CAPTIRALL _ Combination of an Anti-PD1 antibody with CART cells Reinfusion in children, adolescents and young adults with Acute Lymphoblastic Leukemia after loss of persistence

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

15 Mar 2023 → ongoing

Decision date (initial)

2024-08-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

French Health ministry

External identifiers

EU CT number

2024-514345-11-00

EudraCT number

2021-003035-28

ClinicalTrials.gov

NCT05310591

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To determine the safety, efficacy and feasibility of Nivolumab (Opdivo®)- an anti-PD1 treatment- combined to tisagenlecleucel in a cohort of relapsed or refractory B-ALL patients, aged 1-25 years old, previously treated by tisagenlecleucel (Kymriah®), with a demonstrated early loss of B-cell aplasia (within 6 months), a surrogate marker of the loss of CAR T-cells or their non- functionality.

More specifically, the main objectives are:
• In cohort 1 that includes patients with a MRD negative disease status combined to an early loss (within 6 months) of B-cell aplasia
To determine the optimal starting time of Nivolumab (Opdivo®) in terms of safety and efficacy among 4 candidate time points (day 14, day 11, day 5, and day - 1).
• In cohort 2 that includes relapsed patients with an early loss (within 6 months) of B-cell aplasia
To estimate the feasibility in terms of safety and efficacy of a very early start of nivolumab (day-1), prior to the reinfusion of tisagenlecleucel
These objectives will be evaluated on the two following co-primary endpoints: 1. Limiting-toxicities between infusion and D28; 2. Efficacy, which evaluation is delayed at M3 after tisagenlecleucel reinfusion and defined by MRD negative CR* AND B cell aplasia

Secondary objectives 12

1. • Incidence of B cell aplasia at 6 months
2. • Increase of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel (up to 24 months)
3. • Disease best response
4. • Complete remission (at M1 M3 M6 M12 after reinfusion)
5. • Minimal residual disease (at M1 M3 M6 M12 after reinfusion)
6. • 1-year OS
7. • 1-year EFS
8. • Incidence of Grade 3 adverse up to 2 years events such as - nivolumab-related adverse events: myocarditis, pneumonitis, encephalitis - tisagenlecleucel reinfusion-related events, in particular CRS or ICANs or aGVH, prolonged cytopenias
9. • Incidence of Grade 3, 4 or 5 nivolumab-related adverse events up to 2 years: gut, liver, endocrine, stomatitis, rash or hematologic toxicity
10. • Incidence of GVHD up to one year
11. 2-year OS and EFS
12. To explore the PD1 PDL1 axis and its correlation with success or failure

Conditions and MedDRA coding

children, adolescents and young adults with Acute Lymphoblastic Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. • Patients aged from 1 to 25 years (pediatric and young adults) with a history of CD19+ relapsed or refractory B-ALL (any relapse after HSCT, 2nd relapse or later, refractory ALL)
2. • patient must have a second tisagenlecleucel (Kymriah®) product available
3. • Cohort 1: previously treated by tisagenlecleucel (Kymriah®), and who present an early loss of B-cell aplasia defined by blood B lymphocytes < 10 /mm3 and/ or < 3% of total lymphocytes (< 6 months after infusion) while still being in CR with undetectable MRD
4. • Cohort 2: previously treated by tisagenlecleucel (Kymriah®), who present a loss of B-cell aplasia defined by blood B lymphocytes < 10 /mm3 and/ or < 3% of total lymphocytes and a CD19+ ALL detectable disease in the marrow and/or Blood and/or CSF
5. • Life expectancy > 12 weeks.
6. • Karnofsky (age > 16) Lansky (age < 16) > 70 at screening.
7. • No organ dysfunction
8. • Who have signed an informed consent Affiliation to social security or any health insurance (as a beneficiary or assignee)

Exclusion criteria 22

1. • Patient has received intervening systemic therapy* for leukemia after first tisagenlecleucel infusion. (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT) *systemic therapies exclude intrathecal therapy
2. • Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
3. • Prior treatment with any gene therapy product except first tisagenlecleucel (Kymriah®) injection.
4. • Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab and/or tisagenlecleucel (Kymriah®).
5. • Prior anti-cancer monoclonal antibody within 4 weeks before starting the trial.
6. • Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to reinfusion of CAR T cells or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
7. • Active or latent hepatitis B or active hepatitis C (test within 8 weeks of Screening), or any uncontrolled infection at Screening.
8. • Human immunodeficiency virus (HIV) positive test within 8 weeks of Screening.
9. • Presence of grade 2 to 4 acute or extensive chronic GVHD.
10. • Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines at the time of reinfusion of CAR T cells. Note: Patients with history of CNS disease that has been effectively treated will be eligible.
11. • Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.
12. • Patient has an active autoimmune disease requiring systemic treatment within the past 2 years.
13. • Previous or concurrent malignancy with the following exceptions: o Adequately treated basal cell or squamous cell carcinoma o In situ carcinoma of the cervix or breast, treated curatively and without evidence ofreccurrence of at least 3 years prior to the trial o A primary malingnacy completelyresected and in CR for ≥ 5 years
14. • Pregnant or lactating women (female trial participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion) Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/or tisagenlecleucel and/or nivolumab or one of their excipients.
15. • Patient has known history of, or any evidence of active, non-infectious pneumonitis.
16. • Patient has a history of non-infectious pneumonitis that required steroid or has current pneumonitis.
17. • Had receive prior therapy with an anti-PD1, Anti- PDL1 or anti-PDL2 agent
18. • Patient has hypersensivity to pembrolizumab/ nivolumab or one of its excipients
19. • Patient has received a live vaccine injection within 45 days of planned start of trial therapy.
20. • Patients with concomitant genetic syndromes associated with bone marrow failure states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded.
21. • Patients with Burkitt’s lymphoma/leukemia
22. Patient with hypersensivity to Fludarabine and/or cyclophosphamide and/or tisagenlecleucel and/or nivolumab or one of their excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety: absence of Limiting-toxicities between infusion and D28
2. Efficacy: evaluation at M3 after tisagenlecleucel reinfusion and defined by MRD negative CR AND B cell aplasia

Secondary endpoints 12

1. • Incidence of B cell aplasia at 6 months
2. • Increase of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel (up to 24 months)
3. • Disease best response
4. • Complete remission (at M1 M3 M6 M12 after reinfusion)
5. • Minimal residual disease (at M1 M3 M6 M12 after reinfusion)
6. • 1-year OS
7. • 1-year EFS
8. • Incidence of Grade 3 adverse up to 2 years events such as - nivolumab-related adverse events: myocarditis, pneumonitis, encephalitis - tisagenlecleucel reinfusion-related events, in particular CRS or ICANs or aGVH, prolonged cytopenias
9. • Incidence of Grade 3, 4 or 5 nivolumab-related adverse events up to 2 years: gut, liver, endocrine, stomatitis, rash or hematologic toxicity
10. • Incidence of GVHD up to one year
11. Long term efficacy: 2-year OS and EFS
12. To explore the PD1 PDL1 axis and its correlation with success or failure

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating investigator

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating investigator

Locations

1 EU/EEA country · 13 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 16 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