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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01457846
• Collaborator: (none)
• Enrollment: 960
• Locations: 61
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 15.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy, safety and tolerability of AZD4547 compared with paclitaxel in patients with advanced gastric or lower-oesophageal cancer whose tumours are found to have FGFR2 polysomy or gene amplification.

Condition or Disease	Intervention/Treatment	Phase
Gastro-oesophageal Junction Cancer; Gastric Cancer	Drug: AZD4547; Drug: paclitaxel	Phase 2

Detailed Description

A Randomised Open-Label Phase IIa Study to Assess the Efficacy and Safety of AZD4547 monotherapy versus paclitaxel in Patients with Advanced Gastric or Gastro-oesophageal Junction Cancer with FGFR2 Polysomy or Gene Amplification (SHINE study). Patients were to be assigned to strata by FGFR2 status of: polysomy, low or high gene amplification.

Study Design

• Study Type: Interventional
• Actual Enrollment: 960 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomised Open-Label Phase II Study to Assess the Efficacy & Safety of AZD4547 Monotherapy Versus Paclitaxel in Patients With Advanced Gastric Adenocarcinoma (Inc. Adenocarcinoma of the Lower Third of the Oesophagus or the Gastro-Oesophageal Junction)With FGFR2 Polysomy or Gene Amplification.
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD4547 AZD4547 taken orally in tablet formation, 80mg b.d., in a 2 week on, 1 week off schedule	Drug: AZD4547; Tablets taken, oral, twice daily, commencing with a 2 week on AZD4547, 1 week off AZD4547 schedule.
Active Comparator: Paclitaxel Paclitaxel - 80mg/m² as a 1 hour infusion given weekly on days 1, 8 and 15 of a 28 day cycle (up to the maximum number of cycles per local practice)	Drug: paclitaxel; Infusion administered once a week, 3 weeks on and 1 week off

Outcome Measures

Primary Outcome Measures

1. Median Progression Free Survival [Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week)]

   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).

Secondary Outcome Measures

1. Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off) [Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week)]

2. Objective Response Rate [Week 8 (±1 week) and then every 8 weeks (±1 week)]

   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.

3. Percentage Change From Baseline at Week 8 in Target Lesion Size [Baseline, Week 8 (±1 week)]

   A negative change denotes a reduction in target lesion size. Percentage change from baseline in tumour size at 8 weeks in target lesion size.

4. Percentage of Patients Without Progressive Disease at 8 Weeks [Week 8 (±1 week)]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female or male aged 25 or over

• Histological diagnosis of locally advanced or metastatic gastro adenocarcinoma (including adenocarcinoma of the lower third of the oesophagus or the gastro oesophageal junction )

• Radiographically confirmed progression after 1 prior chemotherapy or chemoradiotherapy for gastric cancer. Suitable for and expected to benefit from paclitaxel monotherapy.

• At least one lesion, not previously irradiated, that has baseline at least 10mm in the longest diameter for non nodal lesions and is assessed by Computerised Tomography (CT) or Magnetic Resonance Imaging (MRI)

• Provision of either an archival tumour sample or a fresh tumour sample for confirmation of FGFR2 polysomy/gene amplification

Exclusion Criteria:

• Prior exposure to AZD4547 or history of hypersensitivity other drugs similar in structure or class to AZD4547. Hypersensitivity to paclitaxel or formulated in cremophor EL (polyoxyethylated castor oil)

• Prior taxane treatment for gastric cancer with the exception of adjuvant/neo-adjuvant therapy given > 6 months; Major surgery, radiotherapy with wide field of radiation or any cancer treatment within 4 weeks before the first dose of the study treatment

• With the exception of alopecia, any unresolved toxicities from prior therapy with a Common Terminology Criteria for AE (CTCAE) grade >1 at the time of starting study treatment.

• Blood and Echocardiogram (ECG) readings that are deemed to be abnormal by falling outside of the reference ranges in the protocol inclusion/exclusion section.

