Clinical Trials Register

Summary
EudraCT Number:	2007-003195-19
Sponsor's Protocol Code Number:	ICORG06-36
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2007-06-11
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

Ireland - HPRA

A.2

EudraCT number

2007-003195-19

A.3

Full title of the trial

A Phase III Randomized Trial of Adjuvant Chemotherapy With or Without Bevacizumab for Patients With Completely Resected Stage IB (> 4 cm) - IIIA Non- Small Cell Lung Cancer (NSCLC)

A.3.1

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

A trial to compare chemotherapy + bevacizumab and chemotherapy alone in patients with resected lung cancer (called non-small cell lung cancer)

A.3.2

Name or abbreviated title of the trial where available

E1505

A.4.1

Sponsor's protocol code number

ICORG06-36

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	ICORG
B.1.3.4	Country	Ireland
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	Roche
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	ICORG
B.5.2	Functional name of contact point	Glenn Webb
B.5.3	Address:
B.5.3.1	Street Address	60 Fitzwilliam Square
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	2
B.5.3.4	Country	Ireland
B.5.4	Telephone number	35316677211
B.5.5	Fax number	35316697869
B.5.6	E-mail	glenn.webb@icorg.ie

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	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Bevacizumab
D.3.2	Product code	RO4876646
D.3.4	Pharmaceutical form	Concentrate 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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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)	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	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	Yes
D.3.11.13.1	Other medicinal product type	Recombinant humanised monoclonal antibody

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

Completely Resected Stage IB (≥4 cm)-IIIA Non-Small Cell Lung Cancer (NSCLC).

E.1.1.1

Medical condition in easily understood language

Resected lung cancer (called non-small cell lung 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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10061873
E.1.2	Term	Non-small cell lung cancer
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

Primary Objective
To evaluate overall survival with chemotherapy with or without bevacizumab used in the adjuvant setting in patients with resected stage IB (> 4 cm) - IIIA NSCLC.

E.2.2

Secondary objectives of the trial

Secondary Objectives
To evaluate disease free survival and toxicity with chemotherapy with or without
bevacizumab used in the adjuvant setting in patients with resected stage IB
(>/= 4 cm) - IIIA NSCLC.
To perform analyses of tissue and blood to establish factors that predict for clinical outcome in patients receiving chemotherapy, with or without bevacizumab, for
resected early stage NSCLC.
To determine whether smoking status is linked to outcome for patients with resected
stage IB (>/= 4 cm) - IIIA NSCLC treated with chemotherapy with or without
bevacizumab in the adjuvant setting.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.0 In order to be eligible for this trial, patients must have undergone complete resection of their non-small cell lung cancer (NSCLC) [stage IB (≥/= 4 cm) - IIIA (T2-3N0, T1-3N1, T1-3N2) prior to enrollment. (Refer to Appendix X for staging guidelines per AJCC 6th edition). Accepted types of resection will consist of lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy. Resections by segmentectomy or wedge resection will not be accepted. Mediastinal lymph node sampling at specified levels is required pre-operative (mediastinoscopy) or intraoperatively (level 7 and 4 for right sided tumors or level 7 and 5 and/or 6 for left sided tumors). Please refer to Section 5 for specific details on lymph node level sampling requirements and resection criteria.
2.0 Patients must be no less than 6 weeks (42 days) and no more (84 days) than 12 weeks post-thoracotomy at the time of randomization and must be adequately recovered from surgery.
3.0 Age ≥ 18 years.
4.0 ECOG performance status 0 or 1.
5.0 Patients must not have received the following:
5.1 Prior systemic chemotherapy at any time. Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 2 weeks prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.
5.2 Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years of randomization. (Prior surgery, biologic therapy, hormonal therapy, or radiation therapy for a malignancy over 5 years prior to enrollment that is now considered cured is acceptable.)
6.0 Patients must not have any history of cancer within 5 years from randomization, with the exception of in-situ carcinoma of the cervix or completely resected non-melanoma skin cancer.
7.0 Required laboratory values obtained within two weeks of randomization:
ANC ≥ 1500 mm3
Platelets ≥ 100,000/mm3
Prothrombin time/INR ≤ 1.5
Or, if patient is on therapeutic anticoagulation, prothrombin time/INR ≤ 3.0
PTT ≤ institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be ≤ 1.5 x ULN
Total Bilirubin ≤ 1.5 mg/dL
SGOT (AST) < 5 x upper limit of normal (ULN)
SGPT (ALT) < 5 x upper limit of normal (ULN)
8.0 Patients must have adequate renal function as determined by the following tests within 2 weeks prior to randomization:
Serum Creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1000 mg (1g) for patient enrollment.
9.0 Patients with a known history of myocardial infarction or other evidence of arterial thrombotic disease (angina) will be allowed on study only if they have had no evidence of active disease for at least 12 months prior to randomization.
10.0 Patients with any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA) will not be allowed on trial.
11.0 Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk from bevacizumab. It is also unknown if these agents are excreted into breast milk.
All females of childbearing potential must have a blood or urine test within 2 weeks prior to randomization to rule out pregnancy.
12.0 All patients must have a documented BP with systolic < 150 and diastolic < 90 within 28 days of registration. Patients with known hypertension must be on a stable regimen of anti-hypertensive therapy.
13.0 Patients who will receive pemetrexed/cisplatin therapy must meet all eligibility criteria as well as the following:
13.1 Patients must NOT have squamous cell histology
13.2 Calculated Creatinine Clearance must be obtained within 2 weeks of randomization and calculated CrCl must be ≥ 45mL/min using the standard Cockcroft and Gault formula (see Appendix III) or the measured glomerular filtration rate (GFR) using the appropriate radiolabeled method (51-CrEDTA or Tc99m-DTPA) must be used to calculate CrCl.

