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

Status: complete

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.

Inclusion Criteria

Patients must have histologically or cytologically documented advanced or metastatic adenocarcinoma of the pancreas
Patients must have measurable disease as defined by the RECIST criteria as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20mm with conventional techniques on either CT or MRI; marker (CA19-9 or CEA) elevation alone is insufficient for entry
Patients may have had prior adjuvant treatment for pancreatic cancer; the last dose of chemotherapy must have been > 4 months prior to study entry; patients with prior radiotherapy are acceptable; it must be at least 4 months since administration of radiation therapy and all signs of toxicity must have abated
Patients must have an ECOG performance status of 0-1
The following required Initial Laboratory Values should be obtained within 4 weeks of the start of treatment:
Granulocytes ≥ 1,500/ml
Platelet Count ≥ 100,000/ml
Creatinine ≤ 1.5 x upper limit of normal
Bilirubin ≤ 1.5 x upper limit of normal
AST ≤ 5 x upper limit of normal
Hemoglobin ≥ 9.0g/dL
Patients must not be pregnant or lactating as chemotherapy is thought to present substantial risk to the fetus/infant; women of childbearing potential and sexually active males must use an effective contraception method during treatment and for three months after completing treatment and negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential
Patients must have an accessible primary tumor or metastasis, and be willing to have a pre-treatment and post-treatment tumor biopsy (at 6 to 8 weeks after beginning)
Patients must have a life expectancy of greater than three months
Patients must have the ability to understand and the willingness to sign a written informed consent document
< Grade 2 pre-existing peripheral neuropathy per CTCAE

Exclusion Criteria

Patients may not be receiving any other investigational agents
Known allergy to HCQ
Patients with previous treatment with abraxane
Patients on therapeutic doses of Coumadin (> 1 mg daily); the use of therapeutic or prophylactic low molecular weight heparin or fragmin is permitted
Patients with known G6PD deficiency, severe psoriasis, porphyria, macular degeneration or severe diabetic retinopathy are ineligible because of the potential for greater HCQ toxicity

PRIMARY OBJECTIVES:

I. To define the Phase II dose and to describe the dose-limiting toxicity of the combination of HCQ with gemcitabine/abraxane in previously untreated patients with advanced pancreatic cancer. (Phase I)

II. To describe the one year overall survival of the combination of HCQ with gemcitabine/abraxane in previously untreated patients with advanced pancreatic cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To describe the toxicity associated with the regimen, and to determine pharmacokinetics of HCQ in selected patients. (Phase I)

II. To describe the toxicity associated with the regimen. (Phase II)

II. To describe the progression-free survival, response rates, median overall survival associated with this treatment. (Phase II)

III. To describe the pharmacokinetics of HCQ when administered in this combination, and relate average and peak blood concentrations to toxicity. (Phase II)

IV. To determine the degree of autophagy inhibition in peripheral mononuclear cells as a surrogate tissue, through an analysis of changes in target gene expression, and of the induction of autophagosomes after treatment. (Phase II)

V. To analyze tumor tissue before and after treatment for genomic, metabolic and autophagy markers of treatment effect. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine followed by a randomized phase II study.

PHASE I: Patients receive hydroxychloroquine once daily (QD) or twice daily (BID); paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes on days 1, 8, and 15; and gemcitabine hydrochloride IV over 30-100 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive hydroxychloroquine QD or BID; paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15; and gemcitabine hydrochloride IV over 30-100 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo QD or BID; paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15; and gemcitabine hydrochloride IV over 30-100 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

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

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