Clinical Trials Register

Summary
EudraCT Number:	2017-000440-18
Sponsor's Protocol Code Number:	CD-TCR-001
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-07-12
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

2017-000440-18

A.3

Full title of the trial

A Phase I/II, Open-Label, Non-Randomized, Multicentre, Dose-Escalation Clinical Trial with Control Group to Evaluate the Safety, Feasibility and Preliminary Efficacy of PRAME TCR Modified T Cells, MDG1011, in Subjects with High Risk Myeloid and Lymphoid Neoplasms

A.3.1

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

A clinical dose-finding study to assess the safety and efficacy of gene-modified T cells in patients with high risk blood tumors

A.3.2

Name or abbreviated title of the trial where available

A Phase I/II clinical trial for TCR modified T cells, MDG1011, in HR myeloid and lymphatic neoplasms

A.4.1

Sponsor's protocol code number

CD-TCR-001

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	Medigene AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medigene AG
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	Medigene AG
B.5.2	Functional name of contact point	Jan Laschinger
B.5.3	Address:
B.5.3.1	Street Address	Lochhamer Straße 11
B.5.3.2	Town/ city	Planegg / Martinsried
B.5.3.3	Post code	82152
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49892000330
B.5.5	Fax number	+49892000332920
B.5.6	E-mail	ClinicalOperations@medigene.com

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.3.2	Product code	MDG1011
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	11 Structurally Diverse Substance – Cell therapy
D.3.9.2	Current sponsor code	MDG1011
D.3.9.3	Other descriptive name	PRAME-T-CELL RECEPTOR GENE MODIFIED AUTOLOGOUS T CELLS
D.3.9.4	EV Substance Code	SUB191003
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1x10E5 Tcell/kg to 1x10E7 Tcell/kg
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	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

High Risk Myeloid Neoplasms

E.1.1.1

Medical condition in easily understood language

High risk blood tumors (white blood cell cancer)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10028536
E.1.2	Term	Myelodysplastic syndromes
E.1.2	System Organ Class	100000004851

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	10028557
E.1.2	Term	Myeloid leukemia, acute
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10028533
E.1.2	Term	Myelodysplastic syndrome
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

Phase I part:
• To assess the safety and tolerability of MDG1011
• To establish the maximum tolerated dose (MTD) and/or recommended Phase II dose (RPD2) of MDG1011
• For feasibility, assess the percent of all subjects who receive the planned target dose of MDG1011

Phase II part:
Primary:
• To further assess the safety and tolerability of MDG1011
• To evaluate overall response rate (ORR)

E.2.2

Secondary objectives of the trial

Phase I part:
• To evaluate overall response rate (ORR)
• To evaluate duration of response (DoR)
• To evaluate time to progression (TTP)
• To evaluate progression-free survival (PFS)
• To assess overall survival (OS)
• To evaluate quality of life (QoL)
• To evaluate the correlation of PRAME expression with the antitumor response

Phase II part:
• To evaluate duration of response (DoR)
• To evaluate time to progression (TTP)
• To evaluate progression-free survival (PFS)
• To assess overall survival (OS)
• To evaluate quality of life (QoL)
• For feasibility, assess the percent of all subjects who receive the RP2D of MDG1011
• To evaluate the correlation of PRAME expression with the antitumor response

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key inclusion criteria include:
1. Signed written informed consent prior to any clinical trial related activities
2. Documented diagnosis with the last disease staging within the last 4 weeks prior to screening
3. Human leukocyte antigen (HLA)
a. Phase I and Phase II (treatment group): Subjects positive for HLA-A*02:01 according to genotyping results
b. Phase II (concurrent control group): Subjects negative for HLA-A*02:01 according to genotyping results
4. Age ≥ 18 years
5. Life expectancy of at least 4 months.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
7. Subjects not planned for allogeneic hematopoetic stem cell transplantation (HSCT) (e.g. based on disease characteristics or subject characteristics). Bridging to an allogeneic HSCT will be allowed.
8. Negative pregnancy test in women of childbearing potential (before leukapheresis and before administration of lymphodepleting chemotherapy).
9. For fertile men and women, agreement to use effective contraceptive methods during the clinical trial.

