LATE-R trial. A Phase II, Single-Arm, Open-Label, Multicenter Study to Evaluate the Efficacy of Axicabtagene Ciloleucel in Patients with Late Relapse of Diffuse Large B-Cell Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Geltamo

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

20 Nov 2024 → ongoing

Decision date (initial)

2024-09-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Kite Pharma, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Evaluate the efficacy of axicabtagene ciloleucel in second line for LBCL patients with late relapse (between 1 and 5 years after the end of first-line chemoimmunotherapy) as measured by complete metabolic response

Secondary objectives 9

1. Further evaluate the efficacy of axicabtagene ciloleucel in second line for LBCL patients with late relapse (between 1 and 5 years after the end of first-line chemoimmunotherapy)
2. Evaluate the efficacy of axicabtagene ciloleucel in second line for LBCL patients in two cohorts defined by time to relapse (12-24 months and 24-60 months).
3. Evaluate the safety profile of axicabtagene ciloleucel in second line for LBCL patients with late relapse (between 1 and 5 years after the end of first-line chemoimmunotherapy)
4. Assess the effect of axicabtagene ciloleucel on patient health-related quality of life
5. Evaluate the baseline metabolic tumor volume and early metabolic response
6. Evaluate the characteristics of the tumor, the microenvironment, and the host
7. To compare tumor characteristics between patients relapsing during the second year since induction therapy and after
8. Evaluate pre- and post-treatment blood biomarkers, including inflammation markers and PK/PD profiling
9. Evaluate the host immune response (including epitope spreading) and mechanisms of resistance

Conditions and MedDRA coding

Diffuse Large B-Cell Lymphoma

Regulatory references

Plan to share IPD

Yes

IPD plan description

Data obtained through this study may be provided to qualified researchers with academic interest in hematology diseases. All individual data collected during the trial will be available. Data shared will be coded, with no PHI included. Study protocol, statistical analysis plan, informed consent form and clinical study report will be also available. Information will be available beginning 6 months after final publication with no end date established. Approval of the request and execution of all applicable agreements are prerequisites to the sharing of data with the requesting party. Data requests can be submitted starting 6 months after article publication. Access to trial IPD can be requested by qualified researchers and will be provided following review and approval of a research and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact to GELTAMO though the web page: https://www.geltamo.com/contacto

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Signed written Informed Consent Form
2. Age > 18 years
3. Patient who understands and speaks one of the country official language
4. Histologically proven relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) of the following histology at relapse: diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) and follicular lymphoma Grade 3B per WHO 2016 classification. Indolent B-NHL who transformed into aggressive B-NHL and were previously treated with R-CHOP-like after transformation are eligible. Primary mediastinal B-cell lymphoma are not eligible
5. Positron-emission tomography (PET)-positive disease
6. Patients must have received adequate first-line therapy including at a minimum: An anti-CD20 monoclonal antibody (rituximab or obinutuzumab), and CHOP or CHOP-like chemotherapy. Note: CHOP-like chemotherapy corresponds to ACVBP, EPOCH, or COPADEM. Dose-reduced CHOP (i.e., miniCHOP) is excluded except for dose-reductions of vincristine due to peripheral neuropathy. Patients who have received additional drugs in combination with CHOP or CHOP-like regimen are eligible.
7. Relapsed disease after first line chemo immunotherapy (full dose of R-CHOP or R-CHOP-like regimen), documented by PET-scan and biopsy: Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease relapse after 12 months and up to 5 years from end of first-line therapy.
8. Patients must meet CAR-T-eligible criteria as defined by: Patient deemed eligible for CAR T-cells therapy by the CAR-T physician and all the following criteria: ECOG performance status of 0, 1 or 2; Adequate vascular access for leukapheresis procedure (either peripheral or central venous line); Absolute neutrophil count (ANC) ≥ 1 x 10^9/L; Platelets ≥ 75 x 10^9/L; Absolute lymphocyte count ≥ 0.1 x 10^9/L; Creatinine clearance (CrCl) as estimated by Cockcroft Gault or MDRD ≥ 40 mL/min; Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5xULN; Total bilirubin <1.5 mg/dL, except in patients with Gilbert’s syndrome; Cardiac ejection fraction ≥ 45%; Baseline oxygen saturation ≥ 92% on room air
9. 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 12 months are not considered to be of childbearing potential)

