| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Indolent Non-Hodgkin Lymphoma (r/r) iNHL. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancers of white blood cells, collectively known as B-cell non-Hodgkin lymphoma. |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065856 |
| E.1.2 | Term | Non-Hodgkin's lymphoma unspecified histology indolent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 is to estimate the efficacy of axicabtagene ciloleucel, as measured by overall response rate (ORR), in subjects with relapsed or refractory (r/r) indolent non-Hodgkin lymphoma (iNHL). |
|
| E.2.2 | Secondary objectives of the trial |
| A key secondary endpoint will be progression-free survival (PFS); additional secondary objectives will include additional safety and efficacy endpoints. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Active, histologically proven B-cell NHL that is generally regarded as indolent (eg FL, marginal zone lymphoma, lymphoplasmacytic lymphoma) that is also determined to be high risk as defined by one or more of the criteria below:
o Progression of B-cell iNHL within 24 months of original diagnosis of disease that was subsequently treated with first-line anti-CD20 monoclonal antibody- and cytotoxic agent-containing combination chemoimmunotherapy (eg, R-CHOP, R-Bendamustine, R-CVP, R-fludarabine).
Note: A biopsy of a progressing lesion is required prior to enrollment to show absence of transformation to diffuse large B-cell lymphoma (DLBCL) or other excluded histology (eg, FL Grade 3b)
o Progression of B-cell iNHL within 6 months of the completion of second- or greater-line therapy with anti-CD20 monoclonal antibody- and alkylating agent-containing chemoimmunotherapy (≥ 2 cycles)
o Progression of B-cell iNHL at any point following autologous transplantation
2. At least 1 measurable lesion according to the revised International Working Group (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
3. Magnetic resonance imaging (MRI) of the brain showing no evidence of central nervous system (CNS) lymphoma
4. 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 (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists).
5. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities, such as alopecia).
6. Age 18 or older
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8. Absolute neutrophil count (ANC) ≥ 1000/uL
9. Platelet count ≥ 75000/uL
10. Absolute lymphocyte count ≥ 100/uL
11. Adequate renal, hepatic, pulmonary, and cardiac function defined as:
o Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
o Serum ALT/AST ≤ 2.5 upper limit of normal (ULN)
o Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert’s syndrome
o Cardiac ejection fraction ≥ 50% , no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
o No clinically significant pleural effusion
o Baseline oxygen saturation > 92% on room air
12. 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) |
|
| E.4 | Principal exclusion criteria |
1. Transformed FL
2. Small lymphocytic lymphoma
3. Histological Grade 3b FL
4. Known presence of lymphoma cells in the peripheral blood
5. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) unless disease-free and without anticancer therapy for at least 3 years
6. Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion
7. History of allogeneic stem cell transplantation
8. Prior CD19 targeted therapy with the exception of subjects who received axicabtagene ciloleucel in this study and are eligible for retreatment
9. Prior CAR therapy or other genetically modified T-cell therapy
10. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
11. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management
12. History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis (Hep) B or Hep C infection. Subjects with history of Hep B or Hep C infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines.
13. Presence of lymphoma that is known to involve the full thickness of the gastric wall
14. 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.
15. Subjects with detectable cerebrospinal fluid malignant cells or known brain metastases or with a history of cerebrospinal fluid (CSF) malignant cells or brain metastases
16. 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
17. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
18. 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
19. Possible requirement for urgent therapy within 6 weeks after leukapheresis due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome)
20. History of autoimmune disease (eg, Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus), resulting in end organ injury or requiring systemic immunosuppression or systemic disease modifying agents within the last 2 years. Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and subjects with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
21. History of deep vein thrombosis (DVT) or pulmonary embolism within 6 months of enrollment
22. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
23. History of severe immediate hypersensitivity reaction to any of the agents used in this study
24. Treatment with a live, attenuated vaccine within 6 weeks prior to the planned start of the conditioning regimen or anticipation of need for such a vaccine during the course of the study
25. Women of childbearing 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.
26. Subjects of either sex who are not willing to practice birth control from the time of consent through 6 months following axicabtagene ciloleucel infusion
27. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR is defined as the incidence of a CR or a PR by the revised IWG Response Criteria for Malignant Lymphoma as determined by the study investigators. All subjects who do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy analysis of response rate will be performed when the last treated subject has had the opportunity to be evaluated for response 6 months after the axicabtagene ciloleucel infusion. An additional analysis of 12-month PFS will occur after the last treated subject has had the opportunity to be evaluated for response 12 months after the axicabtagene ciloleucel infusion. The CSR will be written based on the data collected and analyzed from this additional analysis. Additional descriptive analyses may occur after the primary analysis as needed. The final analysis will occur when all subjects have completed the study. |
|
| E.5.2 | Secondary end point(s) |
PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death from any cause. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date. Subjects who receive additional anti-cancer therapy (with the exception of stem cell transplant) in the absence of documented progression will be censored at the last evaluable disease assessment prior to the additional therapy. Death that occurs after additional anti-cancer therapy will be considered a PFS event.
The 12-month PFS rate is defined as the Kaplan-Meier estimate of PFS at 12 months post axicabtagene ciloleucel infusion.
Best objective response is defined as the incidence of CR, partial PR, stable disease (SD), PD, or unevaluable (UE) as best response to treatment.
Duration of Response (DOR) is defined for subjects who experience an objective response and is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007) or death from any cause. Subjects not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date. Subjects who receive additional anti-cancer therapy (with the exception of stem cell transplant) in the absence of documented progression will be censored at the last evaluable disease assessment prior to the additional therapy. Death that occurs after additional anticancer therapy will be considered an event.
OS is defined as the time from axicabtagene ciloleucel infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last date known to be alive.
Other secondary endpoints are as follows:
• Incidence of AEs.
• Clinically significant changes in laboratory values.
• Incidence of anti-axicabtagene ciloleucel antibodies.
• Levels of anti-CD19 CAR T cells in blood.
• Levels of cytokines in serum. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All enrolled subjects will be followed in the long-term follow-up period for survival and disease status if applicable. Subjects will begin the long-term follow-up period after they have completed the Month 3 visit of the post treatment assessment period (whether they have responded to treatment or went straight to the Month 3 visit due to disease progression).
• Every 3 months (± 2 weeks) through Month 18
• Every 6 months (± 1 month) between Month 24 to Month 60 |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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
|
| Completion of the study is defined as the time at which the last subject completes the long term follow-up period visit, is considered lost to follow-up, withdraws consent, or dies. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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