Clinical Trials Register

Summary
EudraCT Number:	2021-004631-92
Sponsor's Protocol Code Number:	WWU20_0041
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-06
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 - BfArM

A.2

EudraCT number

2021-004631-92

A.3

Full title of the trial

Phase I/II dose escalation trial of radiodynamic therapy (RDT) with 5-Aminolevulinic acid in patients with first recurrence of glioblastoma

Eine Phase I/II-Dosis-Eskalations-Studie zur Radiodynamischen Therapie (RDT) mit 5-ALA in Patienten mit erstmaligem Wiederauftreten eines Glioblastoms

A.3.1

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

Radiodynamic therapy (RDT) with Gliolan in patients with first recurrence of brain tumor

Radiodynamischen Therapie (RDT) mit Gliolan in Patienten mit erstmaligem Wiederauftreten eines Hirntumors

A.3.2

Name or abbreviated title of the trial where available

ALA-RDT in GBM

A.4.1

Sponsor's protocol code number

WWU20_0041

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	Westfälische Wilhelms-Universität Münster, C/o Universitätsklinikum Münster Geschäftsbereich Recht u. Drittmittel
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	photonamic GmbH & Co. KG
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	Universitätsklinikum Münster
B.5.2	Functional name of contact point	Klinik für Neurochirurgie
B.5.3	Address:
B.5.3.1	Street Address	Albert-Schweitzer-Campus 1, Geb. A1
B.5.3.2	Town/ city	Münster
B.5.3.3	Post code	48149
B.5.3.4	Country	Germany
B.5.4	Telephone number	004925183547472
B.5.5	Fax number	00492518345646

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	Gliolan 30 mg/ml powder for oral solutions
D.2.1.1.2	Name of the Marketing Authorisation holder	photonamic GmbH & Co. KG
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.3.4	Pharmaceutical form	Powder for oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	5-AMINOLEVULINIC ACID
D.3.9.1	CAS number	106-60-5
D.3.9.4	EV Substance Code	SUB12853MIG
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	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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

recurrence of glioblastoma

Glioblastom Rezidiv

E.1.1.1

Medical condition in easily understood language

recurrent glioblastoma

Wiederaufgetretenes Glioblastom

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma
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

To determine the maximum tolerated dose (MTD*) and safety of (neo)adjuvant RDT; *maxiumun tolerated dose is determined in this study as the maximum tolerated repear RDT consisting og 5-ALA dosing and radiotherapy

Bestimmung der maximal verträglichen Dosis (*MTD) und Sicherheit von einer (neo)adjuvanten RDT
*mit „maximal verträgliche Dosis“ ist in dieser Studie die maximal verträgliche wiederholte RDT, bestehend aus 5-ALA-Gabe und Strahlentherapie, gemeint

E.2.2

Secondary objectives of the trial

determine overall survival rate after 6 months (OSR)
determine time of progression-free survival rate at 6 months (PFS)
determine event-free survival rate after six months (EFS)
determine pharma-radio-dynamic tissue changes in neadjuvant cohorts

Bestimmung der Gesamtüberlebensrate zum Zeitpunkt 6 Monate (OSR)
Bestimmung der progressionsfreien Überlebensrate zum Zeitpunkt 6 Monate (PFS)
Bestimmung der ereignisfreien Überlebensrate zum Zeitpunkt 6 Monate (EFS)
Bestimmung von pharmako-radio-dynamischen Änderungen von Gewebeproben

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

IN1: Written patient consent after comprehensive information
IN2: Age >/=18 years
IN3: Recurrence of supratentorial glioblastoma after initial resection and adjuvant therapy (e.g. radio-chemotherapy, targeted therapies, antiangiogenic therapies as determined by the tumor board) (with planned second resection cohort 0 and 1), second or third recurrences permitted
IN4: Clinically indicated further radiotherapy as per decision of the tumor board as part of therapy for recurrence
IN5: Histological verification of recurrent glioblastoma independent of methylated MGMT promotor status when alkylating chemotherapy failed at this time
IN6: Karnofsky Performance Score ≥ 60
IN7: For female and male patients and their female partners of childbearing/reproductive potential*: Willingness to apply highly effective contraception (Pearl index <1) during the entire study (and for including a period of at least 6 months after the last application of 5-ALA).
Such methods include:
combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
oral
intravaginal
transdermal
progestogen only hormonal contraception associated with inhibition of ovulation:
oral
injectable
implantable
intrauterine device (IUD)
intrauterine hormone-releasing system (IUS)
bilateral tubal occlusion
vasectomised partner
male patients have to use a condom until the end of relevant systemic exposure plus a further 90-day period
sexual abstinence
IN8: Pre-menopausal* female patients with childbearing potential: a negative pregnancy test must be obtained max. 72h prior to treatment start
IN9: Adequate liver function: bilirubin < 1.5 times above upper limit of normal range (ULN), alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/SGOT) < 3 times ULN. In the case of documented or suspected Gilbert’s disease bilirubin < 3 times ULN.
IN10: Adequate renal function: creatinine < 3 times above ULN; eGFR >/= 60 ml/min, Blood clotting: INR/Quick/PT and PTT within acceptable limits according to the investigator

