A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer
18 Years
N/A
Both
Advanced Adenocarcinoma, Metastatic Adenocarcinoma
Trial Information
A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer
Recent strategies have focused on improving the efficacy of gemcitabine either by improving
the method of delivery, or by combining gemcitabine with other non-cross resistant agents. A
sequence of Phase III combination studies of gemcitabine in combination (with oxaliplatin,
and with the targeted therapies bevacizumab and cetuximab) have been negative, though based
on strikingly positive Phase II data generated in cancer centers. Several studies suggest
that taxanes are active in pancreatic cancer, but a randomized trial of gemcitabine with
taxanes has not been preformed, probably on the basis that the differences in Phase II were
insufficiently persuasive. The development of a novel taxane conjugate with albumin,
abraxane, with established activity in breast cancer, prompted a Phase II trial of
gemcitabine/abraxane by Von Hoff (6). Phase I/II data were highly promising, with response
rates of the order of 40%, with tolerable toxicity, and a one-year survival of about 48%. A
phase III trial of gemcitabine versus gemcitabine/abraxane is in progress, and based on
these promising data has served as the control chemotherapy for previous SU2C trials. The
development of a more intensive, but toxic regimen (FOLFIRINOX) in no way diminishes the
enthusiasm for this chemotherapy backbone, given the activity in Phase II trials that
appears comparable (7). Given the promise of this regimen, and the possibility of making a
substantial improvement in outcome with additional targeted interventions, we propose to
continue to use this regimen in the current study.
Of particular interest in extending these studies to pancreatic cancer is the finding that
autophagy inhibition is particularly deleterious to cell lines bearing a mutant Kras
protein. Additional studies as part of the SU2C pancreatic cancer project reveal that an
autophagy program is activated in the presence of mutant Kras, and thus prompts the testing
of this strategy in a setting in which Kras is commonly (about 85%) mutated (SU2C,
unpublished data).
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 be age 18 years or older.
- 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
- Patients must not be pregnant or lactating as chemotherapy is thought to present
substantial risk to the fetus/infant.
- 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.
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.
Type of Study:
Interventional
Study Design:
Primary Purpose: Treatment
Outcome Measure:
Overall survival
Outcome Time Frame:
one year
Safety Issue:
Yes
Principal Investigator
Peter O'Dwyer, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Abramson Cancer Center of the University of Pennsylvania
Authority:
United States: Food and Drug Administration
Study ID:
UPCC 19211
NCT ID:
NCT01506973
Start Date:
December 2011
Completion Date:
December 2014
Related Keywords:
- Advanced Adenocarcinoma
- Metastatic Adenocarcinoma
- histologically or cytologically documented
- Adenocarcinoma
- Adenocarcinoma, Mucinous
- Pancreatic Neoplasms
Name | Location |
|---|---|
| Abramson Cancer Center of the University of Pennsylvania | Philadelphia, Pennsylvania 19104-4283 |
