the control arm of the study, SOC will consist of a
protocol- defined, platinum-based salvage combination chemotherapy regimen.
Subjects who respond to second-line chemotherapy (partial response (PR) or
complete response (CR)) should proceed to high-dose therapy (HDT) and
autologous stem cell transplant (ASCT).
An independent Data Safety Monitoring Board (DSMB) will meet every 6 months
after the first subject is randomized to review safety data and will review
safety and efficacy data at the time of the planned interim futility analysis.
The DSMB will be chartered to make trial conduct recommendations based on an
analysis of risk versus benefit. The DSMB may meet more often as needed. Refer
to protocol Section
9.9 for further details. For study requirements assigned to each study arm,
please refer to the schedule of assessments
(SOA) and Section 7 of protocol for details.
A study schema is drawn out and described at the end of the protocol synopsis
section.
Intervention
- Axicabtagene ciloleucel arm
Subjects randomized to the axicabtagene ciloleucel arm of the study will
receive a 3 day conditioning chemotherapy regimen consisting of fludarabine 30
mg/m2/day and cyclophosphamide 500 mg/m2/day on day -5 to day -3 followed by
two rest days (day -2 and day -1).
A single infusion of axicabtagene ciloleucel administered intravenously at a
target dose of 2 x 106 anti CD19 CAR T cells/kg on day 0.
- Standard of Care arm
Subjects will receive a second-line combination chemotherapy regimen (R-ICE, R
DHAP, R-ESHAP, or R-GDP) as selected by the treating investigator.
Subjects responding to second-line combination chemotherapy after 2 or 3 cycles
(PR or CR) should proceed to high-dose therapy (HDT) and autologous stem cell
transplant (ASCT).
Peripheral stem cell collection, HDT and ASCT infusion will be per
institutional or regional guidelines.
Study burden and risks
As outlined in the SOAs, subjects will undergo the following procedures:
collection of informed consent, medical history, physical exam, bone marrow
biopsy, disease staging including a baseline PET-CT scan, and blood draws for
lactate dehydrogenase levels, complete blood count (CBC) and blood chemistries.
Subjects will also undergo baseline echocardiogram (ECHO) and electrocardiogram
(ECG) assessments and ECOG performance status. Women of child-bearing
potential will undergo a urine or serum pregnancy test.
Subjects randomized to the axicabtagene ciloleucel arm will undergo
leukapheresis for the collection of peripheral blood mononuclear cells
necessary for axicabtagene ciloleucel manufacturing. Conditioning chemotherapy
will be followed by 2 rest days, and then infusion of axicabtagene ciloleucel.
Subjects will be observed in a health care facility for at least 7 days after
axicabtagene ciloleucel infusion to monitor for and manage any adverse events.
Blood draws for the analysis of anti-CD19 CAR T cell levels will be performed.
Additional blood draws for cytokines, anti-axicabtagene ciloleucel antibodies,
and replication competent retrovirus (RCR) may be performed as clinically
indicated.
Subjects randomized to the SOC arm will receive investigator*s choice of
second-line combination chemotherapy from the protocol defined options. Up to
3 cycles (6-9 weeks) of combination chemotherapy will be administered every 2-3
weeks. Subjects with a PR or CR to second-line therapy should proceed to
HDT-ASCT. Peripheral stem cell mobilization and leukapheresis will be performed
according to institutional guidelines after the 2nd or 3rd cycle of second-line
therapy to obtain a minimum target of 2 x 106 CD34+ hematopoietic stem cells
per kilogram. HDT-ASCT will be performed per institutional guidelines.
Routinely throughout the conduct of the study, all subjects will be asked to
report concomitant medications and adverse events, report subsequent lymphoma
therapy, answer patient reported outcomes (PROs) and will have routine disease
assessments as outlined in the SOAs.
Independent of the randomized treatment arm, study procedures and disease
assessments will occur at the same protocol defined time points.
The patients may experience side effects after treatment. The important
identified risks for axicabtagene ciloleucel are: cytokine release syndrome
(CRS, which is a symptom complex associated with the use of monoclonal
antibodies and adoptive cell therapies that activate lymphocytes) and adverse
events that may be attributable to CRS include fever, febrile neutropenia,
hypotension, acute vascular leak
syndrome, renal failure, hypoxia, and pleural effusion; neurologic events (eg,
encephalopathy, somnolence, aphasia); cytopenias and infections.
