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

• ClinicalTrials.gov Identifier: NCT02127710
• Recruitment Status: Completed
• First Posted: May 1, 2014
• Results First Posted: October 12, 2017
• Last Update Posted: April 19, 2021
• Sponsor: AstraZeneca
• Collaborator: SCRI Development Innovations, LLC
• Information provided by (Responsible Party): AstraZeneca

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v1.1 There will be a data cut-off after all patients have completed at least 12 weeks of treatment with AZD6094 or withdrawn.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 (Clinical Trial)
• 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: April 30, 2014
• Actual Primary Completion Date: April 14, 2016
• Actual Study Completion Date: April 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 12 months ]
2. Overall Survival Stratified by c-MET Status in the Efficacy Analysis Set [ Time Frame: Up to 12 months ]
3. Progression Free Survival Stratified by c-MET Status in the Safety Analysis Set [ Time Frame: Up to 12 months ]
4. Overall Survival Stratified by c-MET Status in the Safety Analysis Set [ Time Frame: Up to 12 months ]
5. Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Efficacy Analysis Set [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 24 Hours ]
    The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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:

   1. Absolute neutrophil count ≥1500/μL
   2. Haemoglobin ≥9 g/dL
   3. Platelets ≥100,000/μL

8. Adequate liver function defined as:

   1. Alanine aminotransferase and aspartate aminotransferase ≤2.5 x the upper limit of normal (ULN)
   2. Total bilirubin ≤1.5 x ULN
9. Adequate renal function defined as glomerular filtration rate ≥ 40 mL/min,
10. Adequate coagulation parameters, defined as International Normalisation Ratio <1.5 x ULN or activated partial thromboplastin time <1.5 x ULN.
11. Patients with known tumor thrombus or deep vein thrombosis are eligible if stable on low molecular weight heparin for ≥4 weeks.
12. 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
13. Male patients should be willing to use barrier contraception, i.e. condoms.
14. Ability to swallow and retain oral medications.
15. Predicted life expectancy ≥12 weeks.
16. Aged at least 18 years.
17. Willingness and ability to comply with study and follow-up procedures.
18. 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:

    1. Unstable angina pectoris
    2. Congestive heart failure (New York Heart Association ≥ Grade 2)
    3. Acute myocardial infarction
    4. Stroke or transient ischemic attack
13. 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).
14. Mean resting correct QT interval (QTc) >470 msec obtained from triplicate electrocardiagrams
15. 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.
16. 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.
17. Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin is allowed.
18. 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.
19. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.
20. 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.
21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Contacts and Locations

Locations

United States, Alabama

Research Site

Birmingham, Alabama, United States, 35294

United States, California

Research Site

Duarte, California, United States, 91010

Research Site

Palo Alto, California, United States, 94305

United States, Florida

Research Site

Fort Myers, Florida, United States, 33916

United States, Illinois

Research Site

Chicago, Illinois, United States, 60637

United States, Iowa

Research Site

Iowa City, Iowa, United States, 52242

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02215

United States, Michigan

Research Site

Detroit, Michigan, United States, 48201

United States, New York

Research Site

New York, New York, United States, 10021

United States, Pennsylvania

Research Site

Philadelphia, Pennsylvania, United States, 19111

United States, Tennessee

Research Site

Nashville, Tennessee, United States, 37203

United States, Texas

Research Site

Dallas, Texas, United States, 75246

Research Site

Houston, Texas, United States, 77030

Canada, Alberta

Research Site

Calgary, Alberta, Canada, T2N 4N2

Research Site

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

Research Site

Toronto, Ontario, Canada, M4N 3M5

Research Site

Toronto, Ontario, Canada, M5G 2M9

Spain

Research Site

Barcelona, Spain, 08041

United Kingdom

Research Site

Cambridge, United Kingdom, CB2 0QQ

Research Site

Glasgow, United Kingdom, G12 OYN

Research Site

London, United Kingdom, EC1M 6BQ

Research Site

London, United Kingdom, W1G 6AD

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

More Information

Additional Information:

D5082c00002-revised-csp-3_Redacted 

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02127710
• Other Study ID Numbers: D5082C00002; GU 111 ( Other Identifier: Sarah Cannon Research Institute (SCRI) )
• First Posted: May 1, 2014
• Results First Posted: October 12, 2017
• Last Update Posted: April 19, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

Keywords provided by AstraZeneca:

AZD6094; Savolitinib; Papillary Renal Cell Cancer

Additional relevant MeSH terms:

Carcinoma, Renal Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases