Combined high dose radiation and pazopanib in metastatic renal cell carcinoma: a phase I dose escalation trial

Abstract

Background: The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment.

Methods: Treatment-naïve patients received pazopanib according to standard of care. Stereotactic body radiotherapy (SBRT) was delivered concurrently to the largest metastatic lesion at day 8, 10 and 12. SBRT doses were escalated in 3 dose levels (24 Gy/3, 30 Gy/3 and 36 Gy/3). Dose level was assigned using Time-to-Event Continual Reassessment Method with the target dose-limiting toxicity rate set to 0.25.

Results: Thirteen patients were included. One patient experienced dose limiting toxicity (DLT) at dose level 3 (grade 4 hypoglycemia). Maximum tolerated dose was not reached with a recommended dose of 36 Gy/3 having a probability of DLT of 11%. One-year local control was 83% (95% confidence interval 61-100) and 1-year progression-free survival was 28% (95% confidence interval 1-55).

Conclusions: SBRT in combination with pazopanib is well tolerated with good local control and response rates outside the radiation field.

Trial registration: This trial was retrospectively registered on clinicaltrials.gov( NCT02334709 ) on January 6th, 2015.

Keywords: Immune monitoring; Renal cell carcinoma; Stereotactic body radiotherapy; Tyrosine kinase inhibitors.

Conflict of interest statement

Ethics approval and consent to participate

This trial was approved by the Ethics committee of the Ghent University Hospital (EC2013/1087) and is registered on Participants were at all times fully informed about the trial process and purposes, and gave consent to their participation in the trial.

Consent for publication

Not applicable.

Competing interests

Financial support for the present study was provided by Novartis.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Local control of irradiated lesions and distant control of non-irradiated lesions. a: Greatest percentage change in irradiated tumor volume. Complete response, partial response, stable disease and disease progression were assessed as per RECIST 1.1 or as per MDA criteria for bone lesions. Two patients did not have any change in irradiated tumor volume. b: Greatest percentage change in tumor volume of non-irradiated target lesions. Complete response, partial response, stable disease or disease progression were assessed as per RECIST 1.1 or as per MDA criteria for bone lesions. Three patients did not have any change in non-irradiated target lesions, one patient had a decrease in non-irradiated tumor burden yet had progressive disease due to a new lesion (this is not added to the tumor burden calculation as per RECIST 1.1)

Fig. 2

Frequency of CD8+ and CD4+ lymphocytes during treatment. a: Boxplot comparing the frequency of CD8+ lymphocytes at baseline, before start of SBRT and at the first evaluation visit. b: Boxplot comparing the frequency of CD4+ lymphocytes at baseline, before start of SBRT and at the first evaluation visit

Fig. 3

Frequency of cells before the start of SBRT between good and bad responders. a Frequency of Memory Th17 cells, Naive Th17 cells and CD8+ lymphocytes before the start of SBRT in 1 bad responding study patient compared to 1 good responding study patient. b Boxplot comparing the frequency of Memory Th17 cells, Naive Th17 cells and CD8+ lymphocytes before start of SBRT between bad responding and good responding patients