The primary objective of Phase 1 study is to evaluate the safety of axicabtagene ciloleucel regimens.The primary objective of Phase 2 pivotal study is to evaluate the efficacy of axicabtagene ciloleucel, as measured by objective response rate (ORR)…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's unspecified histology
- Lymphomas non-Hodgkin's unspecified histology
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1 Study:
- Incidence of adverse events defined as dose-limiting toxicities (DLT)
Phase 2 Pivotal Study:
Objective response rate (complete response [CR] + partial response [PR]) per
the revised International Working Group (IWG) Response Criteria for Malignant
Lymphoma (Cheson et al, 2007) as determined by study investigators. All
subjects who do not meet the criteria for an objective response by the analysis
cutoff date will be considered non-responders.
Phase 2 Safety Management Study:
Incidence and severity of CRS and neurologic toxicities.
Secondary outcome
Phase 1 Study:
• Objective response rate (CR + PR) per the revised IWG Response Criteria for
Malignant Lymphoma
• Duration of Response (DOR)
• Overall Survival (OS)
• Progression Free Survival (PFS)
• Incidence of adverse events and clinical significant changes in safety lab
values
• Levels of anti-CD19 CAR T cells in blood
• Levels of cytokines in serum
• Incidence of anti-axicabtagene ciloleucel antibodies
Phase 2 Pivotal Study:
• Objective response rate per Independent Radiology Review Committee (IRRC)
• DOR
• PFS
• OS
• Incidence of adverse events and clinical significant changes in safety lab
values
• Levels of anti-CD19 CAR T cells in blood
• Levels of cytokines in serum
• Incidence of anti-axicabtagene ciloleucel antibodies
Phase 2 Safety Management Study:
• Objective response rate (complete response [CR] + partial response [PR]) per
the revised International Working Group (IWG) Response Criteria for Malignant
Lymphoma (Cheson 2007) as determined by study investigators.
• DOR
• PFS
• OS
• Incidence of adverse events and clinically significant changes in safety lab
values
• Levels of anti-CD19 CAR T cells in blood
• Levels of cytokines in blood
• Incidence of anti-axicabtagene ciloleucel antibodies
• Changes over time in the EQ-5D scale score and visual analogue scale (VAS)
score (Phase 2 SMS only)
Background summary
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of cancers originating in B
lymphocytes, T lymphocytes or natural killer cells. There were an estimated
356,000 new cases of NHL and 192,000 deaths from NHL worldwide in 2008 (Ferlay
et al 2010). NHL is the 8th most commonly diagnosed cancer in men and the 11th
in women. The disease accounts for ~5.1% of all cancer cases and 2.7% of all
cancer deaths (Bofetta 2011). Large B-cell lymphomas represent the most common
sub-group of NHL (Rodriguez-Abreu 2007).
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of NHL,
accounting for approximately 30% of NHL cases.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).
As most advanced cancers eventually become refractory to conventional
therapies, new treatment modalities are needed. Immunotherapy, which is based
on the enhancement of an immune response against the tumour, 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 tumour infiltrating lymphocytes have demonstrated the potential
of T cells to treat cancer. T cells need to possess the appropriate specificity
for a tumour, be present in sufficient numbers, and overcome any local
immunosuppressive factors to be effective. Engineered T cells are a promising
approach for cancer therapy (Kershaw et al 2013).
Engineered Autologous Cell Therapy (eACT*) is a process by which a patient*s
own T cells are collected and subsequently genetically altered to recognize and
target antigens expressed on the cell surface of specific malignancies
(Kochenderfer et al 2013). 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+ T cell therapy may circumvent mechanisms of resistance and
potentially address the unmet medical need for these patients.
An anti-CD19 CAR was generated at the Surgery Branch of the National Cancer
Institute (NCI). This CAR contained the mouse anti-human single chain variable
fragment (scFv) derived from the antibody FMC63, the CD3-zeta T cell activation
domain, and a CD28 co-stimulatory domain. In preclinical models, the anti-CD19
CAR recognized and killed CD19+ target cells in vitro and in vivo. A phase 1
study of this anti-CD19 CAR has been conducted at the NCI using anti-CD19 CAR+
T cells generated by retroviral transduction and manufactured at the NCI.
