A Phase II Trial to Evaluate the Efficacy of AZD6094 (HMPL-504) in Patients With Papillary Renal Cell Carcinoma (PRCC)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02127710
• Collaborator: SCRI Development Innovations, LLC (Other)
• Enrollment: 111
• Locations: 23
• Arm: 1
• Actual Duration (Months): 71.7
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open-label, single-arm, multicentre, global, phase II study designed to evaluate the efficacy and safety of AZD6094 in patients with papillary renal cell carcinoma (PRCC) who are treatment naïve or previously treated.

An independent central pathology review of tumour samples will be used to confirm the diagnosis of PRCC of all patients enrolling. However, locally available pathology results confirming PRCC will be allowed for timely study entry.

Condition or Disease	Intervention/Treatment	Phase
Papillary Renal Cell Cancer	Drug: AZD6094	Phase 2

Detailed Description

The study will comprise two stages. In Stage 1 approximately 20 patients will be enrolled. This group is considered sufficient to provide preliminary assessment of the anti-tumour activity of AZD6094 in the form of non-binding futility analysis.

If ≤ 2 tumour responses are observed in the first 20 evaluable patients termination of the study will be considered taking into account the relevant molecular profile of the patients and additional information from related studies in the drug development programme.

All patients entering the study will take AZD6094 600 mg by mouth (PO) once daily (QD). Treatment will be given continuously.

Following the baseline assessment, efficacy will be assessed by objective tumour assessments every 6 weeks (±7 days), for the first 12 months and every 12 weeks thereafter until objective disease progression as defined by RECIST v1.1 There will be a data cut-off after all patients have completed at least 12 weeks of treatment with AZD6094 or withdrawn. The database will be locked and data analysis will be performed on this dataset.

Any patients still receiving study drug at the time of data cut-off will be able to continue to receive AZD6094 while deriving clinical benefit. Such patients will continue to be monitored for the occurrence of serious adverse events up to 28 days after the last dose of AZD6094.

After database lock (DBL) tumour assessments will be performed every 12 weeks (±7 days) until objective disease progression as defined by RECIST v1.1.

Patients discontinuing treatment due to documented disease progression will enter a survival follow-up period, where they will be followed for the initiation of subsequent anti-cancer therapies every 3 months until death, loss to follow-up or withdrawal of consent, whichever comes first.

Patients discontinuing treatment prior to documented disease progression will enter a progression-free survival follow-up period where they will continue to have disease assessments every 6 weeks (±7 days) for the first 12 months of follow-up and every 12 weeks thereafter until objective disease progression as defined by RECIST v1.1, death, loss to follow-up or withdrawal of consent, whichever comes first. After DBL, tumour assessments will be performed in the progression free survival patient population every 12 weeks (±7 days) until objective disease progression as defined by RECIST v1.1

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial to Evaluate the Efficacy of AZD6094 (HMPL-504) in Patients With Papillary Renal Cell Carcinoma (PRCC)
• Actual Study Start Date: Apr 30, 2014
• Actual Primary Completion Date: Apr 14, 2016
• Actual Study Completion Date: Apr 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD6094 600 mg daily continuously All patients entering the study will take AZD6094 600 mg by mouth (PO) once daily (QD). Treatment will be given continuously.	Drug: AZD6094; AZD6094 is a potent and selective small molecule mesenchymal epithelial transition (c-MET) kinase inhibitor.; Other Names: Savolitinib HMPL - 504

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (RECIST Version 1.1) [Up to 12 months]

   The primary outcome measure was Objective Response Rate (ORR), defined as the proportion of patients with either a complete response or a partial response by investigator assessment according to Response Evaluation Criteria for Solid Tumours (RECIST) v1.1.

2. Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Efficacy Analysis Set [12 Months]

   The primary outcome measure was ORR, defined as the proportion of patients with either a complete response or a partial response by investigator assessment according to RECIST v1.1.

3. Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Safety Analysis Set [12 Months]

   The primary outcome measure was ORR, defined as the proportion of patients with either a confirmed complete response/partial response by investigator assessment according to RECIST v1.1.

Secondary Outcome Measures

1. Progression Free Survival Stratified by c-MET Status in the Efficacy Analysis Set [Up to 12 months]

2. Overall Survival Stratified by c-MET Status in the Efficacy Analysis Set [Up to 12 months]

3. Progression Free Survival Stratified by c-MET Status in the Safety Analysis Set [Up to 12 months]

4. Overall Survival Stratified by c-MET Status in the Safety Analysis Set [Up to 12 months]

5. Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Efficacy Analysis Set [12 Weeks (at 12 weeks timepoint)]

   12 week summary for patients in the Efficacy analysis set, by MET status. The numbers of patients analysed represent the numbers evaluable at the 12 week timepoint.

6. Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Safety Analysis Set. [12 Weeks (at 12 week timepoint)]

   12 week summary for patients in the Safety analysis set by MET Status. The number of patients analysed represent the number of evaluable patients at the 12 week timepoint.

7. Duration of Response [Up to 12 months]

   Duration of Response is the time from the first documentation of confirmed complete response/partial response until the date of progression, or death in the absence of progression. There were 8 responders: one of whom subsequently progressed or died and seven of whom were still classified as responders at the time of data cut-off and were therefore censored. It was not possible to determine a median or 75th percentile.

8. Peak Plasma Concentration of AZD6094 Following Single Dose [24 Hours]

   The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

9. Time to Peak Plasma Concentration of AZD6094 After Single Dose [24 Hours]

   The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

10. Apparent Volume of Distribution of AZD6094 Following Single Dose [24 Hours]

    The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

11. Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose [24 Hours]

    The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

12. Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose (Time Zero to Last Measurement) [24 Hours]

    The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

13. Apparent Total Clearance of AZD6094 From Plasma After Single Dose [24 Hours]

    The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

14. Mean Residence Time of AZD6094 After Single Dose [24 Hours]

    The number of patients analysed represent the number of evaluable PK parameters for this endpoint.

15. Elimination Half-Life of AZD6094 After Single Dose [24 Hours]

    The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria

1. Provision of informed consent prior to any study specific procedures, sampling and analyses.

2. Histologically confirmed PRCC, which is locally advanced or metastatic.

3. Availability of an archival tumor sample or a pre-treatment fresh tumor sample for confirmation of PRCC by a central laboratory and other biomarker

4. Treatment naïve or have failed on previous treatment for PRCC. Previous treatments may include: targeted therapy (i.e. sunitinib, sorafenib, bevacizumab, pazopanib, temsirolimus, and everolimus), traditional immunotherapy (i.e. interferon-a, Interleukin-2), chemotherapy or a combination of chemoimmunotherapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. At least one lesion, not previously irradiated, and not chosen for a biopsy if performed during the screening period that can be accurately measured at baseline and which is suitable for accurate repeated measurements.

7. Adequate hematological function defined as:

8. Absolute neutrophil count ≥1500/μL

9. Haemoglobin ≥9 g/dL

10. Platelets ≥100,000/μL

11. Adequate liver function defined as:

12. Alanine aminotransferase and aspartate aminotransferase ≤2.5 x the upper limit of normal (ULN)

13. Total bilirubin ≤1.5 x ULN

14. Adequate renal function defined as glomerular filtration rate ≥ 40 mL/min,

15. Adequate coagulation parameters, defined as International Normalisation Ratio <1.5 x ULN or activated partial thromboplastin time <1.5 x ULN.

16. Patients with known tumor thrombus or deep vein thrombosis are eligible if stable on low molecular weight heparin for ≥4 weeks.