Brain swelling (cerebral edema) and spinal cord swelling (spinal cord edema)
are important potential risks associated with axicabtagene ciloleucel cells and
brain swelling (cerebral edema) leading to death has occurred rarely in studies
involving CAR T cell products, including axicabtagene ciloleucel cells. This
may require aggressive treatment including placing a breathing tube for
mechanical ventilation (breathing machine), administration of medications, or
surgery to decrease the swelling or pressure. The exact cause of brain and
spinal cord swelling in connection with treatment of CAR T cell products is not
fully understood at this time.
There also risks associated with pre-treatment with chemotherapy. The patient
may experience low blood counts, including a low white blood cell count which
increases the risk of infection, a decrease in the number of platelets which
may cause bleeding or bruising, and a decrease in the red blood cells that
carry oxygen through the body (anemia). Other risks associated with
chemotherapy are infection that may be life threatening, changes in the salt
content of blood and there have been rare cases of strokes.
There are also non-treatment related side effects associated with other
procedures that are carried out. PET-CT scans involve an exposure to radiation
which carry a slight risk of developing new tumours, the patients may also
experience some discomfort, anxiety, or fatigue from lying inside the scanner.
The contrast dye may cause the patient to get a metallic taste in their mouth,
to feel warm and rarely cause nausea or vomiting. A bone marrow biopsy and core
tumour biopsy may cause discomfort, pain, bleeding or infection at the site of
biopsy. Lumbar puncture can be associated with developing a headache which may
be accompanied by nausea, vomiting and dizziness. While rare, lumbar puncture
may also cause a herniation near the insertion site. During the insertion of an
intervenous catheter, bleeding, redness or a bruise could develop and on rare
occasions an infection could occur. During the leukapheresis procedure, rare
complications that could occur are lowered blood pressure, bleeding or
infection. During an MRI, you will lie in a small closed area inside a large
magnetic tube. Some people are scared or anxious in small places
(claustrophobic)
Patients who have r/r DLBCL especially primary refractory and early relapse
within 1 year after first-line rituximab-based chemoimmunotherapy have poor
prognosis even with HDT-ASCT. Conditioning chemotherapy followed by infusion of
axicabtagene ciloleucel has demonstrated durable responses in the majority of
patients with non-Hodgkin lymphoma (NHL) including diffuse large B cell
lymphoma (DLBCL). In ZUMA-1 study, which investigated the safety and efficacy
of axicabtagene ciloleucel in subjects with refractory aggressive NHL,
axicabtagene ciloleucel significantly improved ORR (P < 0.0001). The ORR was
82% with a complete response (CR) rate of 54%. At the primary analysis, 44% of
subjects had ongoing responses (39% in CR).
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Age
Inclusion criteria
101. Histologically proven large B-cell lymphoma including the following types
defined by WHO 2016
o DLBCL not otherwise specified (including ABC/GCB)
o HGBL with or without MYC and BCL2 and/or BCL6 rearrangement
o DLBCL arising from FL
o T-cell/histiocyte rich large B-cell lymphoma
o DLBCL associated with chronic inflammation
o Primary cutaneous DLBCL, leg type
o Epstein-Barr virus (EBV) + DLBCL
102. Relapsed or refractory disease after first-line chemoimmunotherapy
- Refractory disease defined as no complete remission to first-line therapy;
subjects who are intolerant to first-line therapy are excluded
Progressive disease (PD) as best response to first-line therapy
Stable disease (SD) as best response after at least 4 cycles of first-line
therapy (eg, 4 cycles of R-CHOP)
PR as best response after at least 6 cycles, and biopsy-proven residual disease
or disease progression <= 12 months from therapy
- Relapsed disease defined as complete remission to first-line therapy followed
by biopsy-proven disease relapse <= 12 months of first-line therapy
103. Subjects must have received adequate first-line therapy including at a
minimum:
- Anti-CD20 monoclonal antibody unless investigator determines that tumor is
CD20 negative, and
- An anthracycline containing chemotherapy regimen
104. Intent to proceed to HDT and ASCT if response to second-line therapy
105. Subjects must have radiographically documented disease
106. No known history or suspicion of central nervous system (CNS) involvement
by lymphoma
107. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed
since any prior systemic cancer therapy at the time the subject provides
consent
108. Age 18 years or older at the time of informed consent
109. ECOG performance status of 0 or 1
110. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function
