FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal 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:
NCT01206530
First received: September 16, 2010
Last updated: February 25, 2013
Last verified: February 2013
  Purpose

In this Phase I/II clinical trial, the investigators seek to pilot the addition of hydroxychloroquine (HCQ) to the standard front-line therapy of colorectal cancer, FOLFOX/bevacizumab. In toxicity terms, the investigators previous studies lead them to believe that a full dose (800mg) of HCQ will be well-tolerated in this setting. By starting at 600 mg, the investigators will ensure that the full dose is approached with an eye to safety, and if needed, the investigators will use the lower dose. Both doses achieve autophagy inhibition in our current studies.


Condition Intervention Phase
Rectal Cancer
Colon Cancer
Metastasis
Adenocarcinoma
Drug: Hydroxychloroquine
Drug: Oxaliplatin
Drug: Leucovorin
Drug: 5-fluorouracil
Drug: Bevacizumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Primary Purpose: Treatment
Official Title: A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Response Rate [ Designated as safety issue: Yes ]
    We will use response as the primary efficacy marker to investigate the relationship between changes in autophagy markers and SUVs and the efficacy of treatment.


Secondary Outcome Measures:
  • Progression-free survival [ Designated as safety issue: Yes ]
    To evaluate the effects of baseline markers and treatment group on time to progression and survival, we will estimate propportional-hazards regression models. Time-to-event outcomes will be summarized with Kaplan-Meier survival curves.

  • Overall survival [ Designated as safety issue: Yes ]
    To evaluate the effects of baseline markers and treatment group on time to progression and survival, we will estimate propportional-hazards regression models. Time-to-event outcomes will be summarized with Kaplan-Meier survival curves.

  • Incidence of toxicity [ Designated as safety issue: Yes ]
    To evaluate the effects of baseline markers and treatment group on time to progression and survival, we will estimate propportional-hazards regression models. Time-to-event outcomes will be summarized with Kaplan-Meier survival curves.


Estimated Enrollment: 25
Study Start Date: September 2010
Estimated Study Completion Date: September 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Hydroxychloroquine
    Dose:600 or 800 mg Route:PO daily Treatment Administration: Daily
    Drug: Oxaliplatin
    Dose: 85mg/m2 Route: IV infusion over 2 hours Treatment Administration: Day 1
    Drug: Leucovorin
    Dose: 400mg/m2 Route IV infusion over 2 hours Treatment Administration: Day 1
    Drug: 5-fluorouracil
    Dose: 400mg/m2 Route: IV bolus immediately following leucovorin Treatment Administration Day 1
    Drug: 5-fluorouracil

    Dose: 2,400mg/m2 Route: IV continuous infusion over 46 hours immediately following bolus injection.

    Treatment Administration: Days 1-2

    Drug: Bevacizumab
Detailed Description:

In this Phase I/II clinical trial, we seek to pilot the addition of HCQ to the standard front-line therapy of colorectal cancer, FOLFOX/bevacizumab. In toxicity terms, our previous studies lead us to believe that full dose (800mg) of HCQ will be welltolerated in this setting. By starting at 600 mg, we will ensure that the full dose is approached with an eye to safety, and if needed, we will use the lower dose. Both doses achieve autophagy inhibition in our current studies: for this reason, we are comfortable in including accrual to both dose-levels to the Phase II endpoints. If results are particularly striking, we will consider amending the study to expand accrual if the budget permits, but 25 patients permits an adequate assessment of activity of a novel regimen. The correlative endpoints of this trial are directed to the pharmacokinetics of HCQ, and pharmacodynamics of autophagy inhibition. We are currently constructing a population pharmacokinetic model of HCQ based on data from several ongoing trials, and the data from these patients will contribute to refining the model. We will analyze both measured and modelpredicted 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 autophagyrelated proteins on western analysis, quantitated by densitometry. An exploratory correlative endpoint is the induction of metabolic changes as measured by 18FDG-PET. Our mechanistic hypothesis in this work is that the addition of HCQ will lead to a greater amount of cell death in the hypoxic regions of the tumor, that have increased as a consequence of bevacizumab treatment. We 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. Finally, since we have demonistrated the key role of JNK1 in the induction of autophagy, we will analyze archival tumor materials to determine variability in this marker, as a baseline for potential future trials.

  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 documented advanced or metastatic adenocarcinoma of the colon or rectum.
  • 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 