| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Refractory Follicular Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer that forms in white blood cells that has come back or has been resistant to previous therapies |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10085262 |
| E.1.2 | Term | Follicular lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to determine if axicabtagene ciloleucel is superior to
SOCT, as measured by PFS per a blinded independent radiologic review committee (hereafter
referred to as blinded central assessment) in subjects with r/r FL. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to further characterize the efficacy and safety profile and
patient reported outcomes associated with axicabtagene ciloleucel compared with SOCT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Histologically-confirmed FL (Grade 1, 2, or 3a) per local diagnosis. If clinically permissible, a new biopsy is strongly recommended at screening to exclude subjects with transformed disease (ie, subjects with newly elevated lactate dehydrogenase (LDH) compared to previous lab assessments, systemic B symptoms, or high positron emission tomography [PET] avidity) or those who were initially misdiagnosed. Tumor tissue must be provided for retrospective central pathology review. If an archival specimen is not available, a new biopsy is required prior to randomization.
2) R/r disease as defined as one of the following options:
a) First-line systemic chemoimmunotherapy and high-risk disease, defined as relapse or progression within 24 months of initiation of the initial course of chemoimmunotherapy
i) The initial chemoimmunotherapy regimen must consist of an anti-CD20 monoclonal antibody plus either B, CHOP, or CVP. The subject must have received at least 3 cycles of the anti-CD20 monoclonal antibody plus either B, CHOP, or CVP regimen. In the case of the anti-20 monoclonal antibody plus CHOP regimen, the CHOP regimen may have included a prednisone-equivalent dose of any corticosteroid.
ii) Progression is measured from the first day of the first cycle of the initial chemoimmunotherapy.
iii) Note: Subjects who received frontline anti-CD20 monoclonal antibody monotherapy prior to the initial line of chemoimmunotherapy are eligible. However, progression within 24 months will be counted from C1D1 of the chemoimmunotherapy regimen and not from the start of the frontline anti-CD20 monoclonal antibody monotherapy that precedes the chemoimmunotherapy.
Or
b) R/r disease after ≥ 2 prior systemic lines of therapy where:
i) Relapsed disease is defined as subjects who progressed more than 6 months from completion of prior systemic therapy
ii) Refractory disease is defined as subjects who experienced PD within 6 months of prior systemic therapy completion
iii) Note: (1) Involved field/site radiation, maintenance, and consolidation therapies are not considered separate lines of therapy for purposes of eligibility. Single-agent anti-CD20 will not be considered a separate line of therapy for purposes of eligibility.
(2) Prior therapy must have included an anti-CD20 monoclonal antibody combined with an alkylating agent.
3) Clinical indication for treatment, including but not limited to local symptoms due to progressive or bulky disease, systemic B symptoms, compromised organ function due to disease progression, cytopenias due to marrow involvement, or symptomatic extranodal disease.
4) At least 1 measurable lesion per the Lugano Classification on anatomical imaging such as CT imaging. Previously irradiated lesions are considered measurable only if progression was documented following completion of radiation therapy.
5) No known history or suspicion of CNS lymphoma involvement
6) Elapsed time of at least 2 weeks or 5 half-lives, whichever was shorter, since any prior systemic therapy and randomization, except for systemic inhibitory/stimulatory immune checkpoint therapy. Elapsed time of at least 3 half-lives since any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy and randomization.
7) Toxicities due to prior therapy must have been stable and recovered to Grade 1 or lower (except for clinically nonsignificant toxicities, such as alopecia)
8) Age 18 or older
9) Eastern Cooperative Performance Status of 0 or 1
10) Absolute neutrophil count ≥ 1000/μL
11) Platelet count ≥ 75,000/μL unless secondary to bone marrow or spleen involvement by lymphoma where platelet count ≥ 50,000/uL. Bone marrow involvement by lymphoma is demonstrated by bone marrow aspiration or biopsy. Spleen involvement by lymphoma is demonstrated by splenomegaly.
12) Absolute lymphocyte count ≥ 100/μL
13) Adequate renal, hepatic, pulmonary, and cardiac function defined as the following:
a) Creatinine clearance (as estimated by any local institutional method) ≥ 60 mL/min
b) Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 times the upper limit of
normal (ULN)
c) Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s Syndrome or documented FL liver or pancreatic involvement where ≤ 3.0 times the ULN
d) Cardiac ejection fraction ≥ 50% with no evidence of clinically significant pericardial effusion as determined by ECHO. MUGA scan may be used if an ECHO is not available at the site.
e) No evidence of Grade 2 (per Common Terminology Criteria for Adverse Events
[CTCAE] 5.0) or greater pleural effusion or ascites
f) Baseline oxygen saturation > 92% on room air
14) Females of childbearing potential must have a medically supervised negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). |
|
| E.4 | Principal exclusion criteria |
1) History of transformed FL or clinical evidence of transformed FL at the time of screening
2) FL Grade 3b
3) History of malignancy other than nonmelanoma skin cancer or carcinoma in situ unless disease-free and without anticancer therapy (with the exception of hormonal therapy in the case of breast cancer) for at least 3 years. Subjects with asymptomatic localized low-grade prostate cancer, for which a watch-and-wait approach is SOCT, are eligible.
