Savolitinib Plus Durvalumab Versus Sunitinib and Durvalumab Monotherapy in MET-Driven, Unresectable and Locally Advanced or Metastatic PRCC

Study Overview
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Brief Summary
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A clinical trial to compare the effectiveness of savolitinib plus durvalumab versus sunitinib in MET-driven (hepatocyte growth factor receptor), unresectable and locally advanced or metastatic PRCC (Papillary Renal Cell Carcinoma)

Detailed Description
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This is a Phase III, randomised, open label, 3 arm, multi-centre, international study assessing the efficacy and safety of savolitinib plus durvalumab compared with sunitinib in participants with MET-driven (without co-occurring FH mutations), unresectable and locally advanced or metastatic PRCC, who have not received any prior systemic anti-cancer therapy in the metastatic setting. The study will also investigate the contribution of durvalumab to the savolitinib plus durvalumab combination. Approximately 200 participants will be randomised in a 2:1:1 ratio to one of the following intervention groups: savolitinib (600mg, oral, once daily) plus durvalumab (1500mg IV Q4W), sunitinib (50mg, oral, once daily for 4 consecutive weeks, followed by a sunitinib-free interval of 2-weeks, Q6W), or durvalumab monotherapy (1500mg IV Q4W). Participants will continue to receive study intervention until objective radiological PD per RECIST 1.1 is assessed by the investigator, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met. Depending on the preferred subsequent therapy, participants randomised to the durvalumab monotherapy arm will be eligible to switch to receive savolitinib in combination with durvalumab at the time of objective radiological PD assessed by BICR per RECIST 1.1, without any intervening systemic anti-cancer therapy following discontinuation of durvalumab monotherapy.

Official Title
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A Phase III, Open Label, Randomised, 3-Arm, Multi-Centre Study of Savolitinib Plus Durvalumab Versus Sunitinib and Durvalumab Monotherapy in MET-Driven, Unresectable and Locally Advanced or Metastatic Papillary Renal Cell Carcinoma (SAMETA)

Conditions
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Papillary Renal Cell Carcinoma

Intervention / Treatment
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* Drug: savolitinib
* Drug: durvalumab
* Drug: sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed unresectable and locally advanced or metastatic PRCC PRCC must be centrally confirmed as MET-driven using a sponsor-designated central laboratory validated NGS assay No prior systemic anti-cancer treatment in the metastatic setting; no prior exposure to MET inhibitors, Durvalumab or Sunitinib in any setting Karnofsky Score >70 At least one lesion, not previously irradiated, that can be accurately measured at baseline Adequate organ and bone marrow function Life expectancy ≥12weeks at Day 1 Exclusion Criteria: History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement, with or without normal LFTs Spinal cord compression or brain metastases, unless asymptomatic and stable on treatment for at least 14 days prior to study intervention Active or prior cardiac disease (within past 6 months) or clinically significant ECG abnormalities and/or factors/medications that may affect QT and/or QTc intervals Active infection including HIV, TB, HBV and HCV Active or prior documented autoimmune or inflammatory disorders Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>savolitinib 600mg plus durvalumab 1500mg | Drug: savolitinib<br>* Tablets : 3 × 200 mg tablets once daily<br>* Other names: AZD6094, HMPL-504, volitinib;Drug: durvalumab<br>* Concentrate for solution for IV infusion : 1500 mg durvalumab every 4 weeks<br>* Other names: MEDI4736;|
| Active Comparator: Arm B<br>sunitinib 50mg | Drug: sunitinib<br>* Capsules : 2 x 25mg capsules once daily 4 weeks on, 2 weeks off<br>* Other names: Sutent, SU11248;|
| Experimental: Arm C<br>durvalumab 1500mg | Drug: durvalumab<br>* Concentrate for solution for IV infusion : 1500 mg durvalumab every 4 weeks<br>* Other names: MEDI4736;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) /savolitinib plus durvalumab relative to sunitinib | Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The analysis will include all randomised participants as randomised, regardless of whether the participant withdraws from therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST 1.1 progression. | Approximately 28 months post first subject randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) /savolitinib plus durvalumab relative to sunitinib | Defined as time from randomisation until the date of death due to any cause. The comparison will include all randomised participants as randomised regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy. | Approximately 28 months and approximately 42 months post first subject randomized | 
| Objective Response Rate (ORR) / savolitinib plus durvalumab relative to sunitinib | Defined as the proportion of participants who have a Complete Response (CR) or Partial Response (PR) as determined by BICR per RECIST 1.1. | Approximately 28 months post first subject randomized | 
| Duration of Response (DoR) / savolitinib plus durvalumab relative to sunitinib | Defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by BICR or death due to any cause. | Approximately 28 months post first subject randomized | 
| Disease Control Rate (DCR) at 24 and 48 weeks /savolitinib plus durvalumab relative to sunitinib | Defined as the percentage of participants who have a CR or PR or who have Stable Disease (SD) per RECIST 1.1 as assessed by BICR for at least 23 or 47 weeks, respectively after randomisation. | Approximately 28 months post first subject randomized | 
| Time from randomisation to second progression or death (PFS2) /savolitinib plus durvalumab relative to sunitinib | Defined as time from randomisation to the earliest of the progression event (following the initial progression), subsequent to the first subsequent therapy or death. | Approximately 28 months and 42 months post first subject randomized | 
| Assessment of patient-reported symptoms, functioning, and HRQoL /savolitinib plus durvalumab relative to sunitinib | Time to deterioration and change from baseline in symptoms, functioning, and HRQoL as measured by FKSI-19. | Approximately 28 months post first subject randomized | 
| Objective Response Rate (ORR) / savolitinib plus durvalumab relative to durvalumab monotherapy | Defined as the proportion of participants who have a Complete Response (CR) or Partial Response (PR) as determined by BICR per RECIST 1.1 | Approximately 28 months post first subject randomized | 
| Duration of Response (DoR) / savolitinib plus durvalumab relative to durvalumab monotherapy | Defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by BICR or death due to any cause. | Approximately 28 months post first subject randomized | 
| Progression-Free Survival (PFS) /savolitinib plus durvalumab relative to durvalumab monotherapy | Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The analysis will include all randomised participants as randomised, regardless of whether the participant withdraws from therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST 1.1 progression. | Approximately 28 months post first subject randomized | 
| Evaluation of the PK of savolitinib pre-dose | Plasma concentration of savolitinib and its metabolites pre-dose (Ctrough / trough plasma concentration : measured concentration at the end of a dosing interval at steady state [taken directly before next administration]) in participants randomised to savolitinib plus durvalumab. | Approximately 28 months post first subject randomized | 
| Evaluation of the PK of savolitinib post-dose | Plasma concentration of savolitinib and its metabolites post-dose (C1h and C3h) in participants randomised to savolitinib plus durvalumab. | Approximately 28 months post first subject randomized | 
| Evaluation of the PK of durvalumab pre-dose | Serum concentration of durvalumab pre-dose (Ctrough / trough plasma concentration : measured concentration at the end of a dosing interval at steady state [taken directly before next administration]) in participants randomised to savolitinib plus durvalumab or durvalumab monotherapy. | Approximately 28 months post first subject randomized | 
| Evaluation of the PK of durvalumab / Cmax (maximum plasma concentration) | Serum concentration of durvalumab at the end of infusion (Cmax) in participants randomised to savolitinib plus durvalumab or durvalumab monotherapy. | Approximately 28 months post first subject randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cell, Locally, Advanced, Metastatic, Carcinoma, Savolitinib, Sunitinib, Durvalumab, MET Driven, Papillary Renal Cell Carcinoma