| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Mantle Cell Lymphoma (MCL) |
|
| 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 | 10061275 |
| E.1.2 | Term | Mantle cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10026801 |
| E.1.2 | Term | Mantle cell lymphoma refractory |
| 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 evaluate the efficacy of KTE-X19, as measured by objective response rate, in subjects with r/r MCL.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives will include assessing the safety and tolerability of KTE-X19, and additional efficacy endpoints, including duration of response (DOR).
Secondary objectives related to patient-reported outcomes (PROs) in Cohort 1 and Cohort 2 will include change in the European Quality of Life-5 Dimensions (EQ-5D) scores from baseline to Month 6. Secondary objectives related to PROs in Cohort 3 will include change in EQ-5D and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) scores from baseline over time. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
101. Pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or presence of t(11;14)
102. Up to 5 prior regimens for MCL.
Cohort 1 and Cohort 2: Prior therapy must have included:
- Anthracycline or bendamustine-containing chemotherapy and
- Anti-CD20 monoclonal antibody therapy and
- Ibrutinib or acalabrutinib
Cohort 3: Prior therapy must have included anthracycline- or bendamustine or high-dose cytarabine containing chemotherapy and anti-CD20 monoclonal antibody therapy. Subjects in
Cohort 3 must not have received prior therapy with a BTKi.
103. Relapsed or refractory disease, as defined by the following:
- Disease progression after last regimen, or
- Failure to achieve a PR or CR to the last regimen
104. At least 1 measurable lesion. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. If the only measurable disease is lymph node disease, at least one lymph node should be ≥ 2 cm
105. For subjects in Cohort 1 and Cohort 2 only: 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 or BTKi (ibrutinib or acalabrutinib; as applicable for subjects in Cohort 1 and Cohort 2) 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 years or older
109. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
110. ANC ≥ 1000/uL
111. Platelet count ≥ 75,000/μL. For subjects in Cohort 3 with bone marrow involvement, platelet count ≥ 50,000/μL is acceptable.
112. Absolute lymphocyte count ≥ 100/ μL
113. Adequate renal, hepatic, pulmonary and cardiac function defined as:
- Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 cc/min
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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. For subjects in Cohort 3, a multigated acquisition (MUGA) scan may be used in place of ECHO.
- No clinically significant pleural effusion for subjects in Cohort 1 and Cohort 2, and no clinically significant pleural effusion, pericardial effusion, or ascites for subjects in Cohort 3
- 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. |
|
| E.4 | Principal exclusion criteria |
201. History of malignancy other than nonmelanomatous skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years.
202. Autologous stem cell transplant within 6 weeks of planned KTE-X19 or axicabtagene ciloleucel infusion.
203. History of alloSCT, with the exception of subjects in Cohort 3 with no donor cells detected on chimerism > 100 days after alloSCT
204. Prior CD19 targeted therapy with the exception of subjects who received KTE-X19 or axicabtagene ciloleucel in this study and are eligible for retreatment.
205. Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
206. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
207. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the Kite Medical Monitor.
208. History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Subjects with a history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing. For subjects in Cohort 3 enrolled in France, those with any history of acute or chronic hepatitis B or C infection are excluded.
209. Presence of any indwelling line or drain (e.g. percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted
210. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases
211. History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease,
cerebral edema, posterior reversible encephalopathy syndrome (PRES), or any autoimmune disease with CNS involvement
212. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, active arrhythmias, or other clinically significant cardiac disease within 12 months of enrollment
213. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
214. History of deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of enrollment
215. Possible requirement for urgent therapy due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis
syndrome)
216. Primary immunodeficiency
217. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
218. History of severe immediate hypersensitivity reaction to any of the agents used in this study
219. Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen
220. Females of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant
221. Subjects of both genders who are not willing to practice birth control from the time of consent through 6 months after the completion of KTE-X19 or axicabtagene ciloleucel infusion
222. 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.
223. History of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate [ORR] (complete response [CR] + partial response [PR]) per the Lugano Classification (Cheson et al, 2014) per Independent Radiology Review Committee (IRRC) review. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis in Cohort 1 will be performed after 60 KTE-X19 subjects in the mITT set of Cohort 1 have been enrolled and treated with KTE-X19 and have had the opportunity to be evaluated for response 6 months after the Week 4 disease assessment.
The primary analysis in Cohort 3 will occur after 86 subjects in Cohort 3 have been enrolled and treated with KTE-X19 and have had the opportunity to be assessed for response 6 months after the first objective response or 9 months after the KTE-X19 infusion, whichever is earlier. A follow-up analysis will be performed after 86 subjects in Cohort 3 have had the opportunity to be assessed for response 18 months after the first objective response to further evaluate the risk-benefit profile of KTE-X19, including the durability of response. |
|
| E.5.2 | Secondary end point(s) |
- Duration of Response
- Best Objective Response
- Objective response rate as determined by study investigators
- Progression Free Survival
- Overall Survival
- Incidence of adverse events and clinically significant changes in laboratory values
-Incidence of anti-CD19 CAR antibodies
- Levels of anti-CD19 CAR+ T cells in blood
- Levels of cytokines in serum
- Changes over time in the EQ-5D scale score and visual analogue scale score
- Changes over time in the EORTC-QLQ-C30 score (Cohort 3 only) |
|
| 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 (for Cohort 1 and Cohort 2) or through Month 21 (for Cohort 3)
- Month 24 (± 1 month)
- Beginning with Protocol Amendment 8 and after completion of at least 24 months of assessments in KTE-C19-102, subjects who received an infusion of anti-CD19 CAR T cells will be given the opportunity to transition to a separate LTFU study, KT-US-982-5968, after providing signed informed consent. |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Netherlands |
| Spain |
| Germany |
| 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
|
| Defined as when the last subject is assessed or received an intervention for evaluation in the study, including survival assessments |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 16 |
| 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 | 19 |
| 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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