Conditioning chemotherapy followed by infusion of anti-CD19 CAR+ T cells has
demonstrated durable responses in the majority of patients with relapsed and
refractory CLL, indolent NHL, diffuse large B cell lymphoma (DLBCL), and
primary mediastinal B cell lymphoma (PMBCL) with the predominant toxicity of
cytokine release syndrome (CRS). Axicabtagene ciloleucel utilizes the
anti-CD19 CAR from the NCI and is produced through a streamlined, closed
manufacturing process. Axicabtagene ciloleucel will be evaluated in patients
with relapsed or refractory B cell malignancies.
For the ZUMA-1 (KTE-C19-101) study, subjects with the following refractory
aggressive Non-Hodgkin Lymphoma sub-types are to be treated indications are to
be studied within the phase 1/2 multi-center study evaluating the safety and
efficacy of axicabtagene ciloleucel in subjects with refractory aggressive
non-Hodgkin lymphoma: DLBCL, PMBCL, transformed follicular lymphoma (TFL) and
high grade B-cell
lymphoma (HGBCL). Please refer to section 2 of the clinical trial protocol for
a description of the three sub-types.
Study objective
The primary objective of Phase 1 study is to evaluate the safety of
axicabtagene ciloleucel regimens.
The primary objective of Phase 2 pivotal study is to evaluate the efficacy of
axicabtagene ciloleucel, as measured by objective response rate (ORR) in
subjects with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell
lymphoma (PMBCL), and transformed follicular lymphoma (TFL). Secondary
objectives will include assessing the safety and tolerability of axicabtagene
ciloleucel and additional efficacy endpoints.
The primary objective of the Phase 2 safety management study is to assess the
impact of a prophylactic regimen or earlier interventions, debulking therapy,
or prophylactic steroid use on the rate and severity of cytokine release
syndrome (CRS) and neurologic toxicities.
The key secondary objectives include assessment of efficacy, levels of
anti-CD19 chimeric antigen receptor (CAR) T cells, cytokines in blood/serum,
and the change in European Quality of Life-5 Dimensions (EQ-5D) scores from
baseline to Month 6.
Study design
Study KTE-C19-101 is a Phase 1/2 multicenter, open-label studyevaluating the
safety and efficacy of axicabtagene ciloleucel in subjects
with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL).
The trial will be separated into 3 distinct phases designated as the
Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2
safety management study (Cohort 3, Cohort 4, Cohort 5 and
Cohort 6).
> Phase 1 Study
During Phase 1 study, approximately 6 to 24 subjects with DLBCL, PMBCL, or TFL
will be enrolled to evaluate the safety of axicabtagene
ciloleucel regimens. A safety review team (SRT), internal to the study sponsor,
will review the safety data and make recommendations on
further study conduct of Phase 1 and progression to Phase 2 pivotal study as
depicted in Figure 3 and outlined in Section 9.10.
> Phase 2 Pivotal Study In the Phase 2 pivotal study, approximately 92 subjects
will enroll into 2 separate cohorts designated as Cohort 1 and Cohort 2:
- Cohort 1 will enroll approximately 72 adult subjects with refractory DLBCL.
- Cohort 2 will enroll approximately 20 adult subjects with refractory PMBCL
and TFL. TFL is defined as subjects who received prior therapy for follicular
lymphoma.
> Phase 2 Safety Management Study
In the Phase 2 safety management study (SMS), approximately 170 subjects will
enroll into 4 separate cohorts designated as Cohort 3,
Cohort 4, Cohort 5 and Cohort 6.
- Cohort 3 will enroll approximately 40 adult subjects with relapsed or
refractory transplant ineligible DLBCL, PMBCL, or TFL.
- Cohort 4 will enroll and dose approximately 40 adult subjects with relapsed
or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or more lines of systemic
therapy.
- Cohort 5 will enroll and dose approximately 50 adult subjects with relapsed
or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or more lines of systemic
therapy.
- Cohort 6 will enroll and dose approximately 40 adult subjects with relapsed
or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or more lines of systemic
therapy.
