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

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.

Study Overview

• Status: Completed
• Conditions: Papillary Renal Cell Cancer
• Intervention / Treatment: Drug: AZD6094

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v1.1 There will be a data cut-off after all patients have completed at least 12 weeks of treatment with AZD6094 or withdrawn.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 Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Research Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Research Site
• Spain
  • Barcelona, Spain, 08041
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Research Site
  • Glasgow, United Kingdom, G12 OYN
    • Research Site
  • London, United Kingdom, W1G 6AD
    • Research Site
  • London, United Kingdom, EC1M 6BQ
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Research Site
  • California
    • Duarte, California, United States, 91010
      • Research Site
    • Palo Alto, California, United States, 94305
      • Research Site
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Research Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Research Site
  • New York
    • New York, New York, United States, 10021
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (RECIST Version 1.1)	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.	Up to 12 months
Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Efficacy Analysis Set	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.	12 Months
Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Safety Analysis Set	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.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival Stratified by c-MET Status in the Efficacy Analysis Set		Up to 12 months
Overall Survival Stratified by c-MET Status in the Efficacy Analysis Set		Up to 12 months
Progression Free Survival Stratified by c-MET Status in the Safety Analysis Set		Up to 12 months
Overall Survival Stratified by c-MET Status in the Safety Analysis Set		Up to 12 months
Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Efficacy Analysis Set	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.	12 Weeks (at 12 weeks timepoint)
Change From Baseline in Target Lesion Tumour Size at 12 Weeks in Safety Analysis Set.	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.	12 Weeks (at 12 week timepoint)
Duration of Response	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.	Up to 12 months
Peak Plasma Concentration of AZD6094 Following Single Dose	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours
Time to Peak Plasma Concentration of AZD6094 After Single Dose	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours
Apparent Volume of Distribution of AZD6094 Following Single Dose	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours
Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours
Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose (Time Zero to Last Measurement)	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours
Apparent Total Clearance of AZD6094 From Plasma After Single Dose	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours
Mean Residence Time of AZD6094 After Single Dose	The number of patients analysed represent the number of evaluable PK parameters for this endpoint.	24 Hours
Elimination Half-Life of AZD6094 After Single Dose	The number of patients analysed represent the number of patients with evaluable PK parameters for this endpoint.	24 Hours

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: SCRI Development Innovations, LLC
• Investigators: Study Chair: Henrik-Tobias Arkenau, MD,PhD, Sarah Cannon Research Institute United Kingdom

Publications and helpful links

Helpful Links

• D5082c00002-revised-csp-3_Redacted

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2014
• Primary Completion (Actual): April 14, 2016
• Study Completion (Actual): April 20, 2020

Study Registration Dates

• First Submitted: April 23, 2014
• First Submitted That Met QC Criteria: April 28, 2014
• First Posted (Estimate): May 1, 2014

Study Record Updates

• Last Update Posted (Actual): April 19, 2021
• Last Update Submitted That Met QC Criteria: March 23, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Savolitinib; AZD6094; Papillary Renal Cell Cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell
• Other Study ID Numbers: D5082C00002; GU 111 (Other Identifier: Sarah Cannon Research Institute (SCRI))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP