Autophagy Inhibition to Augment Mammilian Target of Rapamycin (mTOR) Inhibition: A Phase I/II Trial of RAD001 and Hydroxychloroquine (HCQ) in Patients With Previously Treated Renal Cell Carcinoma

Metastatic Clear Cell Renal Cell Carcinoma Clinical Trial

Official title: Autophagy Inhibition to Augment Mammilian Target of Rapamycin (mTOR) Inhibition: A Phase I/II Trial of RAD001 and Hydroxychloroquine (HCQ) in Patients With Previously Treated Renal Cell Carcinoma

Status Completed

Clinical Trial Summary

This is an open labeled phase I dose escalation study of hydroxychloroquine (HCQ) and RAD001 in patients with advanced renal cell carcinoma followed by a Phase II trial of RAD001 with HCQ. The target population are patients with one to three prior treatments for advanced renal cell carcinoma. In the phase I portion a traditional 3+3 design will be used to determine the maximal tolerated dose and/or recommended phase II dose for HCQ in combination with RAD001 po 10 mg/day.

Clinical Trial Description

This protocol describes a multicenter phase I/II trial of RAD001 in combination with hydroxychloroquine (HCQ) (phase I anticipated n=6-12) with a 35 patient phase II trial in patients with previously treated (1-3 prior regimens) advanced renal cell carcinoma. The preclinical rationale for this combination is extensive, the safety of HCQ combination strategies has been established, and effective autophagy pharmacodynamics (PD), and pharmacokinetics (PK) assays are available to guide development. The practical advantage of combination with HCQ is that this drug is off patent, commercially available, and is investigational new drug (IND) exempt. The institutions involved have combined 11 clinical protocols open for accrual involving HCQ, so regulatory approval will be rapid. There are no competing HCQ protocols for advanced renal cell carcinoma. As described in the sample size justification we are setting a high threshold to consider RAD001 + HCQ active since there are many competitors and other potential rational combinations. The 35 patient sample size is designed as a 2 stage phase II trial that will guide the go/no-go decision regarding the conduct of a followup randomized study to definitively prove efficacy. The primary (6 month PFS) and secondary outcomes (response rate, toxicity rates, correlative endpoints) will be analyzed for the entire group, and for patient populations stratified by number of prior therapies. The phase I portion of this trial is anticipated to be short, based on our experience from other HCQ trials. As a safety measure we have included intermediate dose levels which will only be used if there are Dose Limiting Toxicities (DLTs). Since we have seen responses at lower doses of HCQ in other trials, and because frequently over months HCQ dose is lowered from Maximum Tolerated Dose (MTD) doses in many trials because of nausea and anorexia, we would like to have some data on renal cell patients treated at the lower dose levels. If there is activity demonstrated at lower doses, this would be informative for dose modification decisions in patients treated on the dose expansion. The patient population for this trial, including the phase I dose escalation portion is advanced renal cell carcinoma with 1-3 prior treatments. ;

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Metastatic Clear Cell Renal Cell Carcinoma

• NCT number: NCT01510119
• Study type: Interventional
• Source: Abramson Cancer Center of the University of Pennsylvania
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 2011
• Completion date: January 5, 2017