Acute Myeloid Leukemia (AML)-specific inclusion criteria:
1. No complete remission response (CR) or no complete remission with incomplete heamatologic recovery (CRi) after completion of at least 2 cycles of intensive induction chemotherapy or 1 cycle of intensive induction and consolidation (intermediate or high dose cytarabine chemotherapy),
and/or
2. No CR or no CRi after completion of at least 1 cycle of intensive induction chemotherapy including at least 5 days of cytarabine 100-200 mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 500 mg/m² per cycle and at least 2 days of an anthracycline (e.g. daunorubicin, idarubicin), unable to undergo allogeneic HSCT
and/or
3. Refractory disease (including stable disease [SD], progressive disease [PD]) or relapsed disease after hypomethylating agent therapy (e.g. azacitidine, decitabine),
and/or
4. Any SD, partial reponse (PR), CRi, CR obtained after re-induction or salvage therapy,
and/or
5. Relapsed AML patients unable to undergo allogeneic HSCT,
and/or
6. Relapsed AML after allogeneic HSCT;
a. at least 100 days after transplant.
b. no evidence of active acute or chronic GvHD at enrolment, in case of history of acute (> overall grade 1) or chronic GvHD (moderate/severe) requiring immunosuppressive treatment no immunosuppression within the last 3 months,
c. no immunosuppression (with the exception of low-dose steroids ≤10 mg prednisone or equivalent) 4 weeks before enrollment and ongoing,
and
7. Myeloid blasts must positively express PRAME

Myelodysplastic Syndrome (MDS)-specific inclusion criteria:
1. International Prognostic Scoring System Intermediate-2 (IPSS INT-2) or High Grade MDS EB-2, not responding to at least 6 courses of azacitidine or 4 courses of decitabine and/or
2. IPSS INT-1, INT-2 or High Grade MDS with recurrence after initial response and
3. Blasts must positively express PRAME

Criteria for pre-emptive leukapheresis procedure:
• subject is positive for HLA-A*02:01 and their blasts/myeloma cells express PRAME,
• subject fulfills at least some inclusion criteria and, based on the judgement of the investigator, have a likelihood of being eligible for IMP administration in the further course of the subjects disease,
• subject does not fulfill any exclusion criterion that would be considered permanent (i.e. irreversible organ function impairment) and therefore would certainly preclude the subject from receiving the IMP in the future.

E.4

Principal exclusion criteria

Key exclusion criteria include:
1. Subjects with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); Promyelocytic Leukemia/Retinoic Acid Receptor Alpha (PML-RARA), or with variant translocations
2. Pregnant or lactating women
3. Known positive for human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
4. Any clinically significant, advanced or unstable disease or inadequate main organ function that may put the subjects at special risk, such as:
a. Creatinine > 2.0 times the upper normal serum level
b. total bilirubin, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) > 3.0 times the upper normal serum level
c. cardiac left ventricular ejection fraction < 40% at rest
d. severe restrictive or obstructive lung disease
5. History of haploidentical allogeneic stem cell transplantation
6. Subjects both with urinary outflow obstructions and on dialysis or subjects for whom cyclophosphamide is contraindicated for other reasons
7. Clinical significant and ongoing immune suppression including, but not limited to: immunosuppressive agents such as cyclosporine or corticosteroids (at an equivalent dose of ≥10 mg prednisone per day). Inhaled steroid and physiological replacement for adrenal insufficiency is allowed.
8. Subjects with currently active autoimmune disease
9. Subjects with a history of primary immunodeficiency
10. Subjects with a currently active second malignancy other than non-melanoma skin cancers or subjects with history of prior malignancy and previously treated with a curative intent therapy less than 1 year ago
11. Known or suspected hypersensitivity or intolerance to IMP, Cyclophosphamide, Fludarabine and/or tocilizumab or to any of the excipients
12. Participation in any clinical trial < 60 days prior to first IMP administration in case of antibodies and < 14 days for all other IMPs
13. Vulnerable subjects and/or subjects unwilling or unable to comply with procedures required in this clinical trial protocol

