Clinical Trials Register

Summary
EudraCT Number:	2016-004808-60
Sponsor's Protocol Code Number:	HD-CAR-1/V04
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-07-25
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

Germany - PEI

A.2

EudraCT number

2016-004808-60

A.3

Full title of the trial

Treatment of patients with relapsed or refractory CD19+ lymphoid disease with T lymphocytes transduced by RV-SFG.CD19.CD28.4-1BBzeta retroviral vector - A unicenter Phase I /II clinical trial

Behandlung von Patienten mit RV-SFG.CD19.CD28.4 retroviralem Vektor transduzierten T-Lymphozyten bei rezidivierenden oder refraktären CD19+ Leukämien und Lymphomen. Eine monozentrische Studie (Phase I/II)

A.3.1

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

Treatment of patients with CD19+ hematologic disease with T lymphocytes transduced retrovirally with a third generation CAR

Behandlung von Patienten mit CD19+ Leukämien und Lymphomen mit retroviral transduzierten T-Lymphozyten (CAR T-Zellen der dritten Generation).

A.3.2

Name or abbreviated title of the trial where available

3G-CART therapy for CD19+ lymphoid disease

A.4.1

Sponsor's protocol code number

HD-CAR-1/V04

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03676504

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	University Hospital Heidelberg
B.1.3.4	Country	Germany
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	University Hospital Heidelberg
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Heidelberg
B.5.2	Functional name of contact point	Prof. Dr. Michael Schmitt
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 410
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49622156-6614
B.5.5	Fax number	+49622156-5740
B.5.6	E-mail	Michael.Schmitt@med.uni-heidelberg.de

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	No
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	CD19.CAR T cells
D.3.4	Pharmaceutical form	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	3G. CD19 CAR T Cells
D.3.9.2	Current sponsor code	HD-CAR-1
D.3.9.3	Other descriptive name	3G. CD19 CAR T Cells
D.3.9.4	EV Substance Code	SUB182373
D.3.10	Strength
D.3.10.1	Concentration unit	m2 square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000000 to 200000000
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.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 and/or refractory CD19+ leukemia and lymphoma

Rezidivierte und/oder refraktäre CD19+ Leukämien und Lymphome

E.1.1.1

Medical condition in easily understood language

Malignant hematopoietic diseases resistant to Treatment or relapsed after Treatment.

Bösartige Erkrankungen des blutbildenden Systems, welche schwer oder nicht auf herkömmliche Therapien ansprechen.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10063625
E.1.2	Term	Acute lymphoblastic leukemia recurrent
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10029595
E.1.2	Term	Non-Hodgkin's lymphoma NOS refractory
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary
Safety:
- Assessment of toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
- Assessment of frequency and grade of cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS)
- Assessment of dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD)

Feasibility:
- Yield of sufficient nucleated cells (NC) by leukapheresis
- Successful transduction (≥ 15%) of CD3+ T cells (TCs)
- Yield of the respective dose of transduced TCs