Independent of the phase of the study each subject will follow the same
study treatment schedule and procedural requirements. Each subject will
proceed through the following study periods:
- Screening
- Enrollment/Leukapheresis period
- Bridging therapy (if applicable; safety management study only) or debulking
therapy (if applicable, safety management study, Cohort 5
only)
- Conditioning chemotherapy period
- Investigational product (IP) treatment period
- Post-treatment assessment period
- Long-term follow-up period
for details.
At the end of KTE-C19-101, subjects who received an infusion of axicabtagene
ciloleucel will complete the remainder of the 15-year follow-up assessments in
a separate long-term Follow-up (LTFU) study, KT-US-982-5968.
Intervention
Investigational Product:
• Axicabtagene ciloleucel treatment consists of a single infusion of CAR
transduced autologous T cells administered intravenously at a target dose of 2
x 10^6 anti-CD19 CAR T cells/kg. For subjects weighing greater than 100 kg, a
maximum flat dose of 2 x 10^8 anti-CD19 CAR T cells will be
administered. Under circumstances where subjects initially respond and
subsequently relapse, subjects may be eligible for a second course of
conditioning chemotherapy and axicabtagene ciloleucel.
Bridging Therapy (Phase 2 Safety Management Study)
• At the discretion of the investigator, bridging therapy may be considered for
subjects particularly with high disease burden at screening or baseline
assessment (eg, bulky disease or rapidly progressing disease).
Debulking Therapy
• Subjects enrolled into the Phase 2 Safety Management Study, Cohort 5 should
receive debulking therapy to reduce lymphoma burden. Debulking therapy options
are outlined in Table 3 of the protocol.
Conditioning Chemotherapy
• Axicabtagene ciloleucel is administered after a conditioning chemotherapy
regimen consisting of fludarabine 30 mg/m2/day and cyclophosphamide 500
mg/m2/day, administered x 3 days.
For subjects enrolled into the Phase 2 Safety Management Study, Cohort 5:
Subjects who have not recovered their white blood cell (WBC) count by the time
conditioning chemotherapy is scheduled to start, may skip the conditioning
chemotherapy if the WBC is <= 1000/µL at this time. This option must be
discussed with the Kite medical monitor.
Additional axicabtagene ciloleucel regimens may be explored in Phase 1 per
Section 9.6 of the study protocol.
Study burden and risks
For a study treatment, the patient needs to be hospitalized for at least 7
days. Before infusion of axicabtagene ciloleucel the patient will receive 3
days of chemotherapy. The patient may experience side effects after treatment.
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Age
Inclusion criteria
101. Histologically confirmed aggressive B cell NHL, including the following
types defined by WHO 2008 (Campo 2011):
- DLBCL not otherwise specified;
- T cell/histiocyte rich large B cell lymphoma;
- DLBCL associated with chronic inflammation;
- Epstein-Barr virus (EBV)+ DLBCL of the elderly; OR
- primary mediastinal (thymic) large B cell lymphoma
- transformation of follicular lymphoma to DLBCL will also be included
102. Chemotherapy-refractory disease, defined as one or more of the following:
- No response to first-line therapy (primary refractory disease); subjects who
are intolerant to first-line therapy chemotherapy are excluded
- PD as best response to first-line therapy
- SD as best response after at least 4 cycles of first-line therapy (e.g., 4
cycles of R-CHOP) with SD duration no longer than 6 months from last dose of
therapy OR
- No response to second or greater lines of therapy
- PD as best response to most recent therapy regimen
- SD as best response after at least 2 cycles of last line of therapy with SD
duration no longer than 6 months from last dose of therapy OR
- Refractory post-ASCT
- Disease progression or relapsed <=12 months of ASCT (must have biopsy proven
recurrence in relapsed subjects)
- If salvage therapy is given post-ASCT, the subject must have had no response
to or relapsed after the last line of therapy
103. Subjects must have received adequate prior therapy including at a
minimum:
- anti-CD20 monoclonal antibody unless investigator determines that tumor is
CD20 negative, and
- an anthracycline containing chemotherapy regimen;
- for subjects with transformed FL must have received prior chemotherapy for
follicular lymphoma and subsequently have chemorefractory disease after
transformation to DLBCL
104. At least 1 measurable lesion according to the revised IWG Response
Criteria for Malignant Lymphoma) (Cheson 2007). Lesions that have been
previously irradiated will be considered measurable only if progression has
been documented following completion of radiation therapy
105. MRI of the brain showing no evidence of CNS lymphoma
