Clinical Trials Register

Summary
EudraCT Number:	2013-005335-25
Sponsor's Protocol Code Number:	BV-NSCLC-002
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:	2014-04-17
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

2013-005335-25

A.3

Full title of the trial

A Phase III, open-label, multicentre, randomised trial to establish safety and efficacy of an EGF cancer vaccine in inoperable, late stage IV biomarker positive, wild type EGF-R, NSCLC patients eligible to receive standard treatment and supportive care.

A.3.1

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

Not Applicable

A.4.1

Sponsor's protocol code number

BV-NSCLC-002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02187367

A.5.4

Other Identifiers

Name:

Final 3.0 Inc. Global Amend. 1 + 2 (Germany only)

Number:

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	Bioven (Europe) Ltd.
B.1.3.4	Country	United Kingdom
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	Bioven Europe Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	EastHORN Clinical Services GmbH
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Im Mediapark 6
B.5.3.2	Town/ city	Cologne
B.5.3.3	Post code	50670
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492214545150
B.5.5	Fax number	+492214545199
B.5.6	E-mail	bettina.geisler@easthorn.eu

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	Epidermal growth factor (EGF} cancer vaccine
D.3.2	Product code	rEGF-rP64k-Montanide ISA 51 VG
D.3.4	Pharmaceutical form	Emulsion for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not yet defined
D.3.9.2	Current sponsor code	rEGF-rP64k-Montanide ISA 51 VG
D.3.9.3	Other descriptive name	rEGF-rP64k conjugate
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.9 to 1.1
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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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.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	Cyclophosphamide Injection 500 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter Healthcare Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Cyclophosphamide Injection 500 mg
D.3.4	Pharmaceutical form	Powder for solution for injection
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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.3	Other descriptive name	cyclophopshamide
D.3.9.4	EV Substance Code	SUB06859MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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

late stage (IIIb/IV) Non-small cell lung carcinoma

E.1.1.1

Medical condition in easily understood language

Non-small cell lung carcinoma

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	10029522
E.1.2	Term	Non-small cell lung cancer stage IV
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess overall survival (OS) of an EGF cancer vaccine in inoperable, stage IV biomarker positive, wild type EGF-R, NSCLC patients when compared to the control group receiving best treatment and supportive care.

E.2.2

Secondary objectives of the trial

To assess progression-free survival (PFS), survival rate, time to progression (TTP), response rate (RECIST criteria) and quality of life (QoL).
To establish the safety of an EGF cancer vaccine in inoperable, stage IV NSCLC patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Are aged 18 or older.
2. Have serum EGF concentration >250 pg/ml determined from sample taken at screening.
3. Have wild type EGF-R sequence.
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Have adequate bone marrow, liver and renal function, as assessed by the Investigator. A sample taken at Screening should confirm that:
• White blood cell (WBC) count ≥ 3000 per µL
• Platelet count ≥ 100,000 per µL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) (or ≤ 5 x ULN when liver metastases are present)
• Total bilirubin ≤ 1.5 x ULN
• Serum creatinine ≤ 1.5 x ULN
6. Have histologically and/or cytologically confirmed diagnosis of NSCLC, corresponding to locally and regionally advanced, inoperable disease (Stage IV [as defined by the American Joint Committee on Cancer staging system- TNM 7th edition 2010]), excluding brain metastases.
7. Are eligible to receive first-line platinum-containing chemotherapy (carboplatin or cisplatin with docetaxel, gemcitabine, paclitaxel, pemetrexed or vinorelbine, without concurrent radiotherapy to thorax measurable lesions or consolidation radiotherapy).
8. A female subject is eligible to participate if she is of:
Non-childbearing potential women refers to those women who are postmenopausal (with at least 2 years from last menstruation) or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the appropriate contraception methods in Section 8.1. This criterion must be followed during their participation in the study, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal
status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval
depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
A negative pregnancy test (based on the β-subunit of HCG) must be documented at Screening for females of childbearing potential and use one of appropriate contraception methods in Section 8.1. This criterion must be followed during their participation in the study.
Note: Females of childbearing potential are defined as those women with less than 2 years after last menstruation and not surgically sterile.

9. Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed during their participation in the study.

10. Have signed a voluntary written informed consent form (ICF). Patients should be cooperative, willing and able to participate and adhere to the Protocol requirements, including their availability for the follow-up.

