Phase III ARISER
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. 20-40% of RCC patients have no evidence of metastases at the time of first diagnosis, but have a high risk of relapse after the surgical resection of the affected kidney. To date, there is no approved treatment for adjuvant therapy of ccRCC after surgery. The Phase III ARISER study with RENCAREX® in non-metastatic ccRCC was a clinical study with the objective of demonstrating safety and efficacy of a medical treatment to address this unmet medical need.
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The double-blind, placebo-controlled Phase III ARISER study (Adjuvant RENCAREX® Immunotherapy Phase III trial to Study Efficacy in non-metastatic RCC) assessed the effect of adjuvant treatment with RENCAREX® on disease-free survival and overall survival in RCC patients with a high risk of recurrence following surgery (nephrectomy). The study goals were to investigate the disease-free survival (the period of time between surgery and detection of metastases) and overall survival of all patients. Furthermore safety and tolerability of the treatment as well as patients’ quality of life were tested.
The ARISER trial recruited 864 patients from over 140 centres in 14 countries. Patients received a once-weekly infusion of RENCAREX® (50%) or placebo (50%) for 24 weeks. Those patients receiving the active drug (RENCAREX®) received a loading dose of 50 mg in week 1, and weekly doses of 20 mg during weeks 2-24.
The study enrolled patients with:
- Prior nephrectomy of primary renal cell carcinoma (RCC) with documented clear cell histology
- ECOG score of 0 or 1
- No evidence of macroscopic or microscopic residual disease
- Study entry no later than 12 weeks after surgery (randomisation).
In addition, patients had to show one of the following “High Risk” criteria:
- Tumour stages > T3aN0/NXM0
- Any tumour stage with N+ and M0
- Tumour stage T1b/T2N0/NXM0 and grading G3 (Fuhrman or any other nuclear grading system with at least 3 grades)
Patients were excluded from this study with:
- Prior chemotherapy/immune therapy/radiotherapy within the past 5 years
- Pre-exposure to murine or chimeric antibody
- Prior organ transplantation
- History of prior malignancies within the past 5 years, except for surgically cured non-melanoma skin cancer or cervical carcinoma in situ
- Any unrelated illness which can significantly jeopardise patients’ clinical status
The recruitment of the study was completed mid 2008, and the last patient finished the 24-week treatment in February 2009. In December 2007, the positive interim analysis for futility by the Independent Data Monitoring Committee (IDMC) after 100 relapses was published. During the course of the study, the recurrence rate decreased steadily, consequently the planned interim analysis based on 343 disease recurrences was further delayed.
In January 2011 the local trial centres reported over 340 recurrences, which started the process for the interim analysis of efficacy for RENCAREX®. In November 2011 the Independent Data Monitoring Committee (IDMC) recommended cancelling the planned interim analysis and performing the final DFS analysis. In February 2012 the FDA approved the protocol amendment for the pivotal Phase III ARISER trial with RENCAREX® and this was implemented in the trial centres. Central, independent radiologists analysed data from all 864 patients and the CRO then entered the blinded and quality-checked data in databases and performed the final DFS analysis.
In October 2012 the Independent Data Monitoring Committee (IDMC) recommended terminating the Phase III ARISER trial. The trial did not meet its primary endpoint. The analysis showed no improvement in median DFS (approximately 72 months) following RENCAREX® treatment compared with placebo.
WILEX AG and the service providers involved carried out intensive analyses of the unblinded data in the months that followed. These showed that there were no indications of errors or discrepancies within the study.
In February 2013, WILEX announced that the results of the subgroup analysis showed that RENCAREX® has a therapeutic effect in the subgroup of patients with a high CAIX score.
Analysis of the data confirmed that CAIX expression is a characteristic of ccRCC. However, the antigen density, as determined by the CAIX score, varies from patient to patient and evidently plays a key role in the efficacy of RENCAREX®. Subgroup analysis for all CAIX scores from 0.0 to 3.0 revealed that as the CAIX score increases, the more pronounced the RENCAREX® treatment effect becomes. A CAIX score of ≥ 2.6 resulted in a clinically and statistically significant treatment effect with median DFS increasing from 51.2 months in the placebo arm to 73.6 months in RENCAREX® patients (N=151; HR=0.54; p=0.02).
Further analyses confirmed this effect:
- Patients who had received at least eight consecutive administrations of study medication (week 1 to 8) and had no major protocol deviation were defined as the per protocol population. In these patients with a CAIX score ≥ 2.6 both the hazard ratio and the significance level (N=139; HR=0.51; p=0.007) improved even further.
- In patients under the age of 65 years RENCAREX® showed a clinically and statistically significant DFS with a CAIX score ≥ 2.0 (N=286; HR=0.60; p=0.01).
Treatment with RENCAREX® has an excellent safety profile and is well tolerated. Based on encouraging Phase III data for a specific subgroup of patients with a high CAIX score, attempts are being made to licence RENCAREX® to a partner for further development in adjuvant treatment of clear cell renal cell carcinoma.