Italian Observational Study on CAR-T Therapy for Lymphoma

Mantle Cell Lymphoma Clinical Trial

— CART-SIE  

Official title:

A Multicenter Prospective Observational Study on Chimeric Antigen Receptor (CAR) T-cell Therapy for Lymphoma: Monitoring Feasibility, Efficacy, Toxicity and Biomarkers in a Real Life Setting

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06339255
• Other study ID #: INT 180/19
• Status: Recruiting
• Start date: October 30, 2019
• Est. completion date: December 31, 2029

Study information

• Verified date: March 2024
• Source: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Contact: Paolo Corradini, Professor
• Phone: +39 02 2390 2950
• Email: paolo.corradini[@]istitutotumori.mi.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this observational study on chimeric antigen receptor T-cell therapy is to monitor the feasibility, efficacy, toxicity and biomarkers in a real life setting.

Partecipants will be asked to agree to their clinical data collection and to partecipate to the optional biological study that aims to evaluate biomarkers of toxicity and response (clinical characteristics, cytokine profile, cellcomposition and type of the CAR-T cell product, lymphoma genomics). The study will evaluate even the disease response according to lugano criteria by PET and CT in routine clinical activity.

Description:

This observational prosopective multicenter study aims to:

1. evaluate the feasibility of CAR T-cell treatment in the real-life setting, with particular regard to eligible patients versus those subjected to leukapheresis versus those finally treated.

2. evaluate the survival outcome of PMBCL, DLBCL, MCL and FL patients treated with CAR T-cells versus those potentially eligible, but excluded from cellular therapy for other causes (either related to the patient or to the manufacturing);

3. monitor the incidence of early and late AEs up to three year after CAR-T;

4. evaluate disease response and immune recovery biomarkers at different time-points up after CAR-T (when clinically indicated or using blood sampling leftover);

5. evaluate biomarkers of toxicity and response (clinical characteristics, cytokine profile, cell composition and type of the CAR T-cell product, lymphoma genomics).

6. evaluate disease response according to Lugano criteria by PET and CT in routine clinical activity.

Primary Objective:

• Feasibility and efficacy of the treatment in the real life practice

Secondary Objectives:

• Evaluation of Outcome [Response rate (ORR), Overall survival (OS), Progression free survival (PFS), duration of response (DoR) non-relapse mortality (NRM)] according to Lugano criteria.

• Evaluation of safety (CRS, neurotoxicity, infections, cytopenias, B cell aplasia, second malignancies) with particular attention to the safety in the new indications

• Evaluation of bridging therapy (outcome and safety)

• Evaluation of salvage therapy after CAR-T failure (outcome and safety)

• Comparison of the different CAR T-cell products (time from patient screening to infusion, disease response and safety)

• Comparison of the different histotypes (PMBCL, DLBCL, MCL FL) according to CAR-T cell products

Biological Studies

• Characterization of biomarkers of early response (circulating tumor cell free DNA versus PET and CT scans)

• Characterization of toxicity biomarkers

• Analysis of the immune reconstitution and CAR-T expression Radiomics Evaluation

• Influence of PET quantitative parameters (tMTV, Distance max, Distance max bulky, metabolic changes between baseline and +30 and +90 after CAR T-cell infusion (ΔSUV max) on outcome

• Influence of PET quantitative parameters (tMTV, Distance max, Distance max bulky, metabolic changes between baseline and +30 and +90 after CAR T-cell infusion (ΔSUV max) on outcome.

Primary endpoint:

to evaluate the percentage of patients infused versus those eligible and leukoapheresed to evaluate the overall response and survival at one year of the patients treated with CAR T cells.

Secondary endpoints:

Overall response rate (ORR) at 3-6-12-18 months Overall survival (OS) for all patients included in the study OS, Progression free survival (PFS), Event free survival (EFS), and duration of response (DoR), non-relapse mortality (NRM) after CAR T-cell therapy at one,two years and 5 years Incidence and grading of CRS and neurotoxicity Number of patients receiving a bridging therapy before lymphodepletion Intensive Care Unit admission rate for all treated patients Lymphoma genomics and circulating cell free DNA as early response biomarker Characterization of toxicity biomarkers Analysis of immune reconstitution and CAR-T expression Early Adverse event (grading/onset/severity/treatment) Long term Safety (AE grading/onset/severity/treatment) Incidence of second malignancies Evaluation of quantitative parameters of PET by central review, when applicable in selected sites This is an observational multicenter prospective study enrolling all consecutive patients referred to the Italian hematologic centers already qualified for CAR T-cell treatment with relapsed/refractory DLBCL, PMBCL, MCL and FL. The screening will be done according to the axi-cel, tisagen-cel, brexucabtagene autoleucel and lisocabtagene maraleucel label criteria, the eligibility of a given patient to CAR-T will be definedaccording to AIFA criteria.

