E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory B-ALL (any relapse after HSCT, 2nd relapse or later, refractory ALL), aged 1-25 years old, previously treated by Tisagenlecleucel (Kymriah ®), Cohort 1 presenting early loss of B cell aplasia (< 6 months after infusion) And being in MRD negative complete remission or Cohort 2: presenting loss of B cell aplasia and having detectable marrow and/or blood CD19+ ALL cells. |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed or refractory B-ALL, aged 1-25 years old, previously treated by Kymriah ® |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of these combined treatments on •Incidence of B cell aplasia at 6 months •Increase of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel. •Disease best response •Complete remission (at M1 M3 M6 M12 after reinfusion) •Minimal residual disease (at M1 M3 M6 M12 after reinfusion) •1-year and 2-year OS •1-year and 2-year EFS •Incidence of Grade 3 or 4 immune related adverse events (gut, liver, lung, endocrine) i.e. linked to Nivolumab treatment •Incidence of Grade 3 or 4 of other related adverse events related to Nivolumab use such as pneumonitis, stomatitis, rash, or hematologic toxicity. •Incidence of Grade 3 or 4 reinfusion of Tisagenlecleucel -related events, in particular -cytokine release syndrome -Immune Effector Cells Associated Neurologic Events (ICANs) -prolonged cytopenias •Incidence of acute and chronic GVHD
To explore the PD1 PDL1 axis and its correlation with success or failure
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) > 50 at screening. •No organ dysfunction •Who have signed an informed consent •Affiliation to social security or any health insurance (as a beneficiary or assignee)
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E.4 | Principal exclusion criteria |
• Patient has received intervening therapy for leukemia after first Tisagenlecleucel infusion. • Patient has an active auto-immune 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 30 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., ≤ Grade 1 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: o Adequately treated basal cell or squamous cell carcinoma o In situ carcinoma of the cervix or breast, treated curatively and without evidence ofrecurrence for at least 3 years prior to the study. o 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)
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E.5 End points |
E.5.1 | Primary end point(s) |
1.1 No limiting-toxicities*** between infusion and D28 1.2 Efficacy, which evaluation is delayed at M3 after Tisagenlecleucel reinfusion and defined by MRD negative CR* AND B cell aplasia**
(*) MRD negative CR: undetectable disease at a 10-4 sensitivity threshold (**) B cell aplasia is defined by blood B lymphocytes < 10 /mm3 (or/and < 3% of total lymphocytes) (***) Limiting toxicities are defined by the occurrence of any non- haematological targeted adverse events: Cytokine Release Syndrome / ICANs (grade ≥4) and aGVH grade ≥4
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
M3 after Tisagenlecleucel reinfusion |
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E.5.2 | Secondary end point(s) |
To assess the effect of these combined treatments on • Incidence of B cell aplasia at 6 months • Increase of B cell aplasia duration compared to the previous one observed after the first infusion of tisagenlecleucel. • Disease best response • Complete remission (at M1 M3 M6 M12 after reinfusion) • Minimal residual disease (at M1 M3 M6 M12 after reinfusion) • 1-year and 2-year OS • 1-year and 2-year EFS • Incidence of Grade 3 or 4 immune related adverse events (gut, liver, lung, endocrine) i.e. linked to Nivolumab (Opdivo®) treatment • Incidence of Grade 3 or 4 of other related adverse events related to Nivolumab (Opdivo®) use such as pneumonitis, stomatitis, rash, or hematologic toxicity. • Incidence of Grade 3 or 4 reinfusion of Tisagenlecleucel (Kymriah®) -related events, in particular - cytokine release syndrome - Immune Effector Cells Associated Neurologic Events (ICANs) - prolonged cytopenias • Incidence of acute and chronic GVHD
To explore the PD1 PDL1 axis and its correlation with success or failure |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
determination of optimal delay between Tisagenlecleucel injection and opdivo injection |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Time to Event Continual Reassessment Method (TITE-CRM) design |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 48 |
E.8.9.1 | In the Member State concerned days | |