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Clinical Trial Results:
A phase II/III, randomised, two-arm comparison of maintenance lapatinib versus placebo after firrst-line chemotherapy in patients with HER1 and/or HER2 over expressing locally advanced or metastatic bladder cancer.

Summary
EudraCT number	2007-001826-28
Trial protocol	GB
Global end of trial date	07 Sep 2015

Results information
Results version number	v1(current)
This version publication date	16 Aug 2017
First version publication date	16 Aug 2017
Other versions
Summary report(s)	JCO 2016 Powles et al

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BL-2007-02

ISRCTN number

ISRCTN35418671

US NCT number

NCT00949455

WHO universal trial number (UTN)

Sponsor organisation name

Queen Mary University London

Sponsor organisation address

5 Walden Street, London, United Kingdom, E1 2EF

Public contact

Charlotte Ackerman, Centre for Experimental Cancer Medicine, +44 2078828497, bci-lamb@qmul.ac.uk

Scientific contact

Thomas Powles, Centre for Experimental Cancer Medicine, +44 2078828497, bci-lamb@qmul.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Sep 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Sep 2015

Was the trial ended prematurely?

Main objective of the trial

The main objective of the study is to compare progression-free survival (PFS) in patients with HER1 and/or HER2 over expressing stage IV bladder cancer who have been randomised to maintenance therapy with lapatinib or placebo following first-line chemotherapy

Protection of trial subjects

Patients were closely monitored as part of the clinical trial and were seen monthly. ECHOs were carried out in case of any cardiac issues from the lapatinib. The standard of care for these patients is surveillance, and therefore no patients were deviating from this by having placebo.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Feb 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 232

Worldwide total number of subjects

232

EEA total number of subjects

232

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

169

85 years and over

Subject disposition

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Recruitment details

From 17/2/2009, 455 patients were screened for eligibility for the LaMB trial. 236 patients were subsequently randomised to treatment. Patients were recruited from multiple centres within the UK only.

Screening details

Patients with histologically confirmed metastatic or locally advanced stage IV transitional cell carcinoma of the urothelium and with an objective response or stable disease upon completion of first-line chemotherapy, were tested for HER1/2 status. Patients with positive status were randomised between lapatinib and placebo maintenance treatment.

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Lapatinib

Arm description

IMP

Arm type

Experimental

Investigational medicinal product name

Lapatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Lapatinib was given continuously at 1500mg once daily (6 x 250mg tablets). In the placebo group 6 visually identical tablets were given instead.

Placebo

Arm description

Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

6 visually identical tablets to lapatinib

Number of subjects in period 1	Lapatinib	Placebo
Started	116	116
Completed	116	116

Baseline characteristics

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Reporting group title

Lapatinib

Reporting group description

IMP

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group values	Lapatinib	Placebo	Total
Number of subjects	116	116	232
Age categorical
Units: Subjects
Adults (18-64 years)	29	30	59
From 65-84 years	81	79	160
85 years and over	2	2	4
Not recorded	4	5	9
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	70.7 (63.9 to 77.2)	71.1 (63.8 to 76.3)	-
Gender categorical
Units: Subjects
Female	28	32	60
Male	88	84	172
ECOG performance status
ECOG performance status
Units: Subjects
Fully active	53	52	105
Ambulatory, capable of light work	52	51	103
Ambulatory but not capable of work	11	13	24
Response to previous chemotherapy
Units: Subjects
CR or PR	80	78	158
SD	36	38	74
PD	0	0	0
Tumour grade
Units: Subjects
Grade 1 or 2	4	4	8
Grade 3 or 4	98	98	196
not recorded	14	14	28
Visceral metastasis
Units: Subjects
Yes	60	47	107
No	52	62	114
not recorded	4	7	11
HER status
Units: Subjects
HER1 positive	53	49	102
HER2 positive	21	21	42
HER1 and HER2 positive	42	46	88
HER negative	0	0	0
Previous cisplatin base chemotherapy
Units: Subjects
Yes	71	73	144
No	40	39	79
Not recorded	5	4	9
Haemoglobin
Units: Subjects
Normal	31	26	57
Low	78	90	168
not recorded	7	0	7
Albumin
Units: Subjects
Normal	108	111	219
Low	1	3	4
not recorded	7	2	9
Creatinine
Units: Subjects
Normal	49	36	85
High	60	78	138
not recorded	7	2	9

