A Phase II study evaluating efficacy of KTE-X19 CAR-T cell therapy in Relapsed or Refractory Mantle-Cell Lymphoma achieving a partial response during Ibrutinib salvage therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

28 Dec 2023 → ongoing

Decision date (initial)

2023-06-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Kite Pharma, Inc.

External identifiers

EU CT number

2022-502907-31-00

WHO UTN

U0000-0000-0000

ClinicalTrials.gov

NCT00000000

ISRCTN

ISRCTN00000000

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

Assess the CR rate at 90 days after KTE-X19 infusion in patients in PR during Ibrutinib single agent therapy

Secondary objectives 4

1. To evaluate efficacy and survival outcomes, including: DOR, CR rate at 180 days and 365 days after KTE-X19 infusion, PFS at one year after KTE-X19 infusion, OS at one year after KTE-X19 infusion, PFS at two and three years after KTE-X19 infusion, OS at two and three after KTE-X19 infusion, non-relapse mortality (NRM)
2. To evaluate safety and incidence of adverse events (AEs), including cytokine release syndrome (CRS), immune-effector associated neurotoxicity syndrome (ICANS), hemophagocytic lymphohistiocytosis / macrophage activation syndrome (HLH/MAS)
3. To evaluate the rate of minimal residual disease (MRD) negativity To describe the efficacy of this treatment in patients with poor clinical and biological risk factors, including progression of disease within 24 months from diagnosis (POD24), high Ki-67 levels, blastoid/pleomorphic morphology and TP53 mutations/deletions
4. ORR/CR rates at 90 days after KTE-X19 infusion for patients with poor clinical and biological risk factors including POD24, high Ki-67 levels, blastoid/pleomorphic morphology and TP53 mutations/deletions

Conditions and MedDRA coding

Relapsed or Refractory Mantle-Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Signed Informed Consent Forms (ICF)
2. Age ≥ 18 years and ≤ 75 years
3. ECOG performance status of 0 or 1
4. Histologically confirmed diagnosis of mantle-cell lymphoma according to the 2016 WHO classification
5. Relapsed or refractory disease after at least one line of systemic therapy prior to Ibrutinib treatment, including anthracyclines or bendamustine in association with Rituximab
6. Currently receiving Ibrutinib at time of enrollment, without drug tolerance issues
7. PET/CT/Magnetic Resonance Imaging (MRI) confirmed and measurable PR disease status, as defined by the Lugano Response Criteria 11 (Cheson, 2014), after a minimum of 6 months of Ibrutinib single agent treatment as current line of therapy at time of enrollment
8. Hematologic laboratory values: Lymphocyte counts ≥ 0.1 x 10^9/L at time of enrollment, Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L, without growth factor support for 7 days (14 days if pegfilgrastim), Untransfused Hemoglobin (Hb) ≥ 8 g/dL, Platelets (PLT) ≥ 75 x 10^9/L or ≥ 30 x 10^9/L in case of documented bone marrow involvement (> 50% or tumor cells), without transfusion for 7 days
9. Adequate organ function; Adequate liver function: aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 x ULN; serum total bilirubin ≤ 1.5 ULN except in cases of Gilbert’s syndrome, then ≤ 3.0 ULN; Adequate renal function: estimated serum creatinine clearance of ≥ 60 mL/min calculated by Cockroft-Gault formula; Adequate cardiac function: ejection fraction ≥ 50%; Adequate lung function: SO2 > 92% at rest and absence of pleural effusions
10. Negative urine and serum pregnancy test within 7 days prior to study treatment in women of childbearing potential. Women who are not of childbearing potential who are considered to be post-menopausal(≥ 12 months of non-therapy amenorrhea) or surgically sterile (absence of ovaries and/or uterus) are not required to have a pregnancy test
11. Female patients of reproductive potential should avoid becoming pregnant by using a highly effective method of contraception or abstaining from sexual activity from the time of consent through 12 months following lymphodepletion chemotherapy administration or 12 months after KTE-X19 infusion
12. Male patients of reproductive potential, even if surgically sterilized (ie, status post-vasectomy), should use an effective method of contraception and are recommended to use a barrier method or abstain from sexual activity from the time of consent through 12 months following lymphodepletion chemotherapy administration or 12 months after KTE-X19 infusion.
13. Patients must be accessible for treatment and follow up as well as they must be willing and capable to comply with the requirements of the study
14. Confirmed availability of archival
15. Life expectancy of at least 12 weeks

Exclusion criteria 15

1. Patients with a known or suspected history of HLH/MAS
2. Patients with acute bacterial, viral, or fungal infection at baseline, confirmed by a positive blood culture within 72 hours prior to apheresis and lymphodepleting chemotherapy or by clinical judgment in the absence of a positive blood culture
3. Patients with known active infection, or reactivation of a latent infection, whether bacterial, viral [including, but not limited to, epstein barr virus (EBV), cytomegalovirus (CMV), hepatitis B (HBV), hepatitis C (HCV), and HIV], fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks of dosing. If there is a positive history of HBV or HCV, the viral load must be undetectable per quantitative PCR and/or nucleic acid testing
4. Pregnant, breast-feeding, or intending to become pregnant during the study
5. Prior exposure to CAR-T cell therapy
6. Prior solid organ transplantation
7. History of allogenic HSCT except if no donor cells are detected on chimerism, the subject is off all immunesuppression, and there is no evidence of active graft-versus-host-disease (GVHD) of any grade, acute or chronic
8. History of autoimmune disease causing clinically significant organ dysfunction or requiring systemic immune suppression or disease-modifying agents in the two years prior to the participation in this study
9. Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to leukapheresis. Inhaled and topical steroids are permitted.
10. Received any other investigational drugs within 30 days before enrollment.
11. Active central nervous system (CNS) involvement by lymphoma, or current or past history of other CNS disease, such as stroke, epilepsy, dementia, CNS vasculitis, neurodegenerative disease, cerebral edema or progressive multifocal leukoencephalopathy (PML); Note: Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits, as judged by the investigator, are allowed
12. History of deep venous thrombosis or pulmonary embolism in 6 months prior to participation in the study
13. Significant or extensive history of cardiovascular disease such as New York Heart Association (NYHA) Class III or IV or Objective Class C or D cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina
14. Patients with another invasive malignancy, with the exception of non-melanomatous skin cancer or carcinoma in situ, and other tumors deemed by the investigator to be of low likelihood for recurrence, unless disease-free for at least 3 years
15. Any medical condition likely to interfere with assessment of safety or efficacy study treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. CR rate at 90 days after KTE-X19 infusion in patients in PR after Ibrutinib single agent therapy

Secondary endpoints 10

1. 12 months PFS
2. 12 months OS
3. 24 and 36 months PFS
4. 24 and 36 months OS
5. DOR
6. CR rate at 180 days and 365 days after KTE-X19 infusion
7. NRM
8. Rates of CRS and ICANS [graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) Grading System], including description of the use of tocilizumab, corticosteroids and other treatments for their management, rate of HLH/MAS and other AEs [graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAEv5)]
9. Rate of MRD negativity for those patients with bone marrow (BM) involvement at study entry
10. ORR/CR rates at 90 days after KTE-X19 infusion for patients with poor clinical and biological risk factors including POD24, high Ki-67 levels, blastoid/pleomorphic morphology and TP53 mutations/deletions

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Paolo Corradini

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Public relations office

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications