Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

Metastatic Cancer Clinical Trial

Official title: A Phase I/II Study to Evaluate the Safety, Pharmacodynamics and Efficacy of Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

Status Suspended

Clinical Trial Summary

This study will assess the immunomodulatory activity of entinostat in patients with advanced renal cell carcinoma receiving the PD-L1 inhibitor atezolizumab. The overall hypothesis is that entinostat will increase the immune response and anti-tumor effect induced by the PD-L1 inhibition by suppressing Treg function. We have chosen renal cell carcinoma that has been reported to respond to PD1/PD-L 1 inhibition. The schedule of entinostat is based on our previous experience with this agent. Based on our working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs but not on T effector cells, the starting dose of entinostat will be 1 mg and will be escalated up to 5 mg rather than the 10 mg dose. The combination also with bevacizumab will provide an effective VEGF inhibition that may potentiate the immune response and anti-tumor effect induced by atezolizumab. The proposed dose and schedule for atezolizumab and bevacizumab has been shown to be well tolerated in prior Phase/I/II studies and is currently tested in a Phase III randomized study in patients with renal cell carcinoma with sunitinib as a control arm. The highest proposed dose level for entinostat (5 mg) represents 50% of the recommended Phase II dose for this compound as a single agent.

Clinical Trial Description

This is a Phase l/II, open-label, safety, pharmacodynamics and efficacy study of atezolizumab in combination with entinostat and bevacizumab in patients with advanced renal cell carcinoma. This clinical study will be composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion.

In Phase 1 Combination Phase), patients will be treated with oral entinostat every 7 days, with bevacizumab at the fixed dose of 15 mg/kg IV every 3 weeks and with atezolizumab at the fixed dose of 1200 mg IV every 3 weeks. Each cycle length is 21 days. Three dose levels of entinostat will be tested in 3-design patient cohorts according to the 3 + 3 standard design (1 mg, 3 mg and 5 mg). For the Dose Finding Phase, the starting dose level of pill be 1 mg by mouth every 7 days. The first dose level will have a minimum of 3 patients treated (unless the first 2 patients experience DLT(s) before the 3rd patient is enrolled). DLTs attributable to entinostat and/or bevacizumab and/or atezolizumab will be evaluated during the first 21 days of the combination treatment.

If a DLT occurs in 1 patient treated at the starting dose level, a minimum of 3 additional patients will be treated at this dose level. If DLTs occur in 2 or more of the first 6 patients, the study will be terminated. If a DLT occurs in 1 out of 6 patients, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the starting dose level 1, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the dose level 2, 3 additional patients will be treated at the next dose level (level 3). If no DLTs occur at dose level 3, this dose level will be recommended for the Phase II portion of the study. Patients who experience Grade ≥ 3 toxicity and recover to ≤ Grade 1 (or to pretreatment baseline level toxicity) may continue treatment at the next lower level. The Phase II Dose will be RP2D of entinostat (i.e., the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor-Investigator).

Once the RP2D is identified, the Phase II portion (Simon's two stage design) will be opened. During Phase II, Cohorts A and B will have a Run-In period with entinostat for one cycle followed by atezolizumab and bevacizumab for the second cycle, and then the Combination Phase. The reason for the Run-In period is to obtain data on the immunomodulatory effects of entinostat separately from bevacizumab and atezolizumab. The run-in period will be optional for patients, including those who are rapidly progressing, or if it is in the patient's best interest clinically as determined by the treating physician's discretion. In Stage I, 27 patients with prior treatments will be enrolled in two Phase II cohorts: 18 treatment naïve (anti-PD1/PDL1 naïve) patients (Cohort A), and 9 anti-PD1 resistant (defined as patients who have been on PD1 inhibitors for at least 3 months and have progressed by either clinical or radiographic assessment) patients (Cohort B). If ≥ 5 responses are observed and confirmed in Cohort A, Stage II will be conducted with 15 additional patients. In Cohort B, if any patients has a response that is observed and confirmed, Stage II will be conducted with 7 additional patients. Patients will be treated on Cohort B with the same combination therapy as in Cohort A.

Cohort B is a pilot arm which aims to test atezolizumab in anti-PD1 resistant patients. If there is no response to atezolizumab, then the RP2D dose of entinostat will be added to the standard dose of atezolizumab. If there is a response to atezolizumab, patients will continue to be treated with atezolizumab alone.

The RP2D is the dose of entinostat, atezolizumab, and bevacizumab in combination chosen for further clinical development. Further experience in the Dose Expansion Cohort may result in a RP2D dose lower than the MTD.

Objectives:

1. Primary Phase I: To assess the safety and tolerability of atezolizumab in combination with entinostat and bevacizumab in patients with advanced renal cell carcinoma.

2. Primary Phase II: To assess the objective response rate of atezolizumab in combination with entinostat and bevacizumab in anti-PD 1 naïve patients and atezolizumab in combination with entinostat in anti-PD 1 resistant patients with advanced renal cell carcinoma.

3. Secondary: To assess the objective response rate (Phase I only), progression-free survival and overall survival.

4. Correlative: To characterize PD-L1/2, immune cell subsets, and miRs in tumor and/or blood in correlation with response. ;

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Kidney Neoplasms
• Metastatic Cancer
• Renal Cancer

• NCT number: NCT03024437
• Study type: Interventional
• Source: Indiana University
• Status: Suspended
• Phase: Phase 1/Phase 2
• Start date: June 29, 2017
• Completion date: June 30, 2024