NCT05188118

Rapid Sequencing of Approved Therapies in Patients with Metastatic or Unresectable Clear Cell Renal Cell Carcinoma

A Pilot, Rapid Sequencing of First Line Cabozantinib, Ipilimumab and Nivolumab, and Lenvatinib and Everolimus in Patients with Metastatic or Unresectable Clear Cell Renal Cell Carcinoma

• Status: Recruiting
• Phase: EARLY_Phase 1
• Study type: Interventional
• Enrollment: 20 (estimated)
• Sponsor: Icahn School of Medicine at Mount Sinai · Academic / Other
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

Summary

This is a pilot, single-center, single-arm study where 20 patients with metastatic or unresectable clear cell renal cell carcinoma will receive same sequential treatment strategy (Cabozantinib for 12 weeks, then proceed with Ipilimumab plus Nivolumab immunotherapy x4 over 12 weeks, then subsequent therapies depending on treatment response for another 12 weeks \[Nivolumab for CR/PR/SD, Cabozantinib or Lenvatinib/Everolimus for PROG\]).

Detailed description

Multi-targeted tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors represent two systemic modalities that has improved outcomes in patient with metastatic clear cell renal cell carcinoma (ccRCC). However, as an increasing number of treatment approaches has been sequentially approved in the front line setting, the optimal treatment selection and sequence have yet to be clearly defined. First line combination immunotherapy with nivolumab (PD-1 inhibitor) plus ipilimumab (CTLA-4 Inhibitor) has demonstrated improved overall survival and patient quality of life compared to Sunitinib in patients with IMDC intermediate and poor risk disease, but the primary progression rate of 20% poses a concern. Comparatively, a number of TKI plus CPI combinations have demonstrated even higher response rates and lower rates of primary progression, however the higher rate of significant adverse events and non-improvement in patient quality of life compared to Sunitinib are areas of concern. Cabozantinib, a potent, multiple-receptor TKI targeting MET, vascular endothelial growth factor receptor (VEGFR), AXL, and RET), is currently approved for the first and second line treatment of advanced RCC. Importantly, AXL and other targets such as TYRO3 and MER have been implicated in promoting tumor-immune suppression, and preclinical studies and clinical observations on circulating immune suppressive cells and immune effector cells suggest that Cabozantinib promotes an immune-permissive environment through inhibition of immune-modulatory targets on immune cells. This presents an opportunity for synergistic effects from combining CPI treatment with Cabozantinib. The researchers hypothesize that a sequential approach of Cabozantinib treatment course followed by immediate Ipilimumab plus Nivolumab may retain synergistic effects seen with concurrent therapy with an improved safety profile. Although anti-angiogenesis TKI therapy is effective both as monotherapy or in combination with ICI, continuous use can lead to persistent side effects, potentially compromising patient's quality of life. Thus, a rapid sequential treatment approach may optimize the therapeutic effect and preserve patient quality of life. The rapidly-cycling treatment regimen contains three, separate, consecutive treatment modules, each lasting 12 weeks: 1. Cabozantinib; 2. Ipilimumab + Nivolumab; 3. Nivolumab or Cabozantinib or Lenvatinib plus Everolimus depending on the response to the first and second modules. Primary objective is to evaluate the overall response rate after treatment with Cabozantinib and Ipilimumab plus Nivolumab. Additional exploratory objective are to evaluate the safety of this rapid sequencing treatment, as well as correlation of tissue and blood based biomarkers at various times-points with clinical outcome measures.

Conditions

• Renal Cell Carcinoma

Interventions

Type	Name	Description
DRUG	Cabozantinib	60mg oral once daily for 12 weeks
DRUG	Ipilimumab	1mg/kg intravenous once every 3 weeks over 12 weeks
DRUG	Nivolumab	3mg/kg intravenous once every 3 weeks over 12 weeks, then 480mg once every 4 weeks after
DRUG	Lenvatinib	18mg oral once daily for 12 weeks
DRUG	Everolimus	5mg oral once daily for 12 weeks

Timeline

• Start date: 2023-02-15
• Primary completion: 2026-09-01
• Completion: 2026-12-01
• First posted: 2022-01-12
• Last updated: 2024-11-06

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study