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Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma.

ABSTRACT: Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice.Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg (n = 10) or 600 mg (n = 10) twice daily. The primary endpoint was 2-month progression-free survival (PFS). We analyzed peripheral lymphocytes from treated mice to identify pharmacodynamic markers of autophagy inhibition that were then assessed in peripheral lymphocytes from patients.Among 20 patients enrolled, 2 (10%) were without progressive disease at 2 months. Median PFS and overall survival were 46.5 and 69.0 days, respectively. Treatment-related grade 3/4 adverse events were lymphopenia (n = 1) and elevated alanine aminotransferase (n = 1). Tolerability and efficacy were similar at the two dose levels. Analysis of treated murine lymphocytes suggested that LC3-II expression by Western blot is a reliable marker for autophagy inhibition. Analysis of LC3-II in patient lymphocytes demonstrated inconsistent autophagy inhibition.Mouse studies identified LC3-II levels in peripheral lymphocytes as a potential pharmacodynamic marker of autophagy inhibition. In patients with previously treated metastatic pancreatic cancer, HCQ monotherapy achieved inconsistent autophagy inhibition and demonstrated negligible therapeutic efficacy.

SUBMITTER: Wolpin BM

PROVIDER: S-EPMC4041680 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma.

Wolpin Brian M BM Rubinson Douglas A DA Wang Xiaoxu X Chan Jennifer A JA Cleary James M JM Enzinger Peter C PC Fuchs Charles S CS McCleary Nadine J NJ Meyerhardt Jeffrey A JA Ng Kimmie K Schrag Deborah D Sikora Allison L AL Spicer Beverly A BA Killion Leah L Mamon Harvey H Kimmelman Alec C AC

The oncologist 20140512 6

<h4>Background</h4>Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice.<h4>Methods</h4>Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg (n = 10) or 600 mg (n = 10) twice daily. T ...[more]

PMID: 24821822

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Project description:BACKGROUND:Combination chemotherapy regimens including fluoropyrimidines as well as albumin-bound paclitaxel have shown promising results in patients with metastatic pancreatic adenocarcinoma (mPC). Based on the recently described excellent therapeutic index of capecitabine plus nab-paclitaxel in metastatic breast cancer, the present phase II trial was initiated. METHODS:Patients with previously untreated mPC were treated with capecitabine (825 mg/m(2) orally bid on days 1-15) and nab-paclitaxel (125 mg/m(2) intravenously on days 1 and 8) every 3 weeks. In patients without clinically relevant adverse reactions after the 1st treatment course (? grade 2 toxicities according to NCI-CTC vs. 4.0, exuding alopecia and fatigue of any degree) and adequate bone marrow function, the nab-paclitaxel dose was escalated to 100 mg/m(2) on days 1, 8 and 15 of each cycle; this intra-individual dose escalation was maintained during subsequent treatment courses if tolerated. The primary endpoint was objective response rate (ORR) according to RECIST criteria, assessed by an independent radiological review committee with evaluation performed every 2 months. RESULTS:Between 12/2013 and 01/2015, 30 patients were entered in this monocentric academic phase II trial. All patients had an ECOG performance status of 0-1, 80% had liver metastases and 23% had biliary stents in place at time of study initiation. Median CA19-9 was 1,004 U/mL (0.9-100.000 U/mL). In all patients except 2, a dose escalation of nab-paclitaxel after the 1st treatment course could be accomplished. The most common grade 3 adverse events (AEs) included transient sensory neuropathy (23%), (afebrile) neutropenia (17%), hand-foot-syndrome (13%) and phototoxic skin reaction (10%). Among 29 RECIST-response assessable patients, the ORR was 41.4% and stable disease (SD) was noted in 34.5%, resulting in a disease control rate (DCR) of 76%. After a median follow-up duration of 10.3 months (range, 1.9-19.0 months), 13/30 patients (43.3%) are presently being alive. CONCLUSIONS:The combination of capecitabine + nab-paclitaxel at these doses and scheduling was well tolerated and showed substantial antitumor efficacy.

Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.

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Dataset Information

Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma.

Publications

Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma.

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