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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2013 by Abramson Cancer Center of the University of Pennsylvania
Sponsor:
Information provided by (Responsible Party):
Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01506973
First received: January 3, 2012
Last updated: February 26, 2013
Last verified: February 2013
  Purpose

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.


Condition Intervention Phase
Advanced Adenocarcinoma
Metastatic Adenocarcinoma
Drug: Hydroxychloroquine (HCQ)
Drug: Gemcitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer

Resource links provided by NLM:


Further study details as provided by Abramson Cancer Center of the University of Pennsylvania:

Primary Outcome Measures:
  • Overall survival [ Time Frame: one year ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 40
Study Start Date: December 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01506973

Contacts
Contact: Peter O'Dwyer, MD 855-216-0098 PennCancerTrials@emergingmed.com

Locations
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Peter O'Dwyer, MD    855-216-0098    PennCancerTrials@emergingmed.com   
Sponsors and Collaborators
Abramson Cancer Center of the University of Pennsylvania
Investigators
Principal Investigator: Peter O'Dwyer, MD Abramson Cancer Center of the University of Pennsylvania
  More Information

No publications provided

Responsible Party: Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01506973     History of Changes
Other Study ID Numbers: UPCC 19211
Study First Received: January 3, 2012
Last Updated: February 26, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Abramson Cancer Center of the University of Pennsylvania:
histologically or cytologically documented

Additional relevant MeSH terms:
Pancreatic Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gemcitabine
Hydroxychloroquine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on September 22, 2014