Efficacy and Safety of AZD4547 Versus Paclitaxel in Patients With Advanced Gastric or Gastro-oesophageal Cancer (SHINE)

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ClinicalTrials.gov Identifier: NCT01457846

Recruitment Status : Terminated

First Posted : October 24, 2011

Results First Posted : March 7, 2017

Last Update Posted : March 7, 2017

Sponsor:

Information provided by (Responsible Party):

AstraZeneca

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Gastro-oesophageal Junction Cancer Gastric Cancer
Interventions	Drug: AZD4547 Drug: paclitaxel
Enrollment	960

Participant Flow

Recruitment Details	This study was conducted in 11 countries. Enrolment started in November 2011 and last patient visit was in August 2013. In total, 960 patients were enrolled out of which 71 were randomised. A total of 67 patients received treatment , 40 of these patients received AZD4547 and 27 received Paclitaxel.
Pre-assignment Details	Patients ≥ 25 years with locally advanced or metastatic gastric adenocarcinoma that had FGFR2 polysomy or FGFR2 gene amplification and whose disease had progressed during or after 1st line therapy. Patients whose disease had progressed within 6 months following adjuvant or neo-adjuvant therapy could be included at the discretion of the investigator


Arm/Group Title	AZD4547	Paclitaxel
Arm/Group Description	80mg BD 2 weeks on/1 week off	80mg / m^2
Arm/Group Description	80mg BD 2 weeks on/1 week off	80mg / m^2
Period Title: Overall Study
Started	41	30
Received Treatment	40	27
Did Not Receive Treatment	1	3
Ongoing Treatment at Data Cut-off	1	1
Completed	0	0
Not Completed	41	30
Reason Not Completed
Death before treatment	1	2
Did not receive treatment	0	1
Death	27	16
Unclassified reason for not completed	11	10
Withdrawal by Subject	1	1
Lost to Follow-up	1	0

Baseline Characteristics

Arm/Group Title		Paclitaxel	AZD4547	Total
Arm/Group Description		80mg / m^2	80mg BD 2 weeks on/1 week off	Total of all reporting groups
Arm/Group Description		80mg / m^2	80mg BD 2 weeks on/1 week off	Total of all reporting groups
Overall Number of Baseline Participants		30	41	71
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous ^[1] Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	30 participants	41 participants	71 participants
		61.9 (10.65)	60.6 (11.38)	61.2 (11.02)
		[1] Measure Description: Age at time of screening
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	30 participants	41 participants	71 participants
<50 years		4	7	11
>=50 - < 65 years		13	20	33
>= 65 years		13	14	27
Gender Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	30 participants	41 participants	71 participants
	Female	8 26.7%	12 29.3%	20 28.2%
	Male	22 73.3%	29 70.7%	51 71.8%

Outcome Measures

1.Primary Outcome


Title	Median Progression Free Survival
Description	PFS is the time from randomisation until the date of objective disease...
Description	PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression).
Time Frame	Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week)

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	AZD4547	Paclitaxel
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Overall Number of Participants Analyzed	41	30
Measure Type: Number Unit of Measure: months
	1.8	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4547, Paclitaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9581
	Comments	1-sided
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 80% 1.12 to 2.21
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off)
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week)

Outcome Measure Data

Analysis Population Description

This secondary analysis included factors for treatment and FGFR2 FISH score (4/5 versus 6) and is based on the Full analysis set (all treated patients).


Arm/Group Title	AZD4547	Paclitaxel
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Overall Number of Participants Analyzed	38	30
Measure Type: Number Unit of Measure: Patients
	27	18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4547, Paclitaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8156
	Comments	1-sided
	Method	Regression, Cox
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 80% 0.89 to 1.95
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Objective Response Rate
Description	ORR=Percentage of patients with at least one visit response of CR (com...
Description	ORR=Percentage of patients with at least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later; CR:disappearance of target lesions and no new lesions; PR is at least 30% decrease in sum of diameters of lesions taking as a reference the smallest sum since treatment started.
Time Frame	Week 8 (±1 week) and then every 8 weeks (±1 week)

Outcome Measure Data

Analysis Population Description

The analysis included factors for treatment and FGFR2 FISH score (4/5 versus 6) and is based on the Full analysis set (all treated patients).


Arm/Group Title	AZD4547	Paclitaxel
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Overall Number of Participants Analyzed	38	30
Measure Type: Number Unit of Measure: Patients (%)
	2.6	23.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4547, Paclitaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9970
	Comments	1-sided
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 80% 0.02 to 0.35
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Percentage Change From Baseline at Week 8 in Target Lesion Size
Description	A negative change denotes a reduction in target lesion size. Percentag...
Description	A negative change denotes a reduction in target lesion size. Percentage change from baseline in tumour size at 8 weeks in target lesion size.
Time Frame	Baseline, Week 8 (±1 week)

Outcome Measure Data

Analysis Population Description

Full analysis set - all treated patients with at least one post baseline RECIST target lesion assessment scan


Arm/Group Title	AZD4547	Paclitaxel
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Overall Number of Participants Analyzed	36	26
Mean (Standard Deviation) Unit of Measure: Percentage change
	28.4 (44.4)	-1.1 (36.18)

5.Secondary Outcome


Title	Percentage of Patients Without Progressive Disease at 8 Weeks
Description	PD = A ≥ 20% increase in the sum of diameters of target lesions ...
Description	PD = A ≥ 20% increase in the sum of diameters of target lesions and an absolute increase of ≥ 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diamters
Time Frame	Week 8 (±1 week)

Outcome Measure Data

Analysis Population Description

Full analysis set - all treated patients


Arm/Group Title	AZD4547	Paclitaxel
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Arm/Group Description:	80mg BD 2 weeks on/1 week off	80mg / m^2
Overall Number of Participants Analyzed	41	30
Measure Type: Number Unit of Measure: Percentage of patients
	24.4	53.3

