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Dose:600 or 800 mg Route:PO daily Treatment Administration: Daily

Dose: 85mg/m2 Route: IV infusion over 2 hours Treatment Administration: Day 1

Dose: 400mg/m2 Route IV infusion over 2 hours Treatment Administration: Day 1

Dose: 400mg/m2 Route: IV bolus immediately following leucovorin Treatment Administration Day 1

5-fluorouracil

Dose: 2,400mg/m2 Route: IV continuous infusion over 46 hours immediately following bolus injection.

Treatment Administration: Days 1-2

Peter J. O'Dwyer, MD

In this Phase I/II clinical trial, the investigators seek to pilot the addition of hydroxychloroquine (HCQ) to the standard front-line therapy of colorectal cancer, FOLFOX/bevacizumab. In toxicity terms, the investigators previous studies lead them to believe that a full dose (800mg) of HCQ will be well-tolerated in this setting. By starting at 600 mg, the investigators will ensure that the full dose is approached with an eye to safety, and if needed, the investigators will use the lower dose. Both doses achieve autophagy inhibition in our current studies.

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.

FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer

A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer

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.

To evaluate the effects of baseline markers and treatment group on time to progression and survival, we will estimate propportional-hazards regression models. Time-to-event outcomes will be summarized with Kaplan-Meier survival curves.

Abramson Cancer Center at Penn Medicine

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer	NCT01206530	Rectal Cancer Colon Cancer Metastasis Adenocarcinoma	Hydroxychloroqu... Oxaliplatin Leucovorin 5-fluorouracil 5-fluorouracil Bevacizumab	18 Years -	Abramson Cancer Center at Penn Medicine
FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer	NCT01206530	Rectal Cancer Colon Cancer Metastasis Adenocarcinoma	Hydroxychloroqu... Oxaliplatin Leucovorin 5-fluorouracil 5-fluorouracil Bevacizumab	18 Years -	Abramson Cancer Center at Penn Medicine

Spots Global Cancer Trial Database for histologically documented