Combination of an Anti-PD1 Antibody With Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia After Loss of Persistence (CAPTiRALL)

Tisagenlecleucel (CTL019) is an anti-CD19 autologous Chimeric Antigen Receptor (CAR) T-cell therapy, which has shown dramatic early results in advanced ALLs. Early loss of B-cell aplasia (recovery of B-cells in marrow/ peripheral blood within 6 months after infusion), a marker of the loss or non-functionality of the CAR T-cells, is associated to a very high risk of relapse. A reinfusion of CTL019, even after Fludarabine-Cyclophosphamide reconditioning, frequently fails to induce further expansion as observed in UPENN studies and in the Robert Debré Hospital experience.

Non-persistence of CAR T-cells may be due to immune- mediated rejection or environment-mediated suppression of their growth. Evidence for increased PD-1 expression in CAR T-cells between infusion and peak expansion has been demonstrated in clinical samples.

Preclinical data and few clinical data support a role of PD- 1-PD-L1 blockade in improving the effectiveness of CAR T-cell therapy.

The objectives of this phase I/II study is 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

Study Overview

• Status: Recruiting
• Conditions: Acute Lymphoblastic Leukemia, in Relapse; B Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) ); Drug: Nivolumab starting at day -1

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Andre Baruchel, Pr; Phone Number: +331 40 03 53 88; Email: andre.baruchel@aphp.fr
• Study Contact Backup: Name: Jérôme Lambert, Pr; Phone Number: +33142499742; Email: jerome.lambert@u-paris.fr

Study Locations

• France
  • Bordeaux, France
    • Recruiting
    • CHRU Bordeaux
    • Contact: Marie Angoso
  • Lille, France
    • Recruiting
    • CHRU Lille
    • Contact: Brigitte Nelken
  • Lyon, France
    • Recruiting
    • HCL
    • Contact: Solene Remy
  • Lyon, France
    • Recruiting
    • HCL - Lyon Sud
    • Contact: Marie Balsat
  • Marseille, France
    • Recruiting
    • Hôpital pour enfants - La Timone
    • Contact: Michel Gerard
  • Montpellier, France
    • Recruiting
    • Chu Montpellier - Hopital Arnaud de Villeneuve
    • Contact: Anne Sirvent
  • Nancy, France
    • Recruiting
    • Chu Nancy
    • Contact: Cécile Pochon
  • Nantes, France
    • Recruiting
    • CHU Nantes - Hopital Mère-enfants
    • Contact: Fanny Rialland
  • Paris, France
    • Recruiting
    • Robert Debre Hospital
    • Contact: André Baruchel
  • Paris, France
    • Recruiting
    • Saint Louis Hospital
    • Contact: Nicolas Boissel
  • Rouen, France
    • Recruiting
    • CHU Rouen
    • Contact: Nimrod Buchbinder
  • Strasbourg, France
    • Recruiting
    • CHRU Strasbourg
    • Contact: Catherine Paillard

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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).
• Patient must have a second tisagenlecleucel (Kymriah ®) product available
• 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
• 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
• Life expectancy > 12 weeks.
• Karnofsky (age > 16) Lansky (age < 16) > 70 at screening.
• No organ dysfunction
• Who have signed an informed consent
• Affiliation to social security or any health insurance (as a beneficiary or assignee)

Exclusion Criteria:

• Patient has received intervening therapy for leukemia after first tisagenlecleucel infusion (chemotherapy, anti leukemic immunotherapy, ITK, allogeneic HSCT).
• Patient has an active autoimmune disease requiring systemic treatment within the past 2 years.
• Patient has known history of, or any evidence of active, non-infectious pneumonitis.
• Patient has a history of non-infectious pneumonitis that required steroid or has current pneumonitis.
• Had receive prior therapy with an anti-PD1, Anti- PDL1 or anti-PDL2 agent.
• Patient has hypersensivity to pembrolizumab/ nivolumab or one of its excipients
• Patient has received a live vaccine injection within 45 days of planned start of study therapy.
• 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.
• Patients with Burkitt's lymphoma/leukemia
• Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• Prior treatment with any gene therapy product except first tisagenlecleucel (Kymriah ®) injection.
• 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®)
• Prior anti-cancer monoclonal antibody within 4 weeks before starting the study.
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade1 or at baseline) from adverse events due to a previously administered agent.
• Active or latent hepatitis B or active hepatitis C (test within 8 weeks of Screening), or any uncontrolled infection at Screening.
• Human immunodeficiency virus (HIV) positive test within 8 weeks of Screening.
• Presence of grade 2 to 4 acute or extensive chronic GVHD.
• Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible.
• Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.

