Clinical Trials Register

Summary
EudraCT Number:	2021-003035-28
Sponsor's Protocol Code Number:	APHP200132
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-10-27
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2021-003035-28

A.3

Full title of the trial

" Combination of an Anti-PD1 antibody with Tisagenlecleucel Reinfusion in children, adolescents and young adults with Acute Lymphoblastic Leukemia after loss of persistence "
CAPTiRALL

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

CAPTIRALL

A.4.1

Sponsor's protocol code number

APHP200132

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Assistance Publique - Hôpitaux de Paris
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DGOS
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assistance Publique - Hôpitaux de Paris
B.5.2	Functional name of contact point	project manager
B.5.3	Address:
B.5.3.1	Street Address	1 Av Claude Vellefaux
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	330144841744
B.5.5	Fax number	330144841701
B.5.6	E-mail	didier.bouton@aphp.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Kymriah
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma SAS
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tisagenleuclecel
D.3.4	Pharmaceutical form	Dispersion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tisagenlecleucel
D.3.9.2	Current sponsor code	Tisagenlecleucel
D.3.9.3	Other descriptive name	KYMRIAH
D.3.9.4	EV Substance Code	SUB177825
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2000000 to 5000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	OPDIVO
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL-MYERS SQUIBB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Nivolumab
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Nivolumab
D.3.9.2	Current sponsor code	Nivolumab
D.3.9.3	Other descriptive name	OPDIVO
D.3.9.4	EV Substance Code	SUB122750
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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.

E.1.1.1

Medical condition in easily understood language

Relapsed or refractory B-ALL, aged 1-25 years old, previously treated by Kymriah ®

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

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

E.2.3

Trial contains a sub-study

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)

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)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

M3 after Tisagenlecleucel reinfusion

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

E.5.2.1

Timepoint(s) of evaluation of this end point

LSLV

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

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

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Time to Event Continual Reassessment Method (TITE-CRM) design

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No specific post trial treatment except standard of care

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-02-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-17

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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