17. Females should be using adequate contraceptive measures should not be breast feeding, and must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential

18. Male patients should be willing to use barrier contraception, i.e. condoms.

19. Ability to swallow and retain oral medications.

20. Predicted life expectancy ≥12 weeks.

21. Aged at least 18 years.

22. Willingness and ability to comply with study and follow-up procedures.

23. Ability to understand the nature of this study and give written informed consent.

Exclusion criteria

1. Most recent chemotherapy, immunotherapy, chemo-immunotherapy, or investigational agents <21 days of the first dose of study treatment. Most recent targeted therapy <14 days of the first dose of study treatment.

2. Unresolved toxicities from any prior therapy greater than Common Terminology Criteria for Adverse Events Grade 1 at the time of starting study treatment with the exception of alopecia.

3. Prior or current treatment with a cMet inhibitor

4. Strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4), strong inhibitors of cytochrome P450 1A2 (CYP1A2), or CYP3A4 substrates with a narrow therapeutic range within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort)

5. Wide field radiotherapy (including therapeutic radioisotopes such as strontium-89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy

6. Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement.

7. Previously untreated brain metastases.

8. Current leptomeningeal metastases or spinal cord compression due to disease.

9. Acute or chronic liver or pancreatic disease.

10. Uncontrolled diabetes mellitus.

11. Gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy

12. Any of the following cardiac diseases currently or within the last 6 months:

13. Unstable angina pectoris

14. Congestive heart failure (New York Heart Association ≥ Grade 2)

15. Acute myocardial infarction

16. Stroke or transient ischemic attack

17. Inadequately controlled hypertension (i.e., systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg) (patients with values above these levels must have their blood pressure controlled with medication prior to starting treatment).

18. Mean resting correct QT interval (QTc) >470 msec obtained from triplicate electrocardiagrams

19. Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiograms, e.g. complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec.

20. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital or familial long QT syndrome or family history of unexplained sudden death under 40 years of age or any concomitant medications known to prolong QT interval.

21. Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin is allowed.

22. Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.

23. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.

24. Presence of other active cancers, or history of treatment for invasive cancer ≤5years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

25. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35294
2	Research Site	Duarte	California	United States	91010
3	Research Site	Palo Alto	California	United States	94305
4	Research Site	Fort Myers	Florida	United States	33916
5	Research Site	Chicago	Illinois	United States	60637
6	Research Site	Iowa City	Iowa	United States	52242
7	Research Site	Boston	Massachusetts	United States	02215
8	Research Site	Detroit	Michigan	United States	48201
9	Research Site	New York	New York	United States	10021
10	Research Site	Philadelphia	Pennsylvania	United States	19111
11	Research Site	Nashville	Tennessee	United States	37203
12	Research Site	Dallas	Texas	United States	75246
13	Research Site	Houston	Texas	United States	77030
14	Research Site	Calgary	Alberta	Canada	T2N 4N2
15	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
16	Research Site	Toronto	Ontario	Canada	M4N 3M5
17	Research Site	Toronto	Ontario	Canada	M5G 2M9
18	Research Site	Barcelona		Spain	08041
19	Research Site	Cambridge		United Kingdom	CB2 0QQ
20	Research Site	Glasgow		United Kingdom	G12 OYN
21	Research Site	London		United Kingdom	EC1M 6BQ
22	Research Site	London		United Kingdom	W1G 6AD
23	Research Site	Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

• AstraZeneca
• SCRI Development Innovations, LLC

Investigators

• Study Chair: Henrik-Tobias Arkenau, MD,PhD, Sarah Cannon Research Institute United Kingdom

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D5082c00002-revised-csp-3_Redacted

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02127710
• Other Study ID Numbers: D5082C00002; GU 111
• First Posted: May 1, 2014
• Last Update Posted: Apr 19, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by AstraZeneca: AZD6094; Savolitinib; Papillary Renal Cell Cancer
• Additional relevant MeSH terms: Carcinoma, Renal Cell

Study Results

Participant Flow

Recruitment Details	111 patients were enrolled; 109 patients received at least one dose of AZD6094 administered orally (po). Two patients withdrew prior to receiving any study drug. The study was conducted at 23 international sites in the United States, Canada, United Kingdom and Spain.
Pre-assignment Detail	All patients were required to provide an archived or fresh tumour sample at enrolment to confirm eligibility, and for performance of the c-MET biomarker analysis. c-MET biomarker results determined the subgroup placement for data analysis as follows: c-MET positive (n=46), c-MET negative (n=47), and c-MET unknown (n=16).