106. At least 2 weeks or 5 half- lives, whichever is shorter, must have elapsed
since any prior systemic therapy at the time the subject is planned for
leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint
therapy. At least 3 half-lives must have elapsed from any prior systemic
inhibitory/stimulatory immune checkpoint molecule therapy at the time the
subject is planned for leukapheresis (e.g. ipilimumab, nivolumab,
pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists etc)
107. Toxicities due to prior therapy must be stable and recovered to <= Grade 1
(except for clinically non-significant toxicities such as alopecia)
108. Age 18 or older
109. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
110. ANC >=1000/uL
111. Platelet count >=75,000/uL
112. Absolute lymphocyte count >=100/uL
113. Adequate renal, hepatic, pulmonary and cardiac function defined as:
- Creatinine clearance (as estimated by Cockcroft Gault) >= 60 mL/min
- Serum ALT/AST <=2.5 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 ECHO, and no clinically significant ECG findings
- No clinically significant pleural effusion
- Baseline oxygen saturation >92% on room air
114. 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)Additional criteria specific for Phase 2 safety
management study (cohorts 3, 4 and 5):
115. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL,
and HGBCL after two systemic lines of therapy**
Exclusion criteria
201. History of malignancy other than nonmelanoma skin cancer or carcinoma in
situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free
for at least 3 years
202. History of Richter*s transformation of CLL
203. Autologous stem cell transplant with therapeutic intent within 6 weeks of
planned axicabtagene ciloleucel infusion
204. History of allogeneic stem cell transplantation
205. Prior CD19 targeted therapy with the exception of subjects who received
axicabtagene ciloleucel in this study and are eligible for re-treatment
206. Prior chimeric antigen receptor therapy or other genetically modified T
cell therapy
207. History of severe, immediate hypersensitivity reaction attributed to
aminoglycosides
208. Presence or suspicion of fungal, bacterial, viral, or other infection that
is uncontrolled or requiring IV antimicrobials for management.
209. History of HIV infection or acute or chronic active hepatitis B or C
infection. Subjects with history of hepatitis infection must have cleared their
infection as determined by standard serological and genetic testing per current
Infectious Diseases Society of America (IDSA) guidelines or applicable country
guidelines.
210. Presence of any indwelling line or drain (e.g., 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
211. Subjects with detectable cerebrospinal fluid malignant cells, or brain
metastases, or with a history of CNS lymphoma or primary CNS lymphoma,
cerebrospinal fluid malignant cells or brain metastases
212. History or presence of CNS disorder such as seizure disorder,
cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any
autoimmune disease with CNS involvement
213. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
214. History of myocardial infarction, cardiac angioplasty or stenting,
unstable angina, or other clinically significant cardiac disease within 12
months of enrollment
215. Expected or possible requirement for urgent therapy within 6 weeks due to
ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis
syndrome)
216. Primary immunodeficiency
217. History of symptomatic deep vein thrombosis or pulmonary embolism requiring
systemic anticoagulation within 6 months of enrollment
218. Any medical condition likely to interfere with assessment of safety or
efficacy of study treatment
219. History of severe immediate hypersensitivity reaction to any of the agents
used in this study
220. Live vaccine <= 6 weeks prior to planned start of conditioning regimen
221. Women of child-bearing potential who are pregnant or breastfeeding because
of the potentially dangerous effects of the preparative chemotherapy on the
fetus or infant. Females who have undergone surgical sterilization or who have
been postmenopausal for at least 2 years are not considered to be of
childbearing potential
222. Subjects of both genders who are not willing to practice birth control
from the time of consent through 6 months after the completion of conditioning
therapy
223. In the investigators 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
224. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis,
systemic lupus) resulting in end organ injury or requiring systemic
immunosuppression/systemic disease modifying agents within the last 2 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 | EUCTR2015-005007-86-NL |
| ClinicalTrials.gov | NCT02348216 |
| CCMO | NL56662.000.16 |