Subject analysis set title

Trial patient analysis

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients who meet inclusion/exclusion criteria and were randomised to receive treatment

Subject analysis sets values	Trial patient analysis
Number of subjects	232
Age categorical
Units: Subjects
Adults (18-64 years)	59
From 65-84 years	160
85 years and over	4
Not recorded	9
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	70.7 (64.2 to 77.1)
Gender categorical
Units: Subjects
Female	60
Male	172
ECOG performance status
ECOG performance status
Units: Subjects
Fully active	105
Ambulatory, capable of light work	103
Ambulatory but not capable of work	24
Response to previous chemotherapy
Units: Subjects
CR or PR	158
SD	74
PD	0
Tumour grade
Units: Subjects
Grade 1 or 2	8
Grade 3 or 4	196
not recorded	28
Visceral metastasis
Units: Subjects
Yes	107
No	114
not recorded	11
HER status
Units: Subjects
HER1 positive	102
HER2 positive	42
HER1 and HER2 positive	88
HER negative	0
Previous cisplatin base chemotherapy
Units: Subjects
Yes	144
No	79
Not recorded	9
Haemoglobin
Units: Subjects
Normal	57
Low	168
not recorded	7
Albumin
Units: Subjects
Normal	219
Low	4
not recorded	9
Creatinine
Units: Subjects
Normal	85
High	138
not recorded	9

End points

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Reporting group title

Lapatinib

Reporting group description

IMP

Reporting group title

Placebo

Reporting group description

Placebo

Subject analysis set title

Trial patient analysis

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients who meet inclusion/exclusion criteria and were randomised to receive treatment

Primary: Progression-free survival

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End point title

Progression-free survival

End point description

End point type

Primary

End point timeframe

Date of randomisation until disease progression or death from any cause

End point values	Lapatinib	Placebo
Number of subjects analysed	116	116
Units: months
median (confidence interval 95%)	4.5 (2.8 to 5.4)	5.1 (3 to 5.8)

Progression-free survival

Comparison groups

Lapatinib v Placebo

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.63

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.43

Secondary: Overall survival

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End point title

Overall survival

End point description

End point type

Secondary

End point timeframe

Date of randomisation until death from any cause

End point values	Lapatinib	Placebo
Number of subjects analysed	116	116
Units: months
median (confidence interval 95%)	12.6 (9 to 16.2)	12 (10.5 to 14.9)

Overall survival

Comparison groups

Lapatinib v Placebo

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.31

Adverse events

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Timeframe for reporting adverse events