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Period Title: Overall Study
STARTED	46	47	16
COMPLETED	46	47	16
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]	Total
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.	Total of all reporting groups
Overall Participants	46	47	16	109
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	24 52.2%	26 55.3%	9 56.3%	59 54.1%
>=65 years	22 47.8%	21 44.7%	7 43.8%	50 45.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	64	61	64
Sex: Female, Male (Count of Participants)
Female	13 28.3%	11 23.4%	7 43.8%	31 28.4%
Male	33 71.7%	36 76.6%	9 56.3%	78 71.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 13%	6 12.8%	2 12.5%	14 12.8%
Not Hispanic or Latino	40 87%	41 87.2%	14 87.5%	95 87.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
ECOG Performance Status (Count of Participants)
PS=0	19 41.3%	25 53.2%	7 43.8%	51 46.8%
PS=1	27 58.7%	22 46.8%	9 56.3%	58 53.2%
PS=2	0 0%	0 0%	0 0%	0 0%
PS=3	0 0%	0 0%	0 0%	0 0%
PS=4	0 0%	0 0%	0 0%	0 0%
PRCC Confirmation from Central Laboratory (Count of Participants)
PRCC Not Confirmed	9 19.6%	7 14.9%	8 50%	24 22%
PRCC Confirmed	37 80.4%	40 85.1%	8 50%	85 78%
Stage Classification (Count of Participants)
Low	1 2.2%	4 8.5%	0 0%	5 4.6%
Intermediate	8 17.4%	12 25.5%	4 25%	24 22%
High	13 28.3%	15 31.9%	3 18.8%	31 28.4%
Missing	24 52.2%	16 34%	9 56.3%	49 45%
Renal Cell Classification (Count of Participants)
Type I PRCC	12 26.1%	2 4.3%	2 12.5%	16 14.7%
Type II PRCC	25 54.3%	38 80.9%	6 37.5%	69 63.3%
Unclassified PRCC	7 15.2%	5 10.6%	2 12.5%	14 12.8%
Other	0 0%	1 2.1%	1 6.3%	2 1.8%
Unknown	2 4.3%	1 2.1%	5 31.3%	8 7.3%
MSKCC Risk Group (Count of Participants)
Favourable Risk	3 6.5%	10 21.3%	2 12.5%	15 13.8%
Intermediate Risk	28 60.9%	14 29.8%	7 43.8%	49 45%
Poor Risk	3 6.5%	5 10.6%	2 12.5%	10 9.2%
Missing	12 26.1%	18 38.3%	5 31.3%	35 32.1%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	78.42 (20.74)	85.38 (23.84)	84.90 (12.55)	82.37 (21.32)
Weight (Kg) [Median (Full Range) ]
Median (Full Range) [Kg]	76.5	83.5	87.65	79.5

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (RECIST Version 1.1)
Description	The primary outcome measure was Objective Response Rate (ORR), defined as the proportion of patients with either a complete response or a partial response by investigator assessment according to Response Evaluation Criteria for Solid Tumours (RECIST) v1.1.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

ORR was assessed on the efficacy analysis set, consisting of all patients with measurable disease, PRCC confirmed by a central laboratory and have received at least 1 dose of AZD6094 (n = 85).