Adverse Events

Time Frame	AEs will be collected throughout the study, from randomisation until the end of the follow-up period. The follow-up period is defined as 28 days after study treatment (AZD4547 or paclitaxel) is discontinued.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	AZD4547		Paclitaxel
Arm/Group Description	80mg BD 2 weeks on/1 week off		80mg / m^2
Arm/Group Description	80mg BD 2 weeks on/1 week off		80mg / m^2
All-Cause Mortality
	AZD4547		Paclitaxel
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	AZD4547		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/40 (20.00%)		6/27 (22.22%)
Blood and lymphatic system disorders
Anaemia ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Gastrointestinal disorders
Dyspepsia ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Dysphagia ^†	0/40 (0.00%)	0	1/27 (3.70%)	1
Intestinal haemorrhage ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Obstruction gastric ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Stomatitis ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Vomiting ^†	1/40 (2.50%)	1	2/27 (7.41%)	2
General disorders
Asthenia ^†	0/40 (0.00%)	0	1/27 (3.70%)	1
Hepatobiliary disorders
Bile duct obstruction ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Infections and infestations
Biliary tract infection ^†	0/40 (0.00%)	0	1/27 (3.70%)	1
Lower respiratory tract infection ^†	0/40 (0.00%)	0	1/27 (3.70%)	1
Pneumonia ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Urinary tract infection ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Investigations
Blood bilirubin increased ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Transaminases increases ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism ^†	0/40 (0.00%)	0	1/27 (3.70%)	1
Vascular disorders
Arterial disorder ^†	1/40 (2.50%)	1	0/27 (0.00%)	0
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	AZD4547		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/40 (97.50%)		26/27 (96.30%)
Blood and lymphatic system disorders
Anaemia ^†	7/40 (17.50%)	7	6/27 (22.22%)	6
Neutropenia ^†	2/40 (5.00%)	2	9/27 (33.33%)	9
Eye disorders
Detatchment of retinal pigment epithelium ^†	6/40 (15.00%)	6	0/27 (0.00%)	0
Dry eye ^†	4/40 (10.00%)	4	0/27 (0.00%)	0
Macular degeneration ^†	2/40 (5.00%)	2	0/27 (0.00%)	0
Gastrointestinal disorders
Nausea ^†	10/40 (25.00%)	10	6/27 (22.22%)	6
Vomiting ^†	8/40 (20.00%)	8	5/27 (18.52%)	5
Stomatis ^†	10/40 (25.00%)	10	2/27 (7.41%)	2
Abdominal pain upper ^†	9/40 (22.50%)	9	0/27 (0.00%)	0
Dyspepsia ^†	4/40 (10.00%)	4	1/27 (3.70%)	1
Dysphagia ^†	0/40 (0.00%)	0	2/27 (7.41%)	2
Constipation ^†	10/40 (25.00%)	10	5/27 (18.52%)	5
Abdominal pain ^†	9/40 (22.50%)	9	5/27 (18.52%)	5
General disorders
Fatigue ^†	6/40 (15.00%)	6	8/27 (29.63%)	8
Oedema peripheral ^†	4/40 (10.00%)	4	2/27 (7.41%)	2
Asthenia ^†	11/40 (27.50%)	11	5/27 (18.52%)	5
Pyrexia ^†	4/40 (10.00%)	4	2/27 (7.41%)	2
Hepatobiliary disorders
Diarrhoea ^†	6/40 (15.00%)	6	6/27 (22.22%)	6
Infections and infestations
Lower respiratory tract infection ^†	0/40 (0.00%)	0	3/27 (11.11%)	3
Urinary tract infections ^†	2/40 (5.00%)	2	2/27 (7.41%)	2
Investigations
Aspartate aminotransferase ^†	7/40 (17.50%)	7	0/27 (0.00%)	0
Blood alkaline phosphatase increased ^†	4/40 (10.00%)	4	1/27 (3.70%)	1
Blood phosphorus increased ^†	3/40 (7.50%)	3	0/27 (0.00%)	0
Blood bilirubin increased ^†	2/40 (5.00%)	2	0/27 (0.00%)	0
Alanine aminotransferase increased ^†	6/40 (15.00%)	6	0/27 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^†	16/40 (40.00%)		8/27 (29.63%)
Dry mouth ^†	9/40 (22.50%)	9	0/27 (0.00%)	0
Hyperkalaemia ^†	2/40 (5.00%)	2	2/27 (7.41%)	2
Hyperphosphataemia ^†	3/40 (7.50%)	3	0/27 (0.00%)	0
Hypokalaemia ^†	1/40 (2.50%)	1	2/27 (7.41%)	2
Musculoskeletal and connective tissue disorders
Arthralgia ^†	3/40 (7.50%)	3	0/27 (0.00%)	0
Myalgia ^†	0/40 (0.00%)	0	3/27 (11.11%)	3
Back pain ^†	1/40 (2.50%)	1	6/27 (22.22%)	6
Nervous system disorders
Dizziness ^†	3/40 (7.50%)	3	1/27 (3.70%)	1
Lethargy ^†	1/40 (2.50%)	1	2/27 (7.41%)	2
Dysgeusia ^†	6/40 (15.00%)	6	4/27 (14.81%)	4
Peripheral sensory neuropathy ^†	0/40 (0.00%)	0	3/27 (11.11%)	3
Hypoaesthesia ^†	0/40 (0.00%)	0	2/27 (7.41%)	2
Headache ^†	4/40 (10.00%)	4	1/27 (3.70%)	1
Psychiatric disorders
Neuropathy peripheral ^†	1/40 (2.50%)	1	4/27 (14.81%)	4
Insomnia ^†	2/40 (5.00%)	2	3/27 (11.11%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^†	3/40 (7.50%)	3	1/27 (3.70%)	1
Dysphonia ^†	2/40 (5.00%)	2	1/27 (3.70%)	1
Productive cough ^†	0/40 (0.00%)	0	2/27 (7.41%)	2
Epistaxis ^†	3/40 (7.50%)	3	1/27 (3.70%)	1
Skin and subcutaneous tissue disorders
Alopecia ^†	2/40 (5.00%)	2	13/27 (48.15%)	13
Dry skin ^†	3/40 (7.50%)	3	1/27 (3.70%)	1
Onychomadesis ^†	3/40 (7.50%)	3	0/27 (0.00%)	0
Nail discolouration ^†	2/40 (5.00%)	2	1/27 (3.70%)	1
Onycholysis ^†	2/40 (5.00%)	2	0/27 (0.00%)	0
Pruritus ^†	2/40 (5.00%)	2	1/27 (3.70%)	1
† Indicates events were collected by systematic assessment

Limitations and Caveats

Prompted by slow recruitment, AZ and the SRC instigated unscheduled analysis of the efficacy and tolerability. It was concluded that the study was unlikely to meet its primary objective. Enrolment ceased and the study closed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Donal Landers
Organization:	Astrazeneca
Phone:	+44 1625 231890
EMail:	Donal.Landers@astrazeneca.com

Layout table for additonal information

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT01457846
Other Study ID Numbers:	D2610C00004
First Submitted:	September 16, 2011
First Posted:	October 24, 2011
Results First Submitted:	February 11, 2016
Results First Posted:	March 7, 2017
Last Update Posted:	March 7, 2017

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