Exclusion criteria 26

1. Patients who received more than one prior line of systemic therapy
2. Early relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease relapse before 12 months from end of first-line therapy
3. Refractory disease defined as: Progressive disease during first-line therapy; Stable disease as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP); Partial response as best response after at least 6 cycles, and biopsy-proven residual disease
4. Patients who received first line of R-CHOP or obinutuzumab-CHOP for an indolent B-NHL who relapse as transformed aggressive B-NHL after a year from the end of first-line therapy are NOT eligible.
5. Prior CD19 targeted therapy
6. Patients with cardiac atrial or cardiac ventricular lymphoma involvement
7. Requirement for urgent therapy due to tumor mass effects, such as bowel obstruction or blood vessel compression
8. Patient with clinically significant pleural effusion
9. History of another primary malignancy that has not been in remission for at least 3 years (except for nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast)). A maintenance treatment is not allowed.
10. Patients with detectable Central Nervous System (CNS) lymphoma. Patients with a history of CNS lymphoma but no active CNS disease (after systematic MRI and lumbar puncture) at the time of enrolment will be eligible
11. Presence of CNS disorder such as dementia, autoimmune disease with CNS involvement, cerebral edema with confirmed structural defects by appropriate imaging, or seizure disorders requiring active anticonvulsive medication. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrolment
12. Presence of any indwelling line or drain (eg, 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
13. History of acute or chronic active hepatitis B or C infection (seropositivity). If there is a positive history of treated hepatitis B or hepatitis C (negative HBsAg and positive Anti-HBc/ positive anti-HCV), the viral load HBV DNA/ HCV RNA) must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing
14. Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a CD4 count > 200 cells/uL.
15. Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antimicrobials or other treatment at the time of leukapheresis or axicabtagene ciloleucel administration
16. History of any one of the following cardiovascular conditions within the past 12 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease
17. Presence of primary immunodeficiency
18. History of any medical condition including but not limited to autoimmune disease (e.g., Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression and/or systemic disease modifying agents within the last year. Endocrine conditions that require maintenance with physiologic dose steroids are allowed.
19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
20. History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study
21. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides, cyclophosphamide or fludarabine
22. Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
23. Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of lymphodepletion chemotherapy on the fetus or infant
24. Patients of either sex who are not willing to practice birth control from the time of consent during treatment and for at least 12 months after conditioning chemotherapy dosing or axicabtagene ciloleucel dosing, whichever is later
25. In the investigator’s judgment, the patient is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
26. Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Complete Metabolic Response, defined as negative findings on a PET/CT scan at Month 3, after receiving axicabtagene ciloleucel infusion at day 0. The negativity of PET/CT findings will be assessed according to Lugano Classification and Deauville criteria

Secondary endpoints 14

1. Complete metabolic response, defined as negative findings on a PET/CT scan at Month 3 after receiving axicabtagene ciloleucel infusion at day 0, as assessed by central imaging review of PET/CT
2. The Overall Response Rate, defined as the percentage of patients who achieved partial metabolic response or complete metabolic response according to the Lugano Classification criteria at Month 3 determined by both central and investigator assessments
3. Best objective response rate defined as the percentage of complete metabolic response + partial metabolic response determined by the investigator assessment among all patients between month 1 and month 12 from axicabtagene ciloleucel infusion
4. Best complete response rate defined as the percentage of complete metabolic response determined by the investigator assessment among all patients between month 1 and month 12 from axicabtagene ciloleucel infusion
5. Overall survival, defined as the time from inclusion to date of death from any cause. Alive patients will be censored at their last follow-up date
6. Progression free survival, defined as the time from axicabtagene ciloleucel infusion to the first observation of documented disease progression/relapse (based on investigator disease assessment or death due to any cause. If a patient has not progressed or died, progression free survival will be censored at the time of last visit with adequate assessment
7. Event-free survival, defined as the time from leukapheresis to any event preventing axicabtagene ciloleucel infusion if axicabtagene ciloleucel is never infused, or death, disease progression, or instauration of a new lymphoma therapy for lymphoma progression after axicabtagene ciloleucel infusion.
8. Duration of Response, defined as the time from attainment of partial metabolic response or complete metabolic response to the date of first documented disease progression/relapse (based on investigator disease assessment) or death from any cause.
9. Duration of complete response, defined as the time from achievement complete metabolic response to the date of first documented disease progression/relapse (based on investigator disease assessment) or death from any cause
10. Type, frequency and severity of adverse events and serious adverse events occurring after leukapheresis procedure to 28 days after the infusion of the study treatment
11. Type, frequency and severity of adverse events of special interest: Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, hypogammaglobulinemia, prolonged cytopenias and infections and emergent secondary malignancies occurring after leukapheresis procedure to the end of follow-up (5 years)
12. The patient quality of life assessed by the administration of the EORTC QLQ-C30, EQ-5D-5L, and QLQ-NHL-HG29 patient reported outcomes at screening and after 4 weeks of infusion and after 3 months of infusion
13. Correlation between total metabolic tumor volume pre-axicabtagene ciloleucel infusion and efficacy/toxicity
14. Biological exploratory endpoints described in relation to efficacy and toxicity based on correlation with biological parameters such as: Histologic, phenotypic, genomic, transcriptomic, and molecular characteristics of malignant cells and tumor microenvironment pre and post-treatment; Immune response markers in tumor and blood (cytokine levels, immune cells, and TCR repertoire); Minimal residual disease; Immune-escape mechanisms

Investigational products

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

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Geltamo

Sponsor organisation

Fundacion Geltamo

Address

Avenida Valdecilla Sn

City

Santander

Postcode

39008

Country

Spain

Scientific contact point

Organisation

Fundacion Geltamo

Contact name

Ana María Méndez López

Public contact point

Organisation

Fundacion Geltamo

Contact name

Ana María Méndez López

Third parties 8

Locations

1 EU/EEA country · 15 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 12 files

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

Application history

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