Arm/Group Title	Efficacy Analysis Set	Safety Analysis Set
Arm/Group Description	All patients with measurable disease, PRCC confirmed by central laboratory and received at least 1 dose of study medication	All patients who have received at least 1 dose of study medication
Measure Participants	85	109
Complete Response	0 0%	0 0%
Partial Response	3 6.5%	8 17%
Stable Disease >= 5 Weeks	46 100%	59 125.5%
Progression	34 73.9%	40 85.1%
Not Evaluable	2 4.3%	2 4.3%

2. Primary Outcome

Title	Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Efficacy Analysis Set
Description	The primary outcome measure was ORR, defined as the proportion of patients with either a complete response or a partial response by investigator assessment according to RECIST v1.1.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

ORR was assessed on the efficacy analysis set, consisting of all patients with measurable disease, PRCC confirmed by a central laboratory and received at least 1 dose of AZD6094 (n = 85).

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]	Total [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.	All participants tested for the presence of c-MET mutations
Measure Participants	37	40	8	85
Complete Response	0 0%	0 0%	0 0%	0 0%
Partial Response	3 6.5%	0 0%	0 0%	3 2.8%
Stable Disease >= 5 weeks	23 50%	19 40.4%	4 25%	46 42.2%
Progression	10 21.7%	20 42.6%	4 25%	34 31.2%
Not Evaluable	1 2.2%	1 2.1%	0 0%	2 1.8%

3. Primary Outcome

Title	Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Safety Analysis Set
Description	The primary outcome measure was ORR, defined as the proportion of patients with either a confirmed complete response/partial response by investigator assessment according to RECIST v1.1.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

ORR was assessed on the safety analysis set, consisting of all patients who received at least one dose of the study drug (n = 109).

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]	Total [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.	All participants tested for the presence of c-MET mutations
Measure Participants	46	47	16	109
Complete Response	0 0%	0 0%	0 0%	0 0%
Partial Response	8 17.4%	0 0%	0 0%	8 7.3%
Stable Disease >= 5 weeks	27 58.7%	21 44.7%	11 68.8%	59 54.1%
Progression	10 21.7%	25 53.2%	5 31.3%	40 36.7%
Not Evaluable	1 2.2%	1 2.1%	0 0%	2 1.8%

4. Secondary Outcome

Title	Progression Free Survival Stratified by c-MET Status in the Efficacy Analysis Set
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Measure Participants	37	40	8
Median (95% Confidence Interval) [Weeks]	18.3	9.7	6.1

5. Secondary Outcome

Title	Overall Survival Stratified by c-MET Status in the Efficacy Analysis Set
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Measure Participants	37	40	8
Median (95% Confidence Interval) [Weeks]	NA	61.1	51.5

6. Secondary Outcome

Title	Progression Free Survival Stratified by c-MET Status in the Safety Analysis Set
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Measure Participants	46	47	16
Median (95% Confidence Interval) [Weeks]	24.7	6.6	12.1

7. Secondary Outcome

Title	Overall Survival Stratified by c-MET Status in the Safety Analysis Set
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Measure Participants	46	47	16
Median (95% Confidence Interval) [Weeks]	NA	61.1	54.9

8. Secondary Outcome

Title	Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Efficacy Analysis Set
Description	12 week summary for patients in the Efficacy analysis set, by MET status. The numbers of patients analysed represent the numbers evaluable at the 12 week timepoint.
Time Frame	12 Weeks (at 12 weeks timepoint)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Measure Participants	22	14	1
Mean (Standard Deviation) [Percent change]	-6.3 (21.56)	3.4 (20.05)	7.1 (0)

9. Secondary Outcome

Title	Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Safety Analysis Set.
Description	12 week summary for patients in the Safety analysis set by MET Status. The number of patients analysed represent the number of evaluable patients at the 12 week timepoint.
Time Frame	12 Weeks (at 12 week timepoint)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	c-MET Positive [600mg AZD6094 po]	c-MET Negative [600mg AZD6094 po]	c-MET Status Unknown [600mg AZD6094 po]
Arm/Group Description	All participants tested for the presence of c-MET mutations	All participants were tested for the presence of c-MET mutations.	All participants were tested for the presence of c-MET mutations.
Measure Participants	30	16	6
Mean (Standard Deviation) [Percent change]	-10.9 (21.39)	4.3 (18.96)	5.1 (17.41)

10. Secondary Outcome

Title	Duration of Response
Description	Duration of Response is the time from the first documentation of confirmed complete response/partial response until the date of progression, or death in the absence of progression. There were 8 responders: one of whom subsequently progressed or died and seven of whom were still classified as responders at the time of data cut-off and were therefore censored. It was not possible to determine a median or 75th percentile.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Safety Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients who have received at least 1 dose of study medication
Measure Participants	109
Median (Inter-Quartile Range) [Weeks]	NA

11. Secondary Outcome

Title	Peak Plasma Concentration of AZD6094 Following Single Dose
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	53
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3038.8984 (44.4184)

12. Secondary Outcome

Title	Time to Peak Plasma Concentration of AZD6094 After Single Dose
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	53
Median (Full Range) [Hours]	2.0

13. Secondary Outcome

Title	Apparent Volume of Distribution of AZD6094 Following Single Dose
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	19
Mean (Standard Deviation) [Liters]	137.4237 (36.5971)

14. Secondary Outcome

Title	Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	19
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	13144.7381 (36.4328)

15. Secondary Outcome

Title	Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose (Time Zero to Last Measurement)
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	53
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	13214.2441 (46.4616)

16. Secondary Outcome

Title	Apparent Total Clearance of AZD6094 From Plasma After Single Dose
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	19
Mean (Standard Deviation) [L/hour]	48.4938 (17.3386)

17. Secondary Outcome

Title	Mean Residence Time of AZD6094 After Single Dose
Description	The number of patients analysed represent the number of evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	19
Mean (Standard Deviation) [Hours]	3.9837 (0.4813)

18. Secondary Outcome

Title	Elimination Half-Life of AZD6094 After Single Dose
Description	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Set [600mg AZD6094 po]
Arm/Group Description	All patients that received at least one dose of study medication and had evaluable PK data
Measure Participants	19
Mean (Standard Deviation) [Hours]	2.0499 (0.3820)