Entire trial

Assessment type

Non-systematic

Dictionary name

CTC

Dictionary version

4.03

Reporting group title

Lapatinib

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Lapatinib	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	82 / 116 (70.69%)	82 / 116 (70.69%)
number of deaths (all causes)	42	42
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified
subjects affected / exposed	4 / 116 (3.45%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 4	0 / 0
Vascular disorders
Vascular disorders
subjects affected / exposed	1 / 116 (0.86%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General disorders and administration site conditions
subjects affected / exposed	10 / 116 (8.62%)	6 / 116 (5.17%)
occurrences causally related to treatment / all	2 / 11	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper Respiratory
subjects affected / exposed	1 / 116 (0.86%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
subjects affected / exposed	3 / 116 (2.59%)	6 / 116 (5.17%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 1	0 / 0
Investigations
Investigations
subjects affected / exposed	2 / 116 (1.72%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
subjects affected / exposed	0 / 116 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac disorders
subjects affected / exposed	2 / 116 (1.72%)	3 / 116 (2.59%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Nervous System Disorder
subjects affected / exposed	2 / 116 (1.72%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Blood and lymphatic system disorders
Blood and lymphatic system disorders
subjects affected / exposed	0 / 116 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal disorders
subjects affected / exposed	7 / 116 (6.03%)	7 / 116 (6.03%)
occurrences causally related to treatment / all	6 / 10	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatobiliary disorders
subjects affected / exposed	1 / 116 (0.86%)	0 / 116 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
subjects affected / exposed	0 / 116 (0.00%)	1 / 116 (0.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal and urinary disorders
subjects affected / exposed	10 / 116 (8.62%)	11 / 116 (9.48%)
occurrences causally related to treatment / all	1 / 14	0 / 13
deaths causally related to treatment / all	0 / 1	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
subjects affected / exposed	0 / 116 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infections and Infestations
subjects affected / exposed	8 / 116 (6.90%)	5 / 116 (4.31%)
occurrences causally related to treatment / all	1 / 9	1 / 6
deaths causally related to treatment / all	0 / 1	0 / 1
Metabolism and nutrition disorders
Metabolism and nutrition disorders
subjects affected / exposed	0 / 116 (0.00%)	2 / 116 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Lapatinib	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	97 / 116 (83.62%)	99 / 116 (85.34%)
Cardiac disorders
Hypertension
subjects affected / exposed	4 / 116 (3.45%)	7 / 116 (6.03%)
occurrences all number	4	7
Nervous system disorders
Neuropathy
subjects affected / exposed	7 / 116 (6.03%)	14 / 116 (12.07%)
occurrences all number	7	14
Neurotoxicity
subjects affected / exposed	7 / 116 (6.03%)	1 / 116 (0.86%)
occurrences all number	7	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 116 (1.72%)	10 / 116 (8.62%)
occurrences all number	2	10
General disorders and administration site conditions
Fatigue
subjects affected / exposed	38 / 116 (32.76%)	42 / 116 (36.21%)
occurrences all number	38	42
Oedema
subjects affected / exposed	5 / 116 (4.31%)	8 / 116 (6.90%)
occurrences all number	5	8
Pain
subjects affected / exposed	47 / 116 (40.52%)	47 / 116 (40.52%)
occurrences all number	47	47
Gastrointestinal disorders
Constipation
subjects affected / exposed	16 / 116 (13.79%)	18 / 116 (15.52%)
occurrences all number	16	18
Diarrhoea
subjects affected / exposed	58 / 116 (50.00%)	23 / 116 (19.83%)
occurrences all number	65	23
Nausea
subjects affected / exposed	23 / 116 (19.83%)	20 / 116 (17.24%)
occurrences all number	23	20
Vomiting
subjects affected / exposed	18 / 116 (15.52%)	16 / 116 (13.79%)
occurrences all number	18	16
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	8 / 116 (6.90%)	10 / 116 (8.62%)
occurrences all number	8	10
Respiratory
subjects affected / exposed	3 / 116 (2.59%)	7 / 116 (6.03%)
occurrences all number	3	7
Shortness of breath
subjects affected / exposed	12 / 116 (10.34%)	10 / 116 (8.62%)
occurrences all number	12	10
Hepatobiliary disorders
Creatinine
subjects affected / exposed	4 / 116 (3.45%)	7 / 116 (6.03%)
occurrences all number	4	7
Skin and subcutaneous tissue disorders
Cutaneous
subjects affected / exposed	5 / 116 (4.31%)	1 / 116 (0.86%)
occurrences all number	5	1
Dry skin
subjects affected / exposed	6 / 116 (5.17%)	2 / 116 (1.72%)
occurrences all number	6	2
Itch
subjects affected / exposed	12 / 116 (10.34%)	10 / 116 (8.62%)
occurrences all number	12	12
Rash
subjects affected / exposed	45 / 116 (38.79%)	21 / 116 (18.10%)
occurrences all number	45	21
Renal and urinary disorders
Bladder symptoms
subjects affected / exposed	5 / 116 (4.31%)	6 / 116 (5.17%)
occurrences all number	6	6
Haematuria
subjects affected / exposed	11 / 116 (9.48%)	6 / 116 (5.17%)
occurrences all number	11	6
Renal Impairment
subjects affected / exposed	6 / 116 (5.17%)	7 / 116 (6.03%)
occurrences all number	6	7
Infections and infestations
Infection
subjects affected / exposed	31 / 116 (26.72%)	18 / 116 (15.52%)
occurrences all number	31	18
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	12 / 116 (10.34%)	7 / 116 (6.03%)
occurrences all number	12	7

