Autophagy Inhibition to Augment mTOR Inhibition: A Phase I/II Trial of RAD001 and Hydroxychloroquine in Patients With Previously Treated Renal Cell Carcinoma
This protocol describes a multicenter phase I/II trial of RAD001 in combination with 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 PD, and 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 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.
Interventional
Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment
PFS
6 months
Yes
United States: Food and Drug Administration
UPCC 07811
NCT01510119
September 2011
September 2014
Name | Location |
---|---|
Abramson Cancer Center of the University of Pennsylvania | Philadelphia, Pennsylvania 19104-4283 |