E.4

Principal exclusion criteria

1. Patient has no measurable disease (as defined by RECIST criteria, version 1.1).
2. Patient has EGF-R mutation.
3. Patient has EGF serum concentration below required threshold.
4. Patient is a candidate for concurrent chemo-radiotherapy or post chemo thoracic radiotherapy.
5. Patient has a history of known or suspected central nervous system (CNS) metastases. Note: For German sites only, CNS metastases suspected during initial neurological and clinical assessments, will be confirmed by MRI scan.
6. Patient has a history of primary malignancy (except resected non-melanoma skin cancer or curatively treated carcinoma in situ of the cervix), unless in complete remission and off all chemotherapy and/or radiotherapy for that disease for a minimum of 5 years. Any palliative radiotherapy to alleviate pain in bone metastases is permitted.
7. Patient is taking immunosuppressant drugs such as azathioprine, tacrolimus, cyclosporine, etc. Use is not permitted within 1 month before Screening.
8. Patient is taking any other immunotherapy.
9. Patient has primary or secondary immunodeficiencies (e.g. for Human Immunodeficiency Virus [HIV] confirmed positive test at screening).
10. Acute or chronic hepatitis B or hepatitis C infection. (confirmed positive test at screening for HBV and/or HCV)
11. Patient has autoimmune disease.
12. Patient has undergone splenectomy.
13. Patient is taking oral, intramuscular or intravenous corticosteroids. Use is not permitted within 1 month before Screening. Inhaled corticosteroids to treat respiratory insufficiency (e.g. chronic obstructive pulmonary disease [COPD]), or topical steroids are permitted.
14. Patient has neurotoxicity (Grade ≥2).
15. Patient has diarrhoea (Grade ≥2).
16. Patient has received other vaccines (with the exception of the influenza vaccine), within 1 month before Screening.
17. Patient has a history of any severe or life-threatening hypersensitivity reaction to the investigational drugs/components being administered in the study.
18. Patient has an unstable systemic disease (including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, myocardial infarction within the previous year, serious cardiac arrhythmia requiring medication, hepatic, renal and metabolic disease).
19. Patient has recent history (within 6 months before Screening) of chronic alcohol or drug abuse which may compromise the patient’s safety or ability to participate in study activities.
20. Patient has a history of psychiatric disorder that prevents patients from providing informed consent or following Protocol instructions.
21. Patient is currently enrolled in an investigational device or drug trial, or <1 month since completing an investigational device or drug trial.
22. Female patients who are pregnant or lactating.
23. Patient has any other factor that in the opinion of the Investigator (or designee) would make the patient unsafe or unsuitable for the study.

E.5 End points

E.5.1

Primary end point(s)

Overall survival.

E.5.1.1

Timepoint(s) of evaluation of this end point

All study visits

E.5.2

Secondary end point(s)

• Progression-free survival.
• Survival rate.
• Time to progression.
• Response rate (RECIST criteria, version 1.1).
• Quality of Life – EORTC QLQ-C30 & EORTC QLQ-LC13 questionnaire.
• Safety (including AEs, laboratory evaluation, vital signs, physical examination).

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 1: Response rate
Visit 2a: Response rate(if required), Quality of Life, Safety
Visit 2b, 2c: Response rate{ if required), Progression-free survival,
Survival rate,Time to progression, Quality of Life,Safety
Visits 3a,3b, 3c,etc: Response rate (at the end of every two cycles of chemotherapy), Progression-free survival, Survival rate, Time to progression,Quality of Life,Safety
Visit 4a, 4b, 4c etc: Progression-free survival, Survival rate, Time to progression,Response rate (if required),Quality of Life, Safety
Visits 5a,5b,5c, etc: Survival rate, Safety

According to protocol, survival rate will be assessed when first 150 patients randomized in trial reach 1 year in trial. The statistical design of the trial is including this planned Interim Analysis.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

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

Treated as per the normal standard of care

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Czech Republic

Germany

Hungary

India

Malaysia

Philippines

Poland

Spain

Thailand

Ukraine

United Kingdom

United States

Vietnam

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

The end of this study is defined as the date of the last visit of the last patient undergoing this study.

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:

334

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

110

F.4.2

For a multinational trial

F.4.2.1

In the EEA

220

F.4.2.2

In the whole clinical trial

418

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)

For patients who leave the study or when the study ends, normal standards of care, according to local practice, will continue as necessary.

Non-progressing patients may continue to receive the study vaccine after the end of the study, if the investigator deems it clinically beneficial to the patient.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	NCRN Coordinating Centre, University of Leeds

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-13

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

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