Adverse Events

Time Frame	Up to 12 months
Arm/Group Title	AZD6094 600 mg Per Day Orally
Arm/Group Description	All patients who received at least one dose of study medication
All Cause Mortality
	AZD6094 600 mg Per Day Orally
	Affected / at Risk (%)	# Events
Total	57/109 (52.3%)
Serious Adverse Events
	AZD6094 600 mg Per Day Orally
	Affected / at Risk (%)	# Events
Total	27/109 (24.8%)
Blood and lymphatic system disorders
Anaemia	3/109 (2.8%)
Cardiac disorders
Pericarditis	1/109 (0.9%)
Myocardial Infaction	1/109 (0.9%)
Endocrine disorders
Adrenal insufficiency	1/109 (0.9%)
Gastrointestinal disorders
Abdominal incarcerated hernia	1/109 (0.9%)
Abdominal pain	1/109 (0.9%)
Ascites	2/109 (1.8%)
Constipation	2/109 (1.8%)
Nausea	1/109 (0.9%)
Vomiting	1/109 (0.9%)
Small intestinal obstruction	1/109 (0.9%)
General disorders
Pain	1/109 (0.9%)
Oedema	1/109 (0.9%)
Hepatobiliary disorders
Cholecystitis	1/109 (0.9%)
Drug-induced Liver Injury	1/109 (0.9%)
Infections and infestations
Cellulitis	1/109 (0.9%)
Lung Infection	1/109 (0.9%)
Pneumonia	1/109 (0.9%)
Sepsis	1/109 (0.9%)
Urinary tract infection	1/109 (0.9%)
Wound infection	1/109 (0.9%)
Investigations
Transaminases increased	1/109 (0.9%)
Metabolism and nutrition disorders
Dehydration	1/109 (0.9%)
Hyperkalemia	1/109 (0.9%)
Hyponatraemia	1/109 (0.9%)
Musculoskeletal and connective tissue disorders
Flank pain	1/109 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer	1/109 (0.9%)
Nervous system disorders
Hepatic encephalopathy	1/109 (0.9%)
Loss of Consciousness	1/109 (0.9%)
Psychiatric disorders
Confusional state	1/109 (0.9%)
Renal and urinary disorders
Acute kidney injury	4/109 (3.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/109 (0.9%)
Pleural effusion	1/109 (0.9%)
Pneumonitis	1/109 (0.9%)
Pulmonary Embolism	1/109 (0.9%)
Vascular disorders
Embolism	1/109 (0.9%)
Other (Not Including Serious) Adverse Events
	AZD6094 600 mg Per Day Orally
	Affected / at Risk (%)	# Events
Total	107/109 (98.2%)
Blood and lymphatic system disorders
Anaemia	17/109 (15.6%)
Gastrointestinal disorders
Nausea	56/109 (51.4%)
Vomiting	34/109 (31.2%)
Constipation	29/109 (26.6%)
Diarrhoea	18/109 (16.5%)
Abdominal pain	9/109 (8.3%)
Abdominal distension	6/109 (5.5%)
Stomatitis	6/109 (5.5%)
Ascites	5/109 (4.6%)
General disorders
Fatigue	49/109 (45%)
Peripheral oedema	35/109 (32.1%)
Asthenia	8/109 (7.3%)
Oedema	8/109 (7.3%)
Chest pain	7/109 (6.4%)
Mucosal inflammation	6/109 (5.5%)
Pain	5/109 (4.6%)
Chills	5/109 (4.6%)
Pyrexia	5/109 (4.6%)
Investigations
Blood creatinine increased	18/109 (16.5%)
Aspartate aminotransferase increased	15/109 (13.8%)
Weight decreased	14/109 (12.8%)
Alanine aminotransferase increased	12/109 (11%)
Weight increased	8/109 (7.3%)
Blood alklaine phosphatase increased	7/109 (6.4%)
Metabolism and nutrition disorders
Decreased appetite	25/109 (22.9%)
Hypoalbuminaemia	13/109 (11.9%)
Hyperglycaemia	8/109 (7.3%)
Hyperkalaemia	7/109 (6.4%)
Hyponatremia	8/109 (7.3%)
Hypomagnesaemia	6/109 (5.5%)
Fluid retention	5/109 (4.6%)
Musculoskeletal and connective tissue disorders
Back pain	16/109 (14.7%)
Arthalgia	13/109 (11.9%)
Musculoskeletal chest pain	9/109 (8.3%)
Pain in extremity	11/109 (10.1%)
Flank pain	9/109 (8.3%)
Musculoskeletal pain	10/109 (9.2%)
Muscle spasm	7/109 (6.4%)
Myalgia	6/109 (5.5%)
Nervous system disorders
Dizziness	11/109 (10.1%)
Dysgeusia	9/109 (8.3%)
Headache	8/109 (7.3%)
Psychiatric disorders
Insomnia	5/109 (4.6%)
Renal and urinary disorders
Proteinuria	11/109 (10.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	16/109 (14.7%)
Cough	16/109 (14.7%)
Dyspnoea exertional	11/109 (10.1%)
Pleural Effusion	5/109 (4.6%)
Skin and subcutaneous tissue disorders
Pruritus	5/109 (4.6%)
Rash maculo-papular	5/109 (4.6%)
Vascular disorders
Hypertension	5/109 (4.6%)
Hypotension	5/109 (4.6%)

Limitations/Caveats

For the secondary outcome measure Duration of Response the median was not calculable because at data cut-off some participants were still responding. Point to note: All patients on this trial received 600mg AZD6094 po.

More Information

Certain Agreements

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

There is NOT 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.