E.2.2

Secondary objectives of the trial

Secondary
- Evaluation of survival and function of chimeric antigen receptor (CAR) TCs directed against CD19 (CD19.CAR TC) in vivo
- Characterization of in vivo cellular pharmakokinetics
- Correlation of clinical response and number of circulating gene modified cells
- Reduction of disease burden with CD19.CAR TC transfusions
- Anti-tumor efficacy of CD19.CAR TCs in patients with CD19+ lymphoid disease (overall response rate (ORR), complete response (CR), partial response (PR)) at day 90 (EOS) after CD19.CAR TC transfusion)
- Time to response (at least PR) after the CD19.CAR TC transfusion
- Duration of overall response (DOR) after the CD19.CAR TC transfusion
- Progression-free survival (PFS) after the CD19.CAR TC transfusion
- Overall survival (OS) after the CD19.CAR TC transfusion
- Correlation of B-cell depletion in vivo and response to CD19.CAR TC treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Stratum 1-2 (Adults):
Inclusion Criteria:
- Confirmed CD19+ ALL, CLL, DLBCL, FL or MCL in patients ≥ 18 years
- ALL: Confirmed CD19+ ALL (Philadelphia (Ph) + and Ph-) by cytology and flow cytometry (FACS) AND
- Relapsed or refractory disease (incl. “molecular relapse” with min. residual disease (MRD) levels > 10-3 at two occasions > 2 weeks apart) with confirmed CD19-expression on malign. cells
- Any relapse after allogeneic stem cell transplantation (alloSCT) (≥ 6 months from alloSCT at time of CAR TC transfusion) OR
- Any relapse failing to achieve an MRD level of < 10-3 after ≥ 2 lines of treatment OR
- Primary refractory as defined by not achieving a CR after ≥ 2 lines of treatment
- CLL/NHL: Confirmed CD19+ CLL/NHL (incl. CLL, DLBCL, FL or MCL):
- CLL in need of treatment with:
(1) Early relapse (within 2 years) after end of chemoimmunotherapy or chemoimmunotherapy refractoriness plus failure or intolerance of both BTK and BCL2 inhibitors OR
(2) Relapse after alloSCT, ineligible for or refractory to standard interventions (donor lymphocyte infusions (DLI), CD20 antibodies, chemoimmunotherapy)
- DLBCL with:
(1) Refractoriness to a 2nd or later line of chemoimmunotherapy OR
(2) Relapse after autoSCT plus ineligibility for alloSCT (incl. refractoriness to one line of salvage chemoimmunotherapy) OR
(3) Relapse after alloSCT
- FL in need of treatment with:
(1) Relapse <2 years after chemoimmunotherapy AND ineligibility for or failure of autoSCT AND ineligibility for or failure of idelalisib OR
(2) Relapse after alloSCT, ineligible for or refractory to standard interventions (donor lymphocyte infusions, CD20 antibodies, chemoimmunotherapy)
- MCL with:
(1) Relapse after standard first-line therapy AND ineligibility for or failure to BTKi salvage therapy OR
(2) Relapse after alloSCT AND ineligibility for or failure to BTKi salvage therapy
- Measurable disease/MRD at time of enrollment
- Life expectancy ≥ 12 weeks
- ECOG performance status ≤ 2 at the time of screening
- Adequate organ function:
- Renal function defined as: serum creatinine of ≤ 2 x ULN or eGFR ≥ 30 mL/min/1.73 m2
- Liver function defined as:
- ALT ≤ 5 times the ULN for the respective age
- Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert–Meulengracht syndrome (may be included if total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) or extrahepatic disease (e.g. chronic hemolytic anemia)
- min. level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation > 90% on room air
- Hemodynamic stability and LVEF ≥ 40% as confirmed by echocardiogram
- Abs. neutrophil count (ANC) ≥ 500/mm3
- Abs. lymphocyte count (ALC) ≥ 100/mm3
- Women of child-bearing potential (defined as all women physiolog. capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for one year following CD19.CAR TC therapy
- Written informed consent must be obtained prior to any screening procedures

Stratum 3 (Children and Adolescents with ALL):
Inclusion Criteria:
- Age of > 3 years until < 18 years at the time of screening
- CD19+ ALL (Ph+ and Ph-) confirmed by cytology and flow cytometry (FACS) AND
- Relapsed or refractory disease (incl. “molecular relapse” with PCR-MRD > 10-3 at two occasions > 2 weeks apart) with confirmed CD19-expression on malign. cells
- Any relapse after alloSCT (≥ 6 months from alloSCT at time of CAR TC transf.) OR
- Any relapse failing to achieve an MRD level of < 10-3 after ≥ 2 lines of treatment OR
- Primary refractory as defined by not achieving a CR after ≥ 2 lines of treatment
- Measurable disease/MRD at time of enrollment
- Life expectancy ≥ 12 weeks
- ECOG performance status ≤ 2 (age ≥ 16 years) or Lansky performance status ≥ 50 (age < 16 years) at time of screening
- Adequate organ function:
- Renal function defined as serum creatinine-clearance ≥ 30 mL/min/1.73 m2
- Liver function defined as:
- ALT ≤ 5 times the ULN for the respective age
- Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert–Meulengracht syndrome or extrahepatic disease (e.g. chronic hemolytic anemia)
- min. level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation > 90% on room air
- Hemodynamic stability and LVEF ≥ 40% or shortening fraction > 29% as confirmed by echocardiogram
- Abs. neutrophil count (ANC) ≥ 500/mm3
- Abs. lymphocyte count (ALC) ≥ 100/mm3
- Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and postpubertal male participants must agree to use highly effective methods of contraception for one year following CD19.CAR TC therapy
- Ability to understand the nature of the trial and the trial related procedures
- Written informed consent of the study patient and the legal representative must be obtained prior to any screening procedures