• Taking other regular medication that are predicted to interact with AZD4547 due to their route of metabolism.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Brussels (Anderlecht)		Belgium
2	Research Site	Brussels (Woluwé-St-Lambert)		Belgium
3	Research Site	Leuven		Belgium
4	Research Site	Liege		Belgium
5	Research Site	Plovdiv		Bulgaria
6	Research Site	Sofia		Bulgaria
7	Research Site	Vratza		Bulgaria
8	Research Site	Fredericton	New Brunswick	Canada
9	Research Site	Toronto	Ontario	Canada
10	Research Site	Brno		Czech Republic
11	Research Site	Olomouc		Czech Republic
12	Research Site	Praha 2		Czech Republic
13	Research Site	Saint Cloud		France
14	Research Site	Villejuif		France
15	Research Site	Hamburg		Germany
16	Research Site	Mainz		Germany
17	Research Site	Budapest		Hungary
18	Research Site	Debrecen		Hungary
19	Research Site	Nyíregyháza		Hungary
20	Research Site	Bangalore		India
21	Research Site	Chennai		India
22	Research Site	Hyderabad		India
23	Research Site	Nagpur		India
24	Research Site	Pune		India
25	Research Site	Vellore		India
26	Research Site	Ancona		Italy
27	Research Site	Milano		Italy
28	Research Site	Pisa		Italy
29	Research Site	Roma		Italy
30	Research Site	Chiba-shi		Japan
31	Research Site	Chuo-ku		Japan
32	Research Site	Koto-ku		Japan
33	Research Site	Nagoya-shi		Japan
34	Research Site	Sapporo-shi		Japan
35	Research Site	Takatsuki-shi		Japan
36	Research Site	Anyang-si		Korea, Republic of
37	Research Site	Daegu		Korea, Republic of
38	Research Site	Hwasun-gun		Korea, Republic of
39	Research Site	Jeonju-si		Korea, Republic of
40	Research Site	Seongnam-si		Korea, Republic of
41	Research Site	Seoul		Korea, Republic of
42	Research Site	Brasov		Romania
43	Research Site	Cluj Napoca		Romania
44	Research Site	A Coruña		Spain
45	Research Site	Barcelona		Spain
46	Research Site	Madrid		Spain
47	Research Site	Oviedo		Spain
48	Research Site	Santander		Spain
49	Research Site	Sevilla		Spain
50	Research Site	Keelung		Taiwan
51	Research Site	Taichung		Taiwan
52	Research Site	Taipei		Taiwan
53	Research Site	Taoyuan		Taiwan
54	Research Site	Kharkiv		Ukraine
55	Research Site	Lviv		Ukraine
56	Research Site	Aberdeen		United Kingdom
57	Research Site	London		United Kingdom
58	Research Site	Maidstone		United Kingdom
59	Research Site	Manchester		United Kingdom
60	Research Site	Sutton		United Kingdom
61	Research Site	Wolverhampton		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Paul Stockman, MD PHD, AstraZeneca
• Principal Investigator: Eric Van Cutsem, MD PHD, University Hospital, Gasthuisberg
• Principal Investigator: Yung-Jue Bang, MD, PHD, Seoul National University Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D2610C00004redacted_protocol

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01457846
• Other Study ID Numbers: D2610C00004
• First Posted: Oct 24, 2011
• Last Update Posted: Mar 7, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by AstraZeneca: gastro-oesophageal junction cancer; gastric cancer; lower third oesophageal cancer; polysomy; amplification; FGFR
• Additional relevant MeSH terms: Stomach Neoplasms; Paclitaxel

Study Results

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 Detail	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
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

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
Overall Participants	30	41	71
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (10.65)	60.6 (11.38)	61.2 (11.02)
Age, Customized (Number) [Number]
<50 years	4 13.3%	7 17.1%	11 15.5%
>=50 - < 65 years	13 43.3%	20 48.8%	33 46.5%
>= 65 years	13 43.3%	14 34.1%	27 38%
Gender (Count of 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 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
Measure Participants	41	30
Number [months]	1.8	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4547, Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9581
	Comments	1-sided
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 80%; 1.12 to 2.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off)
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
Measure Participants	38	30
Number [Patients]	27	18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4547, Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8156
	Comments	1-sided
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 80%; 0.89 to 1.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response Rate
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
Measure Participants	38	30
Number [Patients (%)]	2.6	23.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4547, Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9970
	Comments	1-sided
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 80%; 0.02 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