defined as:
- Absolute neutrophil count (ANC) >=1000/µL
- Platelet count >= 75,000/µL
- Absolute lymphocyte count >= 100/µL
- Creatinine clearance (as estimated by Cockcroft Gault) >= 60 mL/min
- Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) <= 2.5
upper limit of normal (ULN)
- Total bilirubin <= 1.5 mg/dl, except in subjects with Gilbert*s syndrome
- Cardiac ejection fraction >= 50%, no evidence of pericardial effusion as
determined by an echocardiogram (ECHO), and no clinically significant
electrocardiogram (ECG) findings
- No clinically significant pleural effusion
- Baseline oxygen saturation > 92% on room air
111. Females of childbearing potential must have a negative serum or urine
pregnancy test (females who have undergone surgical sterilization or who have
been postmenopausal for at least 2 years are not considered to be of
childbearing potential)
Exclusion criteria
201. History of malignancy other than nonmelanoma skin cancer or carcinoma in
situ (eg cervix, bladder, breast) unless disease free for at least 3 years
202. History of Richter*s transformation of CLL or PMBCL
203. History of autologous or allogeneic stem cell transplant
204. Received more than one line of therapy for DLBCL
205. Prior CD19 targeted therapy
206. Treatment with systemic immunostimulatory agents (including but not
limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug,
whichever is shorter, prior to the first dose of axicabtagene ciloleucel or SOC
207. Prior chimeric antigen receptor therapy or other genetically modified
T-cell therapy, or prior randomization into ZUMA-7
208. History of severe, immediate hypersensitivity reaction attributed to
aminoglycosides
209. Presence of fungal, bacterial, viral, or other infection that is
uncontrolled or requiring intravenous (IV) antimicrobials for management.
Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis
are permitted if responding to active treatment.
210. Known history of infection with human immunodeficiency virus (HIV) or
hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If
there is a positive history of treated hepatitis B or hepatitis C, the viral
load must be undetectable per quantitative polymerase chain reaction (PCR)
and/or nucleic acid testing.
211. Active tuberculosis
212. Presence of any indwelling line or drain (eg, percutaneous nephrostomy
tube, indwelling Foley catheter, biliary drain, or
pleural/peritoneal/pericardial catheter). Dedicated central venous access
catheters such as a Port-a-Cath or Hickman catheter are permitted.
213. Subjects with detectable cerebrospinal fluid malignant cells or known
brain metastases, or with a history of cerebrospinal fluid malignant cells or
brain metastases.
214. History or presence of non-malignant CNS disorder such as seizure
disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or
any autoimmune disease with CNS involvement
215. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
216. History of myocardial infarction, cardiac angioplasty or stenting,
unstable angina, New York Heart Association Class II or greater congestive
heart failure, or other clinically significant cardiac disease within 12 months
of enrollment
217. Requirement for urgent therapy due to tumor mass effects such as bowel
obstruction or blood vessel compression
218. History of autoimmune disease, requiring systemic immunosuppression and/or
systemic disease modifying agents within the last 2 years.
219. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg,
bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or
evidence of active pneumonitis per chest computed tomography (CT) scan at
screening. History of radiation pneumonitis in the radiation field (fibrosis)
is allowed.
220. History of symptomatic deep vein thrombosis or pulmonary embolism within 6
months of enrollment
221. Any medical condition likely to interfere with assessment of safety or
efficacy of study treatment
222. History of severe immediate hypersensitivity reaction to tocilizumab or
any of the agents used in this study
223. Treatment with a live, attenuated vaccine within 6 weeks prior to
initiation of study treatment, or anticipation of need for such a vaccine
during the course of the study
224. Women of childbearing potential who are pregnant or breastfeeding because
of the potentially dangerous effects of chemotherapy on the fetus or infant.
Subjects of either sex who are not willing to practice birth control from the
time of consent and at least 6 months after the last dose of axicabtagene
ciloleucel or SOC chemotherapy
225. In the investigator's judgment, the subject is unlikely to complete all
protocol-required study visits or procedures, including follow-up visits, or
comply with the study requirements for participation
Design
Recruitment
Medical products/devices used
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 | EUCTR2017-002261-22-NL |
| CCMO | NL62980.000.17 |