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.