* Definition: a man is considered of reproductive potential after puberty unless permanently sterile by bilateral orchidectomy.
A woman is considered of childbearing reproductive potential (WOCBP) or as pre-menopausal, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

IN1: Schriftliche Einwilligung des Patienten nach umfassender Information
IN2: Alter >/= 18 Jahre
IN3: Wiederauftreten von supratentoriellen Gliolastomen nach initialer Resektion und adjuvanter Therapie (z.B. Radio-Chemotherapie, zielgerichtete Therapien, von dem Tumorboard festgelegte antiangiogene Therapien) (mit geplanter zweiter Resektion bei den Kohorten 0 und 1), zweites und drittes Wiederauftreten erlaubt
IN4: Klinisch indizierte weitere Radiotherapie als Teil der Behandlung des Wiederauftretens entsprechend der Entscheidung des Tumorboards
IN5: Histologische Bestätigung eines wiederautretenden Glioblastoms unabhängig vom Methylierungsstatus des MGMT Promotors bei in diesem Fall erfolgloser alkylierender Chemotherapie
IN6: Karnofsky-Performance Status ≥ 60
IN7: Für zeugungsfähige weibliche und männliche Patienten und deren weiblichen, zeugungsfähigen Partnern*: Bereitschaft eine hocheffektive Verhütungsmethode (Pearl index < 1) während der gesamten klinischen Studie (und für wenigstens 6 Monate nach der letzten Gabe von 5-ALA) anzuwenden:
Kombinierte (Östrogen- und Progestogen-haltige) hormonelle Verhütung assoziiert mit einer Unterdrückung der Ovulation:
oral
intravaginal
transdermal
Nur Progestogen-haltige hormonelle Verhütung assoziiert mit einer Unterdrückung der Ovulation:
oral
injizierbar
implantierbar
Intrauterinpessar
Hormon-freisetzendes Intrauterinpessar
Bilaterale Tubenligatur
Vasektomierter Partner
Männliche Patienten müssen bis zum Ende der relevanten systemischen Exposition und für weitere 90 Tage ein Kondom benutzen
Sexuelle Abstinenz
IN8: Vor-menopausale, weibliche Patienten im gebärfähigen Alter*: ein negativer Schwangerschafts-Test muss maximal 72 Stunden vor Behandlungsstart vorliegen
IN9: Adäquate Leberfunktion: Bilirubin < 1.5-mal über der oberen Normwertgrenze, Alanin-Transaminase (ALT/SGPT) und Aspartat- Transaminase (AST/SGOT) < 3-mal über der oberen Normwertgrenze. Im Falle von einem dokumentierten oder vermuteten Gilbert-Syndrom muss das Bilirubin < 3-mal über der oberen Normwertgrenze sein.
IN10: Adäquate Nierenfunktion: Kreatinin < 3-mal über der oberen Normwertgrenze, eGFR >/= 60 ml/min, Blutgerinnung: INR/Quick/PT und PTT innerhalb akzeptabler Grenzen aus Sicht des Prüfers

* Definition: Ein Mann gilt nach der Pubertät als fortpflanzungsfähig, sofern er nicht durch eine bilaterale Orchiektomie dauerhaft steril ist.
Eine Frau gilt nach der Menarche und bis zum Eintritt in die Postmenopause als gebärfähig, d. h. als fruchtbar, es sei denn, sie ist dauerhaft steril. Zu den dauerhaften Sterilisationsmethoden gehören die Hysterektomie, die bilaterale Salpingektomie und die bilaterale Oophorektomie.
Eine postmenopausale Phase ist definiert als das Ausbleiben der Menstruation seit 12 Monaten, ohne dass eine andere medizinische Ursache vorliegt. Ein hoher Spiegel des follikelstimulierenden Hormons (FSH) im postmenopausalen Bereich kann bei Frauen, die keine hormonelle Empfängnisverhütung oder Hormonersatztherapie anwenden, zur Bestätigung eines postmenopausalen Zustands herangezogen werden. Liegt jedoch keine 12-monatige Amenorrhoe vor, ist eine einzige FSH-Messung nicht ausreichend.

