Treatment Pause Versus Treatment Continuation in IMDC Good or Intermediate Risk With Only One Adverse Prognostic Factor in mRCC Patients With an Objective Response at 12 Months of Treatment With PD1/ PDL1 ICIs + VEGFR-Tyrosine Kinase Inhibitors

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the non-inferiority of treatment pause versus treatment continuation in good or intermediate risk with only one adverse prognostic factor as per IMDC mRCC patients with a confirmed objective response at 12 months of treatment with PD-1/PD-L1 ICI plus VEGFR-TKI. Tolerance and quality of life of treatment pause with PD-1/PD-L1 ICI + VEGFR-TKI compared to treatment continuation will be reported. In France, its impact on healthcare resource utilization will also be assessed.

Detailed Description
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Although multiple combinations therapies in particular PD-1/PD-L1 immune-checkpoint inhibitors (PD-1/PD-L1 ICIs) in combination with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are approved and have improved patient's outcomes with mRCC, they are maintained until disease progression and treatment pause after an objective response has not been fully explored [5-7]. The good-risk population is characterised by prolonged survival therefore a treatment pause in this population could impact the quality of life, safety and total cost of care, without impacting outcome. As well, intermediate risk population group is heterogeneous, while the one's with only one adverse prognostic factor seems to be closed to the outcome of good risk population [11-15]. As the purpose of the study is to target patients with an objective response, there is already a selection of patients with a better outcome. Patient will be randomised after 12 months of treatment with PD-1/PD-L1 ICI plus VEGFR-TKI (treatment pause versus treatment continuation) and follow every 3 months for a period of 12 months following by 12 additional months for survival follow-up.

Official Title
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SPICI: Strategic Treatment Pause of First-line Immune Check Point Inhibitor + VEGFR-Tyrosine Kinase Inhibitor in Good or Only One Adverse Prognostic Factor in Intermediate Risk Metastatic Renal Cell Carcinoma (mRCC) With an Objective Response: a Randomised, Non-inferiority Phase III Study

Conditions
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Metastatic Renal Cell Carcinoma, Good or Only One Adverse Prognostic Factor Intermediate Risk Per IMDC Score

Intervention / Treatment
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* Drug: Combination PD-1/PD-L1 ICI + VEGFR-TKI
* Other: Treatment pause


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at time of signing informed consent form Signed informed consent form Histological confirmation of RCC with a Clear-cell component, including subject who also have a sarcomatoïd feature Advanced (not amenable to curative surgery or radiation therapy) or Metastatic RCC (American Joint Committee on Cancer [AJCC] Stage IV) Participants with good or intermediate risk with only one adverse prognostic factor will be eligible as per International Metastatic RCC Database Consortium (IMDC) criteria Prior first line therapy for mRCC with the combination of PD-1/ PD-L1 ICI plus VEGFR-TKI First line treatment with the combination of PD-1/PD-L1 ICI and VEGFR-TKI must be ongoing whatever the dose with no period of discontinuation > 6 consecutive weeks in the last 12 months for the PD-1/PD-L1 ICI, and 2 consecutive weeks in the last 3 months before randomisation for the VEGFR-TKI Patients with an objective response (complete response or partial response) after 12 months of the combination treatment with PD-1/PD-L1 ICI and VEGFR-TKI. CT scan at the initiation of this treatment must be available. Karnofsky Performance Status (KPS) grade ≥ 70% Measurable disease as per RECIST v1.1 per investigator Adequate organ function Females of childbearing potential must use a highly effective contraception (combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral ; intravaginal ;transdermal) ; progestogen-only hormonal contraception associated with inhibition of ovulation (oral ; injectable ; implantable ; intrauterine device (IUD) ; intrauterine hormone-releasing system ( IUS)) ; bilateral tubal occlusion ; vasectomised partner ; sexual abstinence) and continue its use for 5 months after the last PD1/PD L1 ICI administration. Sexually active male patients must agree to use condoms and continue its use for 5 months after the last PD1/PD L1 ICI administration. Willingness and ability to comply with study procedures. Patient affiliated to a social security system or benefit from the same system Exclusion Criteria: Any active central nervous system (CNS) metastases Prior therapy with PD-1/PD-L1 ICI or VEGFR-TKI monotherapy. Poorly controlled hypertension despite antihypertensive therapy More than one adverse prognostic factor (IMDC criteria) Women who are pregnant or lactating; Current participation in an investigational program Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study Adults who are the subject of legal protection measures Persons deprived of their liberty by a judicial or administrative decision

Ages Eligible for Study
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Minimum Age: 18 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: Treatment pause<br>Treatment pause for 12 months | Other: Treatment pause<br>* Combination regimens discontinuation until progression with the possibility to resume initial combination regimens at progression<br>|
| Active Comparator: Treatment continuation<br>Treatment continuation regimens with PD-1/PD-L1 ICI + VEGFR-TKI until disease progression or unacceptable toxicity | Drug: Combination PD-1/PD-L1 ICI + VEGFR-TKI<br>* The study will enroll patients achieving an objective response after 12 months of treatment with the combination PD-1/PD-L1 ICI + VEGFR-TKI as recommended in the Summary of Product Characteristics (SmPC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants without progression | Disease progression at up to 12 months after randomisation will be based on a blinded independent central review (BICR) according to RECIST v1.1 criteria, with tumor assessment performed every 12 weeks during study participation | Up to 12 months after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall safety profile and tolerability event | Proportion of participants who experience an adverse event or serious adverse event and mean number of adverse events or serious adverse events up to 12 months after randomisation | Up to 12 months after randomisation | 
| Overall survival (OS) | OS is defined as the time between the date of randomisation and the date of death due to any cause | From randomisation until 2 years of follow-up | 
| Progression-free survival (PFS) | PFS is defined as the time between date of randomisation and the first date of the documented disease progression, or death due to any cause, whichever occurs first | From randomisation until 2 years of follow-up | 
| Mean change in quality of life | Measured by the NCCN functional assessment of cancer therapy-kidney symptom index (FKSI-19). The NCCN FKSI-19 is a 19-item scale that measures tumor specific health-related quality of life in kidney cancer participants. A higher score indicates fewer symptoms | Up to 12 months after randomisation | 
| Quality-adjusted survival | The quality-adjusted time without symptoms or toxicity (Q-TWiST) is a simultaneous assessment of time without toxicity or disease progression, which essentially examines the trade-off between AEs and treatment benefits | Up to 12 months after randomisation | 
| Anxiety and depression | Mean scores in the Hospital Anxiety and Depression Scale at up to 12 months after randomisation | Up to 12 months after randomisation | 
| Site and distribution of the sites of progression: known lesions, new lesion(s) or both |  | From randomisation until 2 years of follow-up | 
| Distribution of treatment modality after progression | Proportion of participants treated after progression with surveillance, focal treatment or general treatment | From randomisation until 2 years of follow-up | 
| Percentage of patients with status SD or in objective response at 6 months after restarting PD-1/PD-L1 ICI + VEGFR-TKI |  | From randomisation until 2 years of follow-up | 
| Healthcare resource utilisation | Costs of care will be estimated in the perspective of the French Healthcare System over a 12-month times horizon. Conventional tariffs of hospitalizations will be used to calculate costs | Up to 12 months after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic renal cell carcinoma (mRCC), Objective response, Treatment pause, Treatment continuation