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).
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objective radiological PD per RECIST 1.1 is assessed by the investigator, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
148
Tablets : 3 × 200 mg tablets once daily
Concentrate for solution for IV infusion : 1500 mg durvalumab every 4 weeks
Capsules : 2 x 25mg capsules once daily 4 weeks on, 2 weeks off
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.
Time frame: Approximately 28 months post first subject randomized
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Research Site
Boston, Massachusetts, United States
Research Site
New York, New York, United States
Research Site
Buenos Aires, Argentina
Research Site
CABA, Argentina
Research Site
Ciudad Autonoma Buenos Aires, Argentina
Research Site
Ciudad Autónoma Buenos Aires, Argentina
Research Site
Córdoba, Argentina
Research Site
La Plata, Argentina
Research Site
Rosario, Argentina
Research Site
San Miguel de Tucumán, Argentina
...and 129 more locations
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Approximately 28 months post first subject randomized