Clinical Trials Register

Summary
EudraCT Number:	2019-004015-31
Sponsor's Protocol Code Number:	WPD-201
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-05-20
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2019-004015-31

A.3

Full title of the trial

A Multicenter, Open-Label Study of the Efficacy, Safety, and Pharmacokinetics of Intravenously Infused Berubicin in Adult Patients with Recurrent Glioblastoma Multiforme (WHO Grade IV) After Failure of Standard First Line Therapy

A.3.1

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

A phase 2 open-label study of Berubicin in adult patients with Recurrent Gliobastoma Multiforme after failure of standard first line therapy

A.4.1

Sponsor's protocol code number

WPD-201

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	WPD Pharmaceuticals Sp. z o.o.
B.1.3.4	Country	Poland
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	WPD Pharmaceuticals Sp. z o.o.
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	WPD Pharmaceuticals Sp. z o.o.
B.5.2	Functional name of contact point	WPD Pharmaceuticals Sp. z o.o.
B.5.3	Address:
B.5.3.1	Street Address	Żwirki i Wigury 101
B.5.3.2	Town/ city	Warsaw
B.5.3.3	Post code	02-089
B.5.3.4	Country	Poland
B.5.6	E-mail	wpd-201@wpdpharmaceuticals.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.3.1	Product name	Berubicin
D.3.2	Product code	WP 744
D.3.4	Pharmaceutical form	Lyophilisate for solution 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	Berubicin
D.3.9.1	CAS number	293736-67-1
D.3.9.2	Current sponsor code	WP744
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 20
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

Glioblastoma Multiforme

E.1.1.1

Medical condition in easily understood language

Glioblastoma Multiforme

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	10018337
E.1.2	Term	Glioblastoma multiforme
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 confirm the efficacy (or futility) of berubicin treatment on ORR defined as a CR or PR per modified Response Assessment in Neuro-Oncology (m-RANO) criteria in patients with GBM (WHO Grade IV) that has recurred after standard initial therapy, based on Simon’s 2-stage design.

E.2.2

Secondary objectives of the trial

To confirm the:
• Safety profile of berubicin that was characterized during Phase 1 studies
• Pharmacokinetic (PK) profile of berubicin and berubicinol that was characterized during Phase 1 studies
To assess the effect of Berubicin on:
• DoR in patients with GBM after failure of standard first line therapy
• The individual components of the ORR (ie CR alone, PR alone)
• OS in patients with GBM after failure of standard first line therapy
• Progression free survival at 6 months (PFS6) per m-RANO criteria in patients with GBM after failure of standard first line therapy
• Disease control rate (DCR) defined as CR or PR or stable disease (SD) per m-RANO criteria in patients with GBM after failure of standard first line therapy
• Event-free survival (EFS) - length of time from the initiation of study drug administration to disease progression, death, or discontinuation of treatment for any reason (eg, toxicity, intolerance, disease-related conditions, or failure to respond)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent prior to any study-related procedure, and willing and able to comply with the protocol and aware of the investigational nature of this study.
2.At least 18 years of age.
3.A diagnosis of GBM (WHO Grade IV) confirmed by:
a.Archived paraffin-embedded tissue (approximately 10 unstained slides or a tumor block) from initial resection for local review of tumor diagnosis OR
b.A tumor tissue form indicating diagnosis from initial resection of glioblastoma completed and signed by a pathologist and/OR
c.Tumor tissue from re-resection, managed as above (a OR b)
4.Measurable disease is required with documented unequivocal evidence of tumor recurrence or progression following prior therapy, confirmed by the following:
a.Recurrent GBM as documented by the principal investigator (PI).
In case of recent interim debulking surgery, the histopathological verification of the resected tissue as recurrent tumor automatically qualifies the patient as eligible for the trial.
b.KPS reduction of 10 units while on stable or increasing doses of corticosteroids as documented by the PI
c.Subject MRI meets at least two of the following three criteria as determined by central review:
1)Presence of measurable disease:the lesion is≥10mm in both max perpendicular diameters
2)Evidence of unequivocal tumor recurrence or progression following prior therapy as determined by a 10% increase in the sum of the products of perpendicular diameters of the contrast-enhancing lesions
3)Substantial increase in the perilesional oedema as shown in T2/FLAIR images.
5.All contrast enhancing disease is located supratentorially
6.O[6]-methylguanine-DNA methyltransferase (MGMT) methylation status must be available, or able to be determined from existing tumor tissue; results of routinely used methods for MGMT methylation testing (e.g., methylation-specific polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable.
7.No more than 1 prior line of treatment (e.g., surgery followed by radiation with concomitant chemotherapy, followed by adjuvant chemotherapy is considered as 1 line of treatment). A second debulking surgery during the first line treatment is acceptable.
8.Recovery from toxicity/side effects of all prior therapy to Grade 1 or less, subject to the investigator’s discretion, except for alopecia; the following time intervals from previous treatments are required to be eligible:
a.12 weeks from the completion of radiation (to reduce risk of pseudoprogression),unless progression is confirmed by biopsy
b.4 weeks from the end of any previous chemotherapy or 6 weeks after the end of treatment with nitrosoureas
c.4 weeks from any major surgery (maximal debulking surgery, either gross total resection or partial resection) or significant traumatic injury, and any surgery incisions or wounds must be completely healed
9.A stable or decreasing dose of corticosteroids (or none) for brain edema for at least 5 days prior to baseline MRI and enrollment in the study as confirmed by the PI.
10.Immunosuppressive therapies allowed include the use of topical, inhalational, ophthalmic, or intra-articular glucocorticoids, or the use of physiologic replacement doses of glucocorticoids.
11.Eligible for chemotherapy based on adequate bone marrow function and organ function within 2 weeks of study treatment as defined by the following laboratory guidelines, subject to the investigator’s discretion:
a.Hematopoietic function: total white blood cell (WBC) count ≥3000/mm³, absolute neutrophil count (ANC) ≥1500/mm³, platelet count ≥75,000/mm³, hemoglobin ≥10 g/dL
b.Hepatic function:bilirubin ≤1.5 × the upper limit of normal (ULN) (excluding Gilberts Syndrome, for which bilirubin must be ≤4 × ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × ULN, and alkaline phosphatase ≤2.5 × ULN
c.Renal function: serum creatinine ≤1.5 × ULN or for patients with creatinine levels above the ULN, or estimated creatinine clearance of ≥60 mL/min/1.73 m2, calculated using the Cockcroft Gault formula
d.Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.
12.Women of childbearing potential must agree to practice a highly effective method of contraception beginning at least 28 days before the start of treatment until at least 6 months after the last dose of study drug. Male study patients and their female sexual partners of childbearing potential must agree to practice a highly effective method of contraception starting from the time of informed consent until at least 3,5 months (no less than 104 days) after the last dose of study drug.
13.Patients with prior malignancies must be disease-free for ≥5 years.