E.4

Principal exclusion criteria

EX1: Patient unable to undergo imaging by MRI, PET or contrast-enhanced CT for whatever reason (e.g. pace-maker)
EX2: Pregnant and breastfeeding women
EX3: Past medical history of diseases with poor prognosis, e.g., severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke, severe mental retardation or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
EX4: Any active infection (at the discretion of the investigator)
EX5: Hypersensitivity against porphyrins
EX6: Known diagnosis of porphyria
EX7: Current participation in another clinical trial with therapeutic intervention or use of any other therapeutic interventional agent other than the standard therapy since diagnosis of glioblastoma
EX8: Known intolerance to study medication
EX9: Pre-treatment with other potentially phototoxic or photosensitizing substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts, products containing St. John's wort ) during the 2 weeks preceding RDT

EX1: Patient nicht fähig, sich einem bildgebenden Verfahren zu unterziehen wie MRT, PET oder Kontrastmittel-CT für was auch immer für Gründe (z.B. Schrittmacher)
EX2: Schwangere und stillende Frauen
EX3: Frühere Krankengeschichte von Krankheiten mit schlechter Prognose, z.B. schwerwiegende koronare Herzerkrankung, Herzfehler (NYHA III/IV), schwerwiegende und schlecht eingestellter Diabetes, Immunschwäche, Restdefizite nach Schlaganfall, schwere mentale Retardierung oder andere schwerwiegende systemische Begleiterkrankungen, die inkompatibel mit der Studie sind (nach Ermessen des Prüfers)
EX4: Aktive Infektionen (nach Ermessen des Prüfers)
EX5: Überempfindlichkeit gegenüber Porphyrinen
EX6: Bekannte diagnostizierte Porphyrie
EX7: Aktuelle Teilnahme an einer anderen klinischen Studie mit therapeutischem Eingriff oder Verwendung eines anderen therapeutischen Eingriffsmittels als der Standardtherapie seit der Diagnose des Glioblastoms
EX8: Bekannte Unverträglichkeit gegen die Studienmedikation
EX9: Vor-Behandlung mit anderen pontentiell phototoxischen oder photosensibilisierenden Substanzen (z.B. Tetracycline, Sulfonamide, Fluorchinolone, Hypericin-Extrakte, Produkte, die Johanniskraut enthalten) während der letzten zwei Wochen vor der RDT)

E.5 End points

E.5.1

Primary end point(s)

MTD is defined as the most frequent repetitive dose of 5-ALA during 4 weeks of fractionated conformal radiotherapy that does not cause unacceptable side effects, i.e. repeated dose at which no more than 1 of 6 patients suffers a dose-limiting toxicity (DLT).
• Toxicological safety of repeat doses of 5-ALA
• Neurological safety of RDT
• Dermatological safety of RDT
• Assess all new AEs CTC AE grade 2 or higher

MTD ist definiert als die höchste Anzahl an RDTs, die nicht unakzeptable Nebenwirkungen hervorruft, das heißt bei der nicht bei mehr als 1 von 6 Patienten eine Dosis-limitierende Toxizität (DLT) auftritt.
• Toxikologische Sicherheit von wiederholten 5-ALA-Gaben
• Neurologische Sicherheit von einer RDT
• Dermatologische Sicherheit einer RDT
• Bewertung von allen neuen Nebenwirkungen, die gemäß CTCAE Grad 2 oder höher sind

E.5.1.1

Timepoint(s) of evaluation of this end point

6 weeks after last RT

6 Wochen nach der letzten RT

E.5.2

Secondary end point(s)

• Six-months overall survival rate (OSR)
• Six-months progression-free survival rate (PFS)
• Six-months event-free survival rate (EFS) defined from the day of inclusion
• Histological tissue changes in neoadjuvant cohorts

• Sechs-Monats-Gesamt-Überlebensrate (OSR)
• Sechs-Monats-Fortschreitenfreie-Überlebensrate (PFS)
• Sechs-Monats-Vorkommenfreie-Überlebensrate (EFS) definiert vom Tag des Einschlusses
• Histologische Gewebeveränderungen in den neoadjuvanten Kohorten

E.5.2.1

Timepoint(s) of evaluation of this end point

six months defined from day of first RDT

6 Monate nach dem ersten Tag der RDT

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

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

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

LVLS

letzte Visite des letzten Patienten

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

After end of study (6 months) patients will be followed according to clinical toutine every 3 months until death or a maximum of 2 years after firt RT-administration for evaluation of progression free survival, OS and neurotoxicity apart from study database. Management in case of radiolocial progression will be at discretion of the responsible 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

2022-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-25

P. End of Trial
P.	End of Trial Status	Ongoing

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