| 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) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancers of white blood cells, collectively known as acute lymphoblastic leukemia. |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000844 |
| E.1.2 | Term | Acute lymphoblastic leukaemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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-C19.
The primary objective of Phase 2 is to evaluate the efficacy of KTE-C19, 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 relapsed/refractory (r/r) B-precursor acute lymphoblastic leukemia (ALL). |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives will include assessing the safety and tolerability of KTE-C19 and additional efficacy endpoints. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
101. Relapsed or refractory B-precursor ALL defined as one of the following:
- Primary refractory disease
- 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 immunosuppressive medications for at least 4 weeks prior to enrollment
102. Morphological disease in the bone marrow (> 5% blasts)
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. Ages 2-21 at the time of Assent or Consent per IRB guidelines
105. Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 80 at screening (Appendix C)
106. ANC ≥ 500/uL unless in the opinion of the PI cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy
107. Platelet count ≥ 50,000/uL unless in the opinion of the PI cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy
108. Absolute lymphocyte count ≥ 100/μL
109. Adequate renal, hepatic, pulmonary and cardiac function defined as:
- Creatinine clearance (as estimated by Cockcroft Gault or Schwartz) ≥ 60 cc/min
- Serum ALT and AST ≤ 5 x ULN
- Total bilirubin ≤ 1.5 x ULN, except in subjects with Gilbert’s syndrome.
- LVSF ≥ 30% or LVEF ≥ 50%, no evidence of pericardial effusion as determined by an ECHO and no clinical significant arrhythmias
- No clinically significant pleural effusion
- Baseline oxygen saturation ≥ 92% on room air
110. Females of childbearing potential (defined as having first menses) must have a negative serum or urine pregnancy test
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. If CD19 expression is quantified, then blasts must be ≥ 90% CD19 positive.
|
|
| E.4 | Principal exclusion criteria |
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
203. History of severe hypersensitivity reaction to aminoglycosides or any of the agents used in this study
204. CNS abnormalities
a. Presence of CNS-3 disease, defined as detectable cerebrospinal blast cells in a sample of CSF with ≥5 WBCs per mm3 with or without neurological changes, and presence of CNS-2 disease defined as detectable cerebrospinal blast cells in a sample of CSF with < 5 WBCs per mm3 with neurological changes
Note: Subjects with CNS-1 (no detectable leukemia in the CSF) and those with CNS-2 without clinically evident neurological changes are eligible to participate in the study.
b. History or presence of any CNS disorder, such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome (PRES), or cerebral edema
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
207. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
208. Primary immunodeficiency
209. Known infection with HIV, hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). A history of treated hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
210. 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
211. Prior medication:
- Salvage systemic therapy (including chemotherapy, TKIs for Ph+ ALL, and blinatumomab) within 1 week or 5 half-lives (whichever is shorter) prior to enrollment
- Prior CD19 directed therapy other than blinatumomab
- History of Grade 4 neurologic event (Common Terminology Criteria for Adverse Events [CTCAE]) or Grade 4 CRS (Lee et al, 2014) with prior CD19-directed therapy
- Alemtuzumab within 6 months prior to enrollment, clofarabine or cladribine within 3 months prior to enrollment, or PEG-asparaginase within 3 weeks prior to enrollment
- Donor lymphocyte infusion (DLI) within 28 days prior to enrollment
- Any drug used for GVHD within 4 weeks prior to enrollment (eg, calcineurin inhibitors, methotrexate, mycophenolyate, rapamycin, thalidomide) or immunosuppressive antibody used within 4 weeks prior to enrollment (eg, anti-CD20, anti-tumor necrosis factor [TNF], anti-interleukin [IL] 6 or anti-interleukin 6 receptor)
- At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy prior to enrollment (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists etc)
- Corticosteroid therapy at a pharmacologic dose (≥ 0.7 mg/kg/day of hydrocortisone or equivalent doses of corticosteroids) and other immunosuppressive drugs must be avoided for 7 days prior to enrollment
212. 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
213. 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
214. Live vaccine ≤ 4 weeks prior to enrollment
215. 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.
216. Subjects of both genders of child-bearing potential who are not willing to practice birth control from the time of consent through 6 months after the completion of KTE-C19.
217. 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.
218. History of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
|
|
| 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: Overall complete remission rate (CR + CRi) per independent review (Appendix A of the protocol). 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.
|
|
| 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 (Appendix A of the protocol)
- Duration of Remission (DOR)
- Minimal Residual Disease (MRD) negative rate
- Allogeneic SCT rate
- Overall survival (OS)
- Relapsed-free Survival (RFS)
- Incidence of AEs and Common Terminology Criteria for Adverse Events
(CTCAE) grade changes in safety laboratory values
- Incidence of anti-KTE-C19 antibodies |
|
| 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 C19 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 | 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) | 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-C19 |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| France |
| Germany |
| Netherlands |
| United States |
|
| 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 | 15 |
| 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 | 15 |
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