A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients

Abstract

Purpose: We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel.

Patients and methods: Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines.

Results: Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). Overall survival (P = 0.59) and relapse-free survival (P = 0.55) did not differ between the two arms.

Conclusions: The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity.

Figure 1.. Consort diagram.

Patients were randomized to receive nab-paclitaxel and gemcitabine with hydroxychloroquine (PGH; 52 patients) or without hydroxychloroquine (PG; 46 patients). A total of 34 PGH and 30 PG patients successfully completed the regimen and were taken to operation for resection of pancreatic cancer. Abbreviations: AE, adverse event; HCQ, hydroxychloroquine; OOW, out of window; PD, progressed disease; PDA, pancreatic ductal adenocarcinoma

Figure 2.. Evans grade response in resected patients.

The primary endpoint for this trial was the evaluation of the Evans grade pathologic response by a blinded expert pancreatic pathologist. Patients receiving chemotherapy and hydroxychloroquine (PGH) demonstrated a statistically significant better pathologic response than those receiving chemotherapy alone (PG). The P value is from Fisher’s exact test.

Figure 3.. Pre- and posttreatment CA 19-9 levels by treatment arm and Evans grade response.

A) Pre-treatment CA 19-9 levels; B) Post-treatment CA 19-9 levels; C) Ratio between post-treatment and pre-treatment CA 19-9 levels. D) Correlation of CA19-9 response to Evan’s grade. The P values are from Wilcoxon tests.

Figure 4.. Decrease in CA 19-9 and link to overall and recurrence-free survival.

Those patients with greater than the median decrease in CA 19-9 demonstrated improved overall survival but not recurrence-free survival. Those patients who normalized their CA19-9 with treatment had both better OS and RFS.

Figure 5.. Tumor immune infiltration score correlates with overall survival.

All resected tumors were evaluated for tumor immune infiltration index. A tumor infiltration index of greater than 0 was positively correlated with recurrence-free survival and overall survival.