All patients eligible to CAR-T will be consecutively enrolled Biological samples will be stored at each institution or centralized at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. Fondazione Italiana Linfomi (FIL) will be in charge of the GCP management of the study. Web-based CRF are prepared by FIL.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5300
• Est. completion date: December 31, 2029
• Est. primary completion date: December 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with diagnosis of DLCBL, PMBCL, MCL and FL eligible for CAR-T treatment with commercialy available products in Italy.

Exclusion Criteria:

• Not applicable

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma
• Primary Mediastinal Large B-cell Lymphoma (PMBCL)

Locations

Country	Name	City	State
Italy	Fondazione IRCCS Istituto Nazionale Tumori	Milan

Sponsors (4)

Lead Sponsor	Collaborator
Paolo Corradini	Anna Dodero, Annalisa Chiappella, Cristiana Carniti

Country where clinical trial is conducted

Italy, 

References & Publications (25)

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Dodero A, Bramanti S, Di Trani M, Pennisi M, Ljevar S, Chiappella A, Massimo M, Guidetti A, Corrado F, Nierychlewska PM, Di Rocco A, Lorenzini D, Daoud R, De Philippis C, Santoro A, Carlo-Stella C, Corradini P. Outcome after chimeric antigen receptor (CAR — View Citation

Guidetti A, Dodero A, Lorenzoni A, Pizzamiglio S, Argiroffi G, Chiappella A, Bagnoli F, Marasco V, Carniti C, Monfrini C, Seregni E, Pennisi M, Verderio P, Alessi A, Corradini P. Combination of Deauville score and quantitative positron emission tomography — View Citation

Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Acharya UH, Cassaday RD, Chapuis AG, Dhawale TM, Hendrie PC, Kiem HP, Lynch RC, Ramos J, Shadman M, Till BG, Riddell SR, — View Citation

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Monfrini C, Stella F, Aragona V, Magni M, Ljevar S, Vella C, Fardella E, Chiappella A, Nanetti F, Pennisi M, Dodero A, Guidetti A, Corradini P, Carniti C. Phenotypic Composition of Commercial Anti-CD19 CAR T Cells Affects In Vivo Expansion and Disease Res — View Citation

Neelapu SS, Jacobson CA, Ghobadi A, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy AH, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Bot AA, Shen — View Citation

Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, West — View Citation

Oliveira G, Ruggiero E, Stanghellini MT, Cieri N, D'Agostino M, Fronza R, Lulay C, Dionisio F, Mastaglio S, Greco R, Peccatori J, Aiuti A, Ambrosi A, Biasco L, Bondanza A, Lambiase A, Traversari C, Vago L, von Kalle C, Schmidt M, Bordignon C, Ciceri F, Bo — View Citation

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Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Bishop MR, Damon LE, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu JM, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradin — View Citation

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Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Milpied N, Fung H, Topp MS, Houot R, Beitinjaneh A, Peng W, Zheng L, Rossi JM, Jain RK, Rao AV, Reagan PM — View Citation