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. 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
Measure Participants	36	26
Mean (Standard Deviation) [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 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
Measure Participants	41	30
Number [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.
Arm/Group Title	AZD4547		Paclitaxel
Arm/Group Description	80mg BD 2 weeks on/1 week off		80mg / m^2
All Cause Mortality
	AZD4547		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AZD4547		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/40 (20%)		6/27 (22.2%)
Blood and lymphatic system disorders
Anaemia	1/40 (2.5%)	1	0/27 (0%)	0
Gastrointestinal disorders
Dyspepsia	1/40 (2.5%)	1	0/27 (0%)	0
Dysphagia	0/40 (0%)	0	1/27 (3.7%)	1
Intestinal haemorrhage	1/40 (2.5%)	1	0/27 (0%)	0
Obstruction gastric	1/40 (2.5%)	1	0/27 (0%)	0
Stomatitis	1/40 (2.5%)	1	0/27 (0%)	0
Vomiting	1/40 (2.5%)	1	2/27 (7.4%)	2
General disorders
Asthenia	0/40 (0%)	0	1/27 (3.7%)	1
Hepatobiliary disorders
Bile duct obstruction	1/40 (2.5%)	1	0/27 (0%)	0
Infections and infestations
Biliary tract infection	0/40 (0%)	0	1/27 (3.7%)	1
Lower respiratory tract infection	0/40 (0%)	0	1/27 (3.7%)	1
Pneumonia	1/40 (2.5%)	1	0/27 (0%)	0
Urinary tract infection	1/40 (2.5%)	1	0/27 (0%)	0
Investigations
Blood bilirubin increased	1/40 (2.5%)	1	0/27 (0%)	0
Transaminases increases	1/40 (2.5%)	1	0/27 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/40 (0%)	0	1/27 (3.7%)	1
Vascular disorders
Arterial disorder	1/40 (2.5%)	1	0/27 (0%)	0
Other (Not Including Serious) Adverse Events
	AZD4547		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/40 (97.5%)		26/27 (96.3%)
Blood and lymphatic system disorders
Anaemia	7/40 (17.5%)	7	6/27 (22.2%)	6
Neutropenia	2/40 (5%)	2	9/27 (33.3%)	9
Eye disorders
Detatchment of retinal pigment epithelium	6/40 (15%)	6	0/27 (0%)	0
Dry eye	4/40 (10%)	4	0/27 (0%)	0
Macular degeneration	2/40 (5%)	2	0/27 (0%)	0
Gastrointestinal disorders
Nausea	10/40 (25%)	10	6/27 (22.2%)	6
Vomiting	8/40 (20%)	8	5/27 (18.5%)	5
Stomatis	10/40 (25%)	10	2/27 (7.4%)	2
Abdominal pain upper	9/40 (22.5%)	9	0/27 (0%)	0
Dyspepsia	4/40 (10%)	4	1/27 (3.7%)	1
Dysphagia	0/40 (0%)	0	2/27 (7.4%)	2
Constipation	10/40 (25%)	10	5/27 (18.5%)	5
Abdominal pain	9/40 (22.5%)	9	5/27 (18.5%)	5
General disorders
Fatigue	6/40 (15%)	6	8/27 (29.6%)	8
Oedema peripheral	4/40 (10%)	4	2/27 (7.4%)	2
Asthenia	11/40 (27.5%)	11	5/27 (18.5%)	5
Pyrexia	4/40 (10%)	4	2/27 (7.4%)	2
Hepatobiliary disorders
Diarrhoea	6/40 (15%)	6	6/27 (22.2%)	6
Infections and infestations
Lower respiratory tract infection	0/40 (0%)	0	3/27 (11.1%)	3
Urinary tract infections	2/40 (5%)	2	2/27 (7.4%)	2
Investigations
Aspartate aminotransferase	7/40 (17.5%)	7	0/27 (0%)	0
Blood alkaline phosphatase increased	4/40 (10%)	4	1/27 (3.7%)	1
Blood phosphorus increased	3/40 (7.5%)	3	0/27 (0%)	0
Blood bilirubin increased	2/40 (5%)	2	0/27 (0%)	0
Alanine aminotransferase increased	6/40 (15%)	6	0/27 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	16/40 (40%)		8/27 (29.6%)
Dry mouth	9/40 (22.5%)	9	0/27 (0%)	0
Hyperkalaemia	2/40 (5%)	2	2/27 (7.4%)	2
Hyperphosphataemia	3/40 (7.5%)	3	0/27 (0%)	0
Hypokalaemia	1/40 (2.5%)	1	2/27 (7.4%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	3/40 (7.5%)	3	0/27 (0%)	0
Myalgia	0/40 (0%)	0	3/27 (11.1%)	3
Back pain	1/40 (2.5%)	1	6/27 (22.2%)	6
Nervous system disorders
Dizziness	3/40 (7.5%)	3	1/27 (3.7%)	1
Lethargy	1/40 (2.5%)	1	2/27 (7.4%)	2
Dysgeusia	6/40 (15%)	6	4/27 (14.8%)	4
Peripheral sensory neuropathy	0/40 (0%)	0	3/27 (11.1%)	3
Hypoaesthesia	0/40 (0%)	0	2/27 (7.4%)	2
Headache	4/40 (10%)	4	1/27 (3.7%)	1
Psychiatric disorders
Neuropathy peripheral	1/40 (2.5%)	1	4/27 (14.8%)	4
Insomnia	2/40 (5%)	2	3/27 (11.1%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/40 (7.5%)	3	1/27 (3.7%)	1
Dysphonia	2/40 (5%)	2	1/27 (3.7%)	1
Productive cough	0/40 (0%)	0	2/27 (7.4%)	2
Epistaxis	3/40 (7.5%)	3	1/27 (3.7%)	1
Skin and subcutaneous tissue disorders
Alopecia	2/40 (5%)	2	13/27 (48.1%)	13
Dry skin	3/40 (7.5%)	3	1/27 (3.7%)	1
Onychomadesis	3/40 (7.5%)	3	0/27 (0%)	0
Nail discolouration	2/40 (5%)	2	1/27 (3.7%)	1
Onycholysis	2/40 (5%)	2	0/27 (0%)	0
Pruritus	2/40 (5%)	2	1/27 (3.7%)	1

Limitations/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.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.