Exclusion Criteria for treatment with IMP in Phase I and Phase II (treatment group):
1. Uncontrolled central nervous system (CNS) disease
2. Uncontrolled infections or uncontrolled disseminated intravascular coagulation; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
3. Ongoing ≥ 3 grade cardiac, renal, pulmonary, gastrointestinal or hepatic toxicities according to National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
4. Evidence of acute or chronic GvHD

Treatment Exemption Criterion:
Unable to generate IMP for infusion; however, if a lower than planned number of cells is available (at least 1 x 105 T cells/kg), the subject in Phase I/II of the clinical trial will have the option to receive IMP and will be analyzed in the safety and full analysis set populations.

E.5 End points

E.5.1

Primary end point(s)

Phase I
• Incidence and severity of adverse events ([AEs] at 3 months) according to the NCI CTCAE, v4.03
• MTD and/or RP2D of IMP measured by dose-limiting toxicities (DLTs) up to 28 days post Infusion

Phase II
• Incidence and severity of adverse events ([AEs] at 3 months) according to NCI CTCAE, v4.03
• Overall response rate (ORR) at 3 months

E.5.1.1

Timepoint(s) of evaluation of this end point

• Primary endpoint: Last Subject Last Visit 8 (month 3)

E.5.2

Secondary end point(s)

Phase I
• Incidence and severity of adverse events ([AEs] at 6 and 12 months) according to the NCI CTCAE, v4.03
• Overall response rate (ORR) at 3, 6 and 12 months
• Time to event and OS rate at 3, 6 and 12 months
• Time to event and PFS rate at 3, 6 and 12 months
• Time to event and DoR rate at 3, 6 and 12 months
• Time to event and TTP rate at 3, 6 and 12 months
• Percent of subjects undergoing HSCT after receiving IMP
• Quality of Life (before infusion of IMP and after 3, 6, and 12 months)
• Correlation of PRAME expression with the antitumor response

Phase II
• Incidence and severity of adverse events ([AEs] at 6 and 12 months) according to NCI CTCAE, v4.03
• Overall response rate (ORR) at 6 and 12 months
• Time to event and OS rate at 3, 6 and 12 months
• Time to event and PFS rate at 3, 6 and 12 months
• Time to event and DoR rate at 3, 6 and 12 months
• Time to event and TTP rate at 3, 6 and 12 months
• Percent (%) of subjects undergoing HSCT after receiving IMP
• Quality of Life (before infusion of IMP and after 3, 6, and 12 months)
• Correlation of PRAME expression with the antitumor response

E.5.2.1

Timepoint(s) of evaluation of this end point

• Secondary endpoint:
Last Subject Last Visit 9 (month 6)
Last Subject Last EoT Visit (month 12)

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Feasibility

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

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

Yes

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

Yes

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

Yes

E.8.2.3.1

Comparator description

The patient in the control group will receive therapy as per Investigator's discretion

E.8.2.4

Number of treatment arms in the trial

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

• Primary endpoint: LSLV 8 (month 3)
• Secondary endpoint:
LSLV Visit 9 (month 6)
LSLV EoT (month 12)

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

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)

F.1.1.6

Adolescents (12-17 years)

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

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.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)

Subjects will be followed up in a separate long-term follow-up clinical trial, for which they can be enrolled upon leaving this clinical trial. Long-term follow-up is defined as an additional 14 years.
Subjects will no longer receive IMP MDG1011 but will be allowed to receive any treatment chosen by their treating physician.

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

2017-12-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-07-15

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