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Characterization of biomarkers of early response (circulating tumor cell free DNA versus PET and CT scans)	To study the circulating cell free DNA modulation during time, besides descriptive statistical analyses, we will use non parametric factorial models for longitudinal data [Brunner E, Domhof S, Langer F. Nonparametric analysis of longitudinal data in factorial experiments. John Wiley & Sons 2002, New York]. Such models were chosen because they allow take into account measurement incompleteness and positive asymmetry of biomarker distribution, and because they are robust to outliers. The models also allow to test the difference in the longitudinal profiles according to specific covariates.	10 years, minimum f-up 1 year
Other	Characterization of toxicity biomarkers	Biomarkers will be analysed in relation to toxicities occurrence on order to identify predictors of toxicity onset and severity	10 years, minimum f-up 1 year
Other	Analysis of the immune reconstitution	Evaluate disease response and immune recovery biomarkers at different time-points up after CAR-T (when clinically indicated or using blood sampling leftover)	10 years, minimum f-up 1 year
Other	Analysis of the CAR-T expression	Evaluate the persistence of CAR-T after administration	10 years, minimum f-up 1 year
Other	Influence of PET quantitative parameters: tMTV changes between baseline and +30 and +90 after CAR T-cell infusion (?SUV max) related to outcome	In our study, the PET scans will be collected and anonymized. A central review with analyses of quantitative parameters will be performed. Evaluation of baseline tMTV calculated by MTV4 method which automatically segments area with SUV =4.0.	10 years, minimum f-up 1 year
Other	Influence of PET quantitative parameters: Distance max	In our study, the PET scans will be collected and anonymized. A central review with analyses of quantitative parameters will be performed. Dmax between baseline and +30 and +90 after CAR-T cells infusion	10 years, minimum f-up 1 year
Other	Influence of PET quantitative parameters: Distance max bulky	In our study, the PET scans will be collected and anonymized. A central review with analyses of quantitative parameters will be performed. Dmax bulk is the maximum distance to the bulk and we wil analyse its change between baseline and day +30 and +90.	10 years, minimum f-up 1 year
Primary	Feasibility of the CAR-T cells treatment in lymphomas in the italian real life practice	Evaluate the feasibility of CAR T-cell treatment in the real-life setting, with particular regard to eligible patients versus those subjected to leukapheresis versus those finally treated. The percentage of patients infused will be estimated as the number of patients infused divided by the total number of those declared eligible; the corresponding exact confidence intervals at 95% will also be estimated.	10 years enrollment, minimum 1 year follow-up
Primary	Efficacy of the CAR-T cells treatment in lymphomas in the italian real life practice	Evaluate the survival outcome of PMBCL, DLBCL, MCL and FL patients treated with CAR T-cells versus those potentially eligible, but excluded from cellular therapy for other causes (either related to the patient or to the manufacturing)	10 years enrollment, minimum 1 year follow-up
Secondary	Evaluation of Outcome: Overall Response rate (ORR), according to Lugano criteria.	Overall response rate (ORR): the percentage of responding patients will be estimated as the number of patients with complete response (CR) + partial response (PR) divided by the total number of patients assessable at each specific timepoint (3-6-12-18 months). Patients not assessable for response for any reason will be considered as non-responding in the calculation of the response rate. The exact 95% confidence intervals of the response percentage will also be estimated.	10 years, minimum f-up 1 year
Secondary	Evaluation of Outcome: Overall survival (OS), according to Lugano criteria.	Overall survival (OS): time will be measured as the interval between the date of CAR-T infusion and the date of death for all causes, with censoring at the date of the latest follow-up in alive patients. OS curves will be estimated with the Kaplan Meier method.	10 years, minimum f-up 1 year
Secondary	Evaluation of Outcome: Progression free survival (PFS)	Progression-free survival (PFS): time will be measured as the interval between the CAR-T infusion and the date of progression disease (PD), or death, whichever occurs first.	10 years, minimum f-up 1 year
Secondary	Evaluation of Outcome: duration of response (DoR)	Duration of Response (DoR): for patients who will respond to treatment, the duration of response will be measured as the interval between the response achievement and the date of progression or death, whichever occurs first, with censoring at the date of the latest follow-up in alive patients without progression. DoR curves will be estimated with the Kaplan Meier method.	10 years, minimum f-up 1 year
Secondary	Evaluation of Outcome: Overall Response rate (ORR)	Overall response rate (ORR): the percentage of responding patients will be estimated as the number of patients with complete response (CR) + partial response (PR) divided by the total number of patients assessable at each specific timepoint (3-6-12-18 months). Patients not assessable for response for any reason will be considered as non-responding in the calculation of the response rate. The exact 95% confidence intervals of the response percentage will also be estimated.	10 years, minimum f-up 1 year
Secondary	Evaluation of Outcome: Overall survival (OS)	Overall survival (OS): time will be measured as the interval between the date of CAR-T infusion and the date of death for all causes, with censoring at the date of the latest follow-up in alive patients. OS curves will be estimated with the Kaplan Meier method.	10 years, minimum f-up 1 year
Secondary	Evaluation of Outcome: non-relapse mortality (NRM)	Non-relapse mortality (NRM) after CAR-T cell therapy: time will be measured as the interval between the date of treatment start and the date of non-relapse death, with censoring at the date of the latest follow-up in alive patients without relapse. NRM cumulative incidence curves will be estimated regarding disease recurrence as competing event, and between groups comparisons will be performed using the Gray test.	10 years, minimum f-up 1 year
Secondary	Evaluation of safety (CRS, neurotoxicity, infections, cytopenias, B cell aplasia, second malignancies) with particular attention to the safety in the new indications	CRS and ICANS will be measured according to ASCTC. Other toxicities will be measured according to CTCAE.	10 years, minimum f-up 1 year
Secondary	Evaluation of bridging therapy: safety	Bridging therapy will be analysed in terms of safety as per adverse event occurrence (according to CTCAE).	10 years, minimum f-up 1 year
Secondary	Evaluation of bridging therapy: efficay	Bridging therapy will be analysed in terms of efficacy in terms of response achievement compared to response assessment prior to bridging therapy.	10 years, minimum f-up 1 year
Secondary	Evaluation of salvage therapy after CAR-T failure	In case of relapse after CAR-T, data regarding salvage therapy will be collected in terms of reponse (PFS)	10 years, minimum f-up 1 year
Secondary	Evaluation of salvage therapy after CAR-T failure	In case of relapse after CAR-T, data regarding salvage therapy will be collected in terms of survival (OS).	10 years, minimum f-up 1 year
Secondary	Comparison of the different CAR T-cell products (time from patient screening to infusion, disease response and safety)	Time form screening to infusion will be compared between CAR-T products, disease response will be evaluated in terms of CR, PR and SD.	10 years, minimum f-up 1 year
Secondary	Comparison of the different histotypes (PMBCL, DLBCL, MCL FL) according to CAR-T cell products	Study popoulation will be analysed in terms of reponse and type CAR-T product.	10 years, minimum f-up 1 year