A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer
In this Phase I/II clinical trial, we seek to pilot the addition of HCQ to the standard
front-line therapy of colorectal cancer, FOLFOX/bevacizumab. In toxicity terms, our previous
studies lead us to believe that full dose (800mg) of HCQ will be welltolerated in this
setting. By starting at 600 mg, we will ensure that the full dose is approached with an eye
to safety, and if needed, we will use the lower dose. Both doses achieve autophagy
inhibition in our current studies: for this reason, we are comfortable in including accrual
to both dose-levels to the Phase II endpoints. If results are particularly striking, we will
consider amending the study to expand accrual if the budget permits, but 25 patients permits
an adequate assessment of activity of a novel regimen. The correlative endpoints of this
trial are directed to the pharmacokinetics of HCQ, and pharmacodynamics of autophagy
inhibition. We are currently constructing a population pharmacokinetic model of HCQ based on
data from several ongoing trials, and the data from these patients will contribute to
refining the model. We will analyze both measured and modelpredicted indices for their
relationship to autophagy induction. Autophagy will be assessed as the accumulation of
autophagocytic vesicles in the PMNs of treated patients, together with the induction of the
expression of autophagyrelated proteins on western analysis, quantitated by densitometry. An
exploratory correlative endpoint is the induction of metabolic changes as measured by
18FDG-PET. Our mechanistic hypothesis in this work is that the addition of HCQ will lead to
a greater amount of cell death in the hypoxic regions of the tumor, that have increased as a
consequence of bevacizumab treatment. We will document the rates of metabolic response as a
consequence of treatment, as a therapeutic marker that may be related to the degree of
autophagy inhibition. Finally, since we have demonistrated the key role of JNK1 in the
induction of autophagy, we will analyze archival tumor materials to determine variability in
this marker, as a baseline for potential future trials.
Interventional
Endpoint Classification: Efficacy Study, Primary Purpose: Treatment
Response Rate
We will use response as the primary efficacy marker to investigate the relationship between changes in autophagy markers and SUVs and the efficacy of treatment.
Yes
Peter J. O'Dwyer, MD
Principal Investigator
Abramson Cancer Center of the University of Pennsylvania
United States: Institutional Review Board
UPCC 07210
NCT01206530
September 2010
September 2013
Name | Location |
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Abramson Cancer Center of the University of Pennsylvania | Philadelphia, Pennsylvania 19104-4283 |