E.4

Principal exclusion criteria

1.Unable or not willing to comply with the protocol regulations.
2.Any additional concurrent radiation therapy or chemotherapy (including but not limited to temozolomide [TMZ]) for recurrent or progressive GBM after a first line treatment.
3.Prior treatment with bevacizumab.
4. The presence of IDH mutation prior to enrolment.
5.Screening MRI showing a mass effect defined as significant compression of the ventricular system and/or a midline shift (≥10 mm) as determined by central MRI review.
6.Any condition (medical, social, psychological) that would prevent adequate information and follow-up, including but not limited to clinically relevant psychiatric disorders, legal incapacity, dementia, or altered mental status.
7.Presence of poorly controlled seizures, defined as occurring despite standard of care (SOC) or requiring hospitalization.
8.Widespread of focal leptomeningeal disease measuring ≥10mm by ≥10mm.
9.Prior anthracycline cumulative dose more than 550 mg/m2.
10.Heart disease:
a.LVEF <50%
b.Unstable angina
c.Congestive heart failure with New York Heart Association (NYHA) classification of 3 or 4
d.Patients with baseline QT/QTc interval >480 msec, a history of additional risk factors for torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome) and using concomitant medications that significantly prolong the QT/QTc interval
e.History of myocardial infarction within 12 months of enrollment.
11.Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg and/or diastolic BP >100 mmHg).
12.Known to be positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV), human immunodeficiency virus (HIV), coronavirus disease-2019 (COVID-19) or any other acute viral, bacterial, or fungal infection (testing not required unless symptomatic or suspected disease).
13.Any other uncontrolled intercurrent medical conditions, including but not limited to diabetes mellitus or chronic obstructive pulmonary disease that have not been well controlled by medical management over the prior 3 months are ineligible unless approved by the sponsor.

E.5 End points

E.5.1

Primary end point(s)

ORR, defined as CR or PR per m-RANO criteria within 6 months

E.5.1.1

Timepoint(s) of evaluation of this end point

within 6 months

E.5.2

Secondary end point(s)

• DoR within 6 months
• Proportion of patients achieving CR within 6 months
• Proportion of patients achieving PR within 6 months
• Proportion of patients achieving CR vs. PR within 6 months
• OS within 6 months
• PFS6, defined as the proportion of patients who are alive 6 months after enrollment and have no evidence of disease progression
• DCR, defined as CR or PR or SD within 6 months
• EFS, defined as the length of time from the initiation of study drug administration to disease progression, death, or discontinuation of treatment for any reason (eg, toxicity, intolerance, disease-related conditions, or failure to respond)

Pharmacokinetic Endpoints
Standard PK parameters for berubicin and its metabolite, berubicinol, as derived from noncompartmental analysis of plasma drug concentration-time data.

E.5.2.1

Timepoint(s) of evaluation of this end point

Within 6 Months
• Proportion of patients achieving CR
• Proportion of patients achieving PR
• Proportion of patients achieving CR vs. PR
• OS
• DCR, defined as CR or PR or SD
• PFS6

Duration of trial:
• EFS, defined as the length of time from the initiation of study drug administration to disease progression, death, or discontinuation of treatment for any reason (eg, toxicity, intolerance, disease-related conditions, or failure to respond)
• Standard PK parameters for berubicin and its metabolite, berubicinol, as derived from noncompartmental analysis of plasma drug concentration-time data.

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

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)

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

Yes

E.8.1.7.1

Other trial design description

Simon's 2-stage 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.8.2.4

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

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)

Treatment may be conitnue in the absence of clinical and/or neurological deterioration, or unacceptable toxicity, and as long as both the patient and investigator agree that further therapy is in the patient’s best interest. After patient is discontinued, they will be return to their standard of care with regular healthcare provider.

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

2021-09-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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