E.4

Principal exclusion criteria

1.0 Patients less than 6 weeks (42 days) and more than 12 weeks (84 days) post-thoracotomy at the time of randomization and must be adequately recovered from surgery.
2.0 Age ≤ 18 years.
3.0 Patients who have received the following:
3.1 Prior systemic chemotherapy at any time. (Please refer to principal inclusion criteria 5.1 for exception)
3.2 Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years of randomization. (Prior surgery, biologic therapy, hormonal therapy, or radiation therapy for a malignancy over 5 years prior to enrollment that is now considered cured is acceptable.)
4.0 Patients with history of cancer within 5 years from randomization, with the exception of in-situ carcinoma of the cervix or completely resected non-melanoma skin cancer.
5.0 Required laboratory values not obtained within two weeks of randomization
6.0 Inadequate renal function.
7.0 Evidence of active myocardial infarction or other evidence of arterial thrombotic disease (angina) within 12 months prior to randomization.
8.0 History of cerebral vascular accident (CVA) or transient ischemic attack (TIA).
9.0 Pregnant or breast-feeding women due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk from bevacizumab. It is also unknown if these agents are excreted into breast milk.
All females of childbearing potential who have not had a blood or urine test within 2 weeks prior to randomization to rule out pregnancy.
10.0 Both fertile men and women not agreeing to use adequate contraceptive measures during study treatment and for at least 6 months after completion of bevacizumab.
11.0 Any clinically significant ongoing, active or serious infection, symptomatic or uncontrolled congestive heart failure, symptomatic or uncontrolled cardiac arrhythmia or any other medical condition or psychiatric illness/social situations that would limit compliance with study requirements.
12.0 History of bleeding diathesis or coagulopathy.
13.0 History of hypertension not well controlled (controlled BP defined as systolic < 150 and diastolic < 90 mm Hg within 28 days of registration) on a stable regimen of anti-hypertensive therapy.
14.0 Treatment with dipyridamole (Persantine), ticlopine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal). Patients must have stopped taking any of these agents at least 7 days prior to randomization.
15.0 Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization OR core biopsy within 7 days prior to randomization.
16.0 History of abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 28 days prior to randomization.
17.0 Anticipated major surgical procedure(s) during the course of the study.
18.0 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.
19.0 Patients with ongoing post-operative hemoptysis (defined as bright red blood of ½ teaspoon or more).
20.0 Patients who will recieve pemetrexed/cisplatin therapy must NOT have squamous cell histology.

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

Survival - patients will be followed up for 10 years.

E.5.2

Secondary end point(s)

- Disease free survival
- analysis of tissue and blood to establish factors that predict for clinical outcome in patients receiving chemotherapy, with or without bevacizumab
- Determine whether smoking status is linked to outcome

E.5.2.1

Timepoint(s) of evaluation of this end point

- Disease free survival - patients will be followed up for 10 years
- analysis of tissue and blood - samples will be collected at the following time points: pre-study, Week 13, Week 25 and Month 15 (Arm B only)
- Determine whether smoking status is linked to outcome - smoking surveys will be completed 3 monthly post registration up to 12 months

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

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)

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

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)

Yes

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

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

Canada

United States

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

A maximum of 10 years after the last patient is enrolled into the 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