A Proof of Principle Study of Pembrolizumab With SBRT in TKI mRCC Patients

Official Title

A Phase II Proof of Principle Study of the Activity of Pembrolizumab (MK-3475) in Combination With SBRT in Primary Tyrosine Kinase Inhibitor (TKI) Refractory Metastatic Kidney Cancer (mRCC) Patients

Summary:

This study is designed as a phase-II proof of concept trial to investigate if a treatment strategy where stereotactic body radiation therapy (SBRT) is given with pembrolizumab is sufficiently active to warrant further investigation in randomized phase II or III studies. Metastatic renal cell cancer (mRCC) patients with PD-1 expressing immune cells are more likely to have larger more aggressive tumours and reduced survival and renal tumours that express PD-L1 are more aggressive with poorer outcome. Blocking this receptor/ligand interaction with monoclonal antibodies can restore the activity of tumour specific T-cells within the tumour with durable responses documented in early clinical trials in several tumour types including renal cell carcinoma. The study drug pembrolizumab is designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. SBRT will be given to the 1-3 most clinically significant lesions at the time of progression on pembrolizumab or at the 2nd course of pembrolizumab treatment in an effort to improve the activity of pembrolizumab. A total of 35 patients refractory to the approved first line therapy with a targeted drug (Sunitinib or Pazopanib) or untreated RCC patients with sarcomatoid differentiation will be enrolled on study. This group of patient has a poor outcome on any other 2nd line therapy and urgently need novel therapy.

Trial Description

Primary Outcome:

• Progression-free survival, as per irRC, for pembrolizumab, given with SBRT in metastatic RCC patients where progression is the best response to their first line therapy with a TKI, and in untreated patients with sarcomatoid differentiation.

Secondary Outcome:

• Overall survival
• Objective response rate by immune related response criteria (irRC), and RECIST 1.1 criteria
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.03

A phase II proof of concept, multi-centre, safety and efficacy study with a biomarker component to investigate if a treatment strategy where stereotactic body radiation therapy (SBRT) is given with pembrolizumab is sufficiently active to warrant further investigation in randomized phase II or III studies. The study will run for approximately 3 years, including 2 year of recruitment and 1 year of follow up. There will be two study arms. Enrollment of 15 patients into arm A will occur before the start of enrollment of the next 20 patients on arm B. In arm A, pembrolizumab will be started and SBRT will be given to the 1-3 most clinically significant lesions only at the time of progression on pembrolizumab. Pembrolizumab will be continued after progression to detect if the addition of SBRT leads to stability or response in progressing lesions. After SBRT, untreated measurable disease must remain to assess the activity of continued pembrolizumab. Pembrolizumab and SBRT will continue until progression as per immune related response criteria (irRC). This cohort of patients will allow us to more clearly understand if SBRT does play a part in improving progression free survival when given in combination with pembrolizumab. In arm B, pembrolizumab will be started and SBRT given before the 2nd course of pembrolizumab to the 1-3 most clinically significant lesions. After SBRT, untreated measurable disease must remain to assess the activity of pembrolizumab. The value of a treatment strategy that combines pembrolizumab and SBRT up-front is evaluated in this arm. Giving SBRT early to the most clinically significant cancer lesions may give pembrolizumab more time to work and may improve response by generating neo-antigens. Patients will remain on study until progression as per irRC, withdrawal of consent or if they meet any of the premature withdrawal/discontinuation criteria.

View this trial on ClinicalTrials.gov