E.4

Principal exclusion criteria

Exclusion Criteria
Stratum 1-2 (Adults):
- The following medications are excluded:
- Immunosuppressive medication with the exception of ≤ 30 mg prednisolone/d or equivalent at the time of CAR TC transfusion
- Bridging/maintenance therapy including chemo- and immunotherapy must be stopped ≥ 2 weeks prior to leukapheresis, but can be continued between leukapheresis and lymphodepletion
- Intrathecal chemotherapy is possible at any time, but not during lymphodepletion until 14 days after CD19.CAR TC transfusion
- Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CD19.CAR TC transfusion
- Florid/acute or chronic Graft-versus-Host disease (GvHD)
- Uncontrolled active hepatitis B or C
- HIV-positivity
- Uncontrolled acute life-threatening bacterial, viral or fungal infection
- Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure NYHA III-IV, uncontrolled diabetes mellitus, uncontrolled hyperlipidemia)
- Unstable angina and/or myocardial infarction within 3 months prior to screening
- Any previous or concurrent malignancy.
- The following exceptions do not constitute exclusion criteria:
- Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
- In situ carcinoma of the cervix or breast, treated curatively without evidence of recurrence ≥ 3 years prior to the study
- CLL or FL transformed into an aggressive B cell lymphoma
- A primary malignancy which is in complete remission for ≥ 5 years
- Pregnant or nursing (lactating) women
- Intolerance to the excipients of the cell product
- Active CNS involvement in ALL patient at the time of screening is not an exclusion criterion, but patients with CNS 3 status at clinical screening (d-14) are not eligible for CD19.CAR TC transfusion
- Participation in another clinical trial at the time of screening

Exclusion Criteria
Stratum 3 (Children and Adolescents with ALL):
- The following medications are excluded:
- immunosuppressive medication with the exception of < 0.5 mg/d*kg BW prednisolone-equivalent at the time of CD19.CAR TC transfusion
- Bridging/Maintenance therapy including chemo- and immunotherapy must be stopped ≥ 2 weeks prior to leukapheresis, but can be continued between leukapheresis and lymphodepletion.
- Intrathecal chemotherapy is possible at any time, but not during lymphodepletion until 14 days after CD19.CAR TC transfusion
- Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CD19.CAR TC transfusion
- Florid/acute or chronic Graft-versus-Host disease (GvHD)
- Uncontrolled active hepatitis B or C
- HIV-positivity
- Uncontrolled acute life-threatening bacterial, viral or fungal infection
- Severe concomitant disease (e.g. any life-limiting genetic disorder). Patients with Down Syndrome will not be excluded.
- Any previous or concurrent malignancy.
- The following exceptions do not constitute exclusion criteria:
- Lymphoblastic lymphoma transformed into a CD19+ acute lymphoblastic leukemia
- A primary malignancy which is in complete remission for ≥ 5 years
- Pregnant or nursing (lactating) women
- Intolerance to the excipients of the cell product
- Active CNS involvement at the time of screening is not an exclusion criterion, but patients with CNS 3 status at clinical screening (d-14) are not eligible for CD19.CAR TC transfusion
- Participation in another clinical trial at the time of screening

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

- End of Trial: d+28
+/- 3d (after CAR T-Cell Administration)

- End of Study: d+90
+/- 3d (after CAR T-Cell Administration)

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

- End of Trial: d+28
+/- 3d (after CAR T-Cell Administration)

- End of Study: d+90
+/- 3d (after CAR T-Cell Administration)

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

Yes

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

Phase I/II: safety and feasibiltiy

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

End of trial (EOT) is set on day 28+/-3 days after CAR TC application. 2 further visits will follow until end of study (EOS) is achieved on day +90+/-days. EOS is 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)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.3.3.1

Women of childbearing potential not using contraception