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jan 2008

Addition of an interim analysis to the protocol Prohinbited drugs list added to PIS Scan schedule changed to every 12 weeks rather than 10 weeks Correction to IMP storage conditions in protocol.

11 Feb 2009

Study amended from Phase III to Phase II/III. Administrative corrections throughout protocol. Two stratification factors removed from the randomisation (prior ciplatin chemotherapy, hospital site) Inclusion of patients with HER2+ intensity on IHC Haemaglobin levels (>8.0 g/dL) added to inclusion criteria Clarifications to assessment schedule Instructions to sites regarding IMP management at end of the study added to protocol Dose management guidance added to protocol in the event of liver chemistry, LVEF and hepatobiliary abnormalities

02 Jul 2009

Patients with bladder cancer in the urothelial tract eligible for entry. Following updated safety information from IMP manufacturer - herbal supplements are prohibited from use and diarrhoea supportive care guidance provided.

25 Aug 2009

Amendment to allow metastatic bladder cancer patients with bone metastases (alkaline phosphatase levels removed from the inclusion criteria). Administrative clarifications to assessment schedule

24 May 2010

Amendment to protocol to allow for capture of follow-up data for all patients screened that are HER negative, but did not proceed to study treatment. Addition of testing for HER3 and 4 status Administrative clarifications to protocol

18 Oct 2010

Update to exclusion criteria - remove previous HER1/2 therapy from the exclusion criteria Time allowed between randomisation and treatment commencement increased to 10 weeks

13 Jan 2011

Addition of sites and change of Principal Investigator only

19 May 2011

Amendment to protocol to allow for capture of follow-up data for all patients screened that are HER positive, but did not proceed to study treatment.

23 Jun 2011

Addition of sites and change of Principal Investigator only

30 Nov 2011

Changes to Principal Investigators only

17 Apr 2012

Addition of new sites only

01 Aug 2012

Change of Principal Investigator only

22 Oct 2012

Change of Principal Investigator only

30 Jul 2013

Increase to sample size Change to Principal Investigators

27 Jan 2015

Clarification of end of trial procedures in protocol

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/28034079

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Clinical trials

Clinical Trial Results:
A phase II/III, randomised, two-arm comparison of maintenance lapatinib versus placebo after firrst-line chemotherapy in patients with HER1 and/or HER2 over expressing locally advanced or metastatic bladder cancer.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free survival

Primary: Progression-free survival

Secondary: Overall survival

Secondary: Overall survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: A phase II/III, randomised, two-arm comparison of maintenance lapatinib versus placebo after firrst-line chemotherapy in patients with HER1 and/or HER2 over expressing locally advanced or metastatic bladder cancer.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free survival

Primary: Progression-free survival

Secondary: Overall survival

Secondary: Overall survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A phase II/III, randomised, two-arm comparison of maintenance lapatinib versus placebo after firrst-line chemotherapy in patients with HER1 and/or HER2 over expressing locally advanced or metastatic bladder cancer.