Metastatic Adenocarcinoma clinical trials

A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer

In this Phase I/II clinical trial, the investigators seek to pilot the addition of Hydroxychloroquine (HCQ) to a commonly-used front-line therapy of pancreatic cancer, gemcitabine/nab-paclitaxel. The investigators plan a run-in to define tolerable doses, and will explore doses of 800 and 1200 mg/day in successive cohorts of 6 patients. The investigators will assess toxicity continuously, and determine the dose for the Phase II trial based on standard toxicity criteria. The correlative endpoints of this trial are directed to the pharmacokinetics of HCQ, and pharmacokinetic model of HCQ based on data from several ongoing trials, and the data from these patients will contribute to refining the model. The investigators will analyze both measured and model-predicted 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 autophagy-related proteins on western analysis, quantitated by densitometry. The investigators 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. Since the investigators have previously demonstrated a key role of JNK1 in the induction of autophagy by chemotherapy, the investigators will analyze archival tumor materials to determine variability in this marker, as a baseline for potential future trials. Finally, this study will incorporate metabolic profiling by mass spectrometry, which will be related to mutations (including Kras) in pretreatment tumor specimens. Mutational analysis will be accomplished by targeted sequencing or by next-generation sequencing, and the need for fresh tissue for all these endpoints will require patients to have a biopsy performed before treatment at at 6-8 weeks after beginning treatment. In the previous study of the Hh inhibitor GDC-0973 with the same chemotherapy, the investigators were able to obtain repeat biopsies successfully on all patients. The importance of these biopsies, to move the science forward in an era in which the tools now exist to provide meaningful correlative science, cannot be overstated.