4) Intention for subject to proceed to auto-SCT or allogeneic SCT
5) History of allogenic SCT except if no donor cells are detected on chimerism, the subject is off all immunosuppression, and there is no evidence of active GVHD of any grade 6) Auto-SCT within 6 weeks of the planned axicabtagene ciloleucel infusion
7) Prior CD19-targeted therapy
8) Prior CAR therapy or other genetically modified T-cell therapy
9) History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
10) Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if the subject is responding to active treatment and after consultation with the Kite medical monitor.
11) Infection with human immunodeficiency virus, hepatitis B virus , or hepatitis C virus . If there is a positive history of HBV or hepatitis C virus, the viral load must be undetectable per quantitative polymerase chain reaction and/or nucleic acid testing.
a) Note: Subjects who are seropositive for HBV are eligible if they are HBsAgnegative
and negative for viral DNA. Subjects who are seropositive because of HBV vaccination are eligible. subjects on prophylactic and suppressive antiviral medications against HBV or/and HCV administered per institutional or clinical practice guidelines are eligible. The axicabtagene ciloleucel IB is a central source for guidance on the management of important risks and AEs including the important risks for reactivation of HBV and strategies to prevent such cases in the future.
12) History or presence of a CNS disorder, such as hemorrhage, dementia, cerebellar disease, or
any autoimmune disease with CNS involvement, posterior reversible encephalopathy
syndrome, or cerebral edema with confirmed structural defects by appropriate imaging.
History of stroke or transient ischemic attack within 12 months before randomization, or
seizure disorders requiring active anticonvulsive medication.
13) History of autoimmune disease (eg, Crohn’s, rheumatoid arthritis, or systemic lupus)
resulting in or requiring systemic immunosuppression and/or systemic disease-modifying
agents within the last 2 years.
14) Detectable cerebral spinal fluid (CSF) malignant cells or brain metastases or a history of
CNS lymphoma, primary CNS lymphoma, or spinal epidural involvement.
15) Cardiac atrial or cardiac ventricular lymphoma involvement
16) History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other
clinically significant cardiac disease within 6 months of randomization
17) History of concomitant genetic syndrome associated with bone marrow failure such as
Fanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome
18) History of non-line associated, clinically significant (CTCAE 5.0 Grade 2) deep-vein
thrombosis (ie, proximal deep vein thrombosis) or pulmonary embolism requiring therapeutic
anticoagulation within the 6 months before randomization
19) Any medical condition likely to interfere with assessment of safety or efficacy study
treatment
20) History of severe hypersensitivity reaction to any of the agents used in this study
21) Live vaccine ≤ 6 weeks of randomization
22) Neuropathy greater than Grade 1 (per CTCAE 5.0; subjects with neuropathy with Grade 1
neuropathy are eligible)
23) Females who are pregnant or breastfeeding (due to potentially dangerous effects of the
preparative chemotherapy or SOCT on the fetus or infant).
24) Subjects of both genders who are not willing to practice birth control from the time of
consent through 12 months following lymphodepletion chemotherapy administration or
12 months after the completion of axicabtagene ciloleucel or SOCT, whichever is longer.
Females who have undergone surgical sterilization or who have been postmenopausal for at
least 2 years are not considered to be of childbearing potential. Subjects of both genders must
also comply with any relevant REMS or aRMMs as part of an RMP.
25) As per 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 (eg, subjects who are at a risk for a thromboembolic event and are not willing to take venous thromboembolism prophylaxis if R2 is prescribed should be excluded).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is PFS, defined as the time from randomization to disease
progression per the International Working Group Lugano Classification {Cheson 2014} as
determined per a blinded central assessment, or death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Schedules of assessments and procedures to be performed for subjects in the axicabtagene
ciloleucel treatment arm during the treatment and post-treatment follow-up periods and the longterm
follow-up (LTFU) period are provided in Table 10 and Table 11, respectively.
Schedules of assessments and procedures to be performed for subjects in the standard of care
therapy (SOCT) arm during the treatment and post-treatment follow-up periods and the LTFU
period are provided in Table 12 and Table 13, respectively. |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoint of this study is:
CR rate per Lugano Classification {Cheson 2014} as determined per a blinded central
assessment
The additional secondary endpoints are:
ORR (CR + PR per Lugano Classification {Cheson 2014}) as determined per a blinded
central assessment
DOR
Duration of CR
OS
EFS
TTNT
Incidence of adverse events (AEs) and clinically significant changes in safety laboratory
values
Changes from baseline in the Global Health Status Quality of Life scale and the physical
functioning domain of the European Organisation for Research and Treatment of
Cancer-Quality of Life Questionnaire-30 (EORTC QLQ-C30) and the Low Grade
Non-Hodgkin Lymphoma-20 (NHL-LG20)
Changes from baseline in |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Schedules of assessments and procedures to be performed for subjects in the axicabtagene
ciloleucel treatment arm during the treatment and post-treatment follow-up periods and the longterm
follow-up (LTFU) period are provided in Table 10 and Table 11, respectively.
Schedules of assessments and procedures to be performed for subjects in the standard of care
therapy (SOCT) arm during the treatment and post-treatment follow-up periods and the LTFU
period are provided in Table 12 and Table 13, respectively. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| Germany |
| Italy |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End-of-study is defined as the time when all subjects, regardless of whether they receive study
treatment, have been followed for at least 5 years after randomization, are lost to follow-up,
withdraw consent, or die. Five years after the last study subject is randomized, subjects in the
axicabtagene ciloleucel treatment arm who received axicabtagene ciloleucel will be transitioned
to a separate LTFU study of subjects who have received an infusion of gene-modified cells |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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