| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL)
Relapsed/Refractory B-cell non-Hodgkin lymphoma (r/r NHL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancers of white blood cells |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000844 |
| E.1.2 | Term | Acute lymphoblastic leukaemia |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006595 |
| E.1.2 | Term | Burkitt's 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036710 |
| E.1.2 | Term | Primary mediastinal large B-cell lymphoma |
| 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 of phase 1 is to evaluate the safety of KTE-X19.
The primary objective of Phase 2
ALL Cohort: The primary objective is to evaluate the efficacy of KTE-X19, as measured by the overall complete remission rate defined as complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) in pediatric and adolescent subjects with r/r B-precursor ALL.
NHL Cohort: The primary objective is to estimate the efficacy as measured by the objective response rate (ORR) defined as a complete response or a partial response (CR+PR) in pediatric subjects with r/r NHL. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives will include assessing the safety and tolerability of KTE-X19, additional efficacy endpoints, and (for Phase 2 only) changes in PRO scores. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
ALL Cohort
101. Relapsed or refractory B-precursor ALL defined as one of the following:
- Primary refractory disease
-Any relapse within 18 months after first diagnosis
- Relapsed or refractory disease after 2 or more lines of systemic therapy
- Relapsed or refractory disease after allogeneic transplant provided subject is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment
102. Disease burden defined as at least 1 of the following:
-Morphological disease in the bone marrow (>5% blasts)
-MRD positive (threshold 10-4 by flow or PCR)
103. Subjects with Ph+ disease are eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have relapsed/refractory disease despite treatment with at least 2 different TKIs
104. Age ≤ 21 years and weight ≥ 6 kg.
111. In subjects previously treated with blinatumomab, CD19 tumor expression on blasts obtained from bone marrow or peripheral blood must be documented after completion of the most recent prior line of therapy and blasts must be ≥ 90% CD19 positive.
NHL Cohort
301. Histologically confirmed aggressive B cell NHL:
- DLBCL not otherwise specified
- Primary mediastinal large B-cell lymphoma (including Mediastinal gray zone lymphoma)
- Burkitt lymphoma, Burkitt-like lymphoma and Unclassified B-cell lymphoma intermediate between DLBCL and Burkitt lymphoma
302. Relapsed or refractory disease defined as 1 or more of the following:
- Primary refractory disease
- Relapsed or refractory disease after 2 or more lines of systemic therapy
- Relapsed or refractory disease after autologous /allogeneic SCT provided subject is at least 100 days from SCT at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment
303. Subjects must have received adequate prior therapy including at a minimum all of the following:
- Anti-CD20 monoclonal antibody, unless the investigator determines that the tumor is CD20 negative
- An anthracycline-containing chemotherapy regimen
304. At least 1 measurable lesion according to the revised International Pediatric Non-Hodgkin Lymphoma Staging System {Rosolen 2015}. Lesions that have been previously irradiated will be considered measurable only if progression has been
documented following completion of radiation therapy.
305. Magnetic resonance imaging (MRI) of the brain showing no evidence of CNS lymphoma
308. Age <18 years old and weight > or = 6kg
Both Cohort
105. and 309. Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age > or = 16 years at the time of assent/consent) performance status > or = 80 at screening
106. and 310. ANC > or = 500/uL unless, in the opinion of the PI, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy
107. and 311. Platelet count > or = 50,000/uL unless, in the opinion of the PI, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy
108. and 312. Absolute lymphocyte count > or = 100/µL
109. and 313. Adequate renal, hepatic, pulmonary and cardiac function
110. and 314. Females of childbearing potential must have a negative serum or urine pregnancy test |
|
| E.4 | Principal exclusion criteria |
ALL Cohort
201. Diagnosis of Burkitt’s leukemia/lymphoma according to WHO classification or chronic myelogenous leukemia lymphoid blast crisis
202. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years
205. History of concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome
206. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment
NHL Cohort
401. History of malignancy other than nonmelanoma skin cancer, carcinoma in situ (eg, cervix, breast), or FL unless disease free for at least 3 years
402. Autologous SCT within 100 days of planned KTE-X19 infusion
403. Prior CD19 targeted therapy other than blinatumomab (subjects who received KTE-X19 in this study are eligible for re-treatment)
404. Prior CAR therapy or other genetically modified T-cell therapy
409. Acute GVHD grade II-IV by Glucksberg criteria or severity B-D by IBMTR index; acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment.
Both Cohort
204. and 410. CNS involvement and abnormalities:
a. Any CNS tumor mass by imaging and/or parameningeal mass (cranial and/or spinal).
b. Presence of CNS-3 disease, defined as WBC ≥5/µL in CSF with presence of lymphoblasts with or without neurologic symptoms.
c. Presence of CNS 2 disease defined as WBC <5/µL in CSF with presence of lymphoblasts and with neurologic symptoms (see note below for further clarification).
Note: Neurologic symptoms may include but are not limited to cranial nerve palsy (if not explained by extracranial tumor) and clinical cord compression.
[Subjects with CNS-1 (no detectable lymphoblasts in the CSF) and those with CNS 2 without clinically evident neurological changes are eligible to participate in the study].
d. History or presence of any CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome (PRES), or cerebral edema with confirmed structural defects by appropriate imaging. History of stroke or transient ischemic attack within 12 months before enrollment. Patients with seizure disorders requiring active anti-convulsive medication.
208. and 416. Any medical condition likely to interfere with assessment of the safety or efficacy of study treatment
209. and 414. Primary immunodeficiency
210. and 407. History of HIV infection or acute /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 per current Infectious Diseases Society of America guidelines or applicable country guidelines
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs).
Phase 2:
ALL Cohort: Overall complete remission rate (CR + CRi) per independent review. All subjects who do not meet the criteria for CR or CRi by the analysis data cutoff date will be considered non-responders for the overall complete remission rate evaluation.
NHL Cohort: ORR per investigator assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will occur when the overall study enrollment is complete and all treated subject in the mITT set have had the opportunity to complete the month 6 disease assessment. |
|
| E.5.2 | Secondary end point(s) |
- Overall complete remission rate (CR + CRi) per investigator assessment
- Duration of Remission (DOR) in the ALL and NHL cohort
- Minimal Residual Disease (MRD) negative rate in ALL cohort
- Allogeneic SCT rate
- Overall survival (OS) in the ALL and NHL cohort
- Relapsed-free Survival (RFS) in ALL cohort
- Incidence of AEs and Common Terminology Criteria for Adverse Events (CTCAE) grade changes in safety laboratory values in the ALL and NHL cohort
- Incidence of anti-KTE-X19 antibodies in the ALL and NHL cohort
- Progression free survival in the NHL cohort |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All subjects will be followed in the long term follow-up (LTFU) 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 - Month 60
- Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time annually up to 15 years after the last subject receives their KTE X19 infusion. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I to assess safety, Phase II to assess efficacy of KTE-X19 |
|
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Canada |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| Czechia |
|
| 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 | 21 |
| 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 | 23 |
| 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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