• Previous or concurrent malignancy with the following exceptions:

  • Adequately treated basal cell or squamous cell carcinoma
  • in situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study.
  • A primary malignancy completely resected and in CR for ≥ 5 years
• Pregnant or lactating women (female study 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with MRD negative disease status: Time to Event Continual Reassessment Method (TITE-CRM)	Drug: Decreasing starting times for beginning nivolumab (Time to Event Continual Reassessment Method (TITE-CRM) ); Patients included first receive a lympho-depleting chemotherapy by Fludarabine / Cyclophosphamide. tisagenlecleucel infusion should then be administered 2 to 14 days after completion of chemotherapy. Nivolumab (Opdivo®) will be given intravenously at 3mg/kg every 2 weeks. It will include patients with MRD negative disease status.; Four decreasing starting times for beginning nivolumab (day 14, day 11, day 5 and day -1) will be available for testing; Patients will be enrolled sequentially by cohorts of 3 with escalation between cohorts based only on the limiting toxicities between infusion and D28 Nivolumab will be given until 12 months after tisagenlecleucel infusion in case of response.
Experimental: For relapsed patients	Drug: Nivolumab starting at day -1; It will include relapsed patients. Patients included first receive a lympho-depleting chemotherapy by Fludarabine / Cyclophosphamide. tisagenlecleucel infusion should then be administered 2 to 14 days after completion of chemotherapy. Nivolumab (Opdivo®) will be given intravenously at 3mg/kg every 2 weeks. -nivolumab starting at day -1. Nivolumab will be given until 12 months after tisagenlecleucel infusion in case of response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with limiting-toxicities	Limiting toxicities are defined by the occurrence of either - Related to CAR-T cells infusion: CRS or aGVH: limiting toxicity will be defined as toxicity ≥ 4 ICANs: limiting toxicity will be defined as toxicity ≥ 3 (excepted grade 3 seizure, ie focal, generalized seizure that resolves rapidly) - Related to nivolumab: immune related myocarditis, pneumonitis, encephalitis: limiting toxicity will be defined as toxicity ≥ 4	at day 28
Efficacy assessed by Minimal residual disease (MRD) negative Complete remission (CR) and B cell aplasia.	MRD negative CR is defined by undetectable disease at a 10-4 sensitivity threshold B cell aplasia is defined by blood B lymphocytes < 10 /mm3 and/or < 3% of total lymphocytes	at 3 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of B cell aplasia	at 6 months
Increase of B cell aplasia duration compared to the previous one observed	up to 24 months
Proportion of patients with Disease best response	up to three months
Proportion of patients with Complete remission	at 1 month
Proportion of patients with Complete remission	at 3 months
Proportion of patients with Complete remission	at 6 months
Proportion of patients with Complete remission	at 12 months
Proportion of patients with Minimal residual disease	at 1 month
Proportion of patients with Minimal residual disease	at 3 months
Proportion of patients with Minimal residual disease	at 6 months
Proportion of patients with Minimal residual disease	at 12 months
Overall survival	at one year
Overall survival	at 2 years
Event Free Survival (EFS)	at 1 year
Event Free Survival (EFS)	at 2 years
Incidence of Grade 3 adverse events	up to 2 years
Incidence of Grade 3, 4 or 5 nivolumab-related adverse events	up to 2 years
Incidence of GVHD	up to one year

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2023
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: March 9, 2022
• First Submitted That Met QC Criteria: April 4, 2022
• First Posted (Actual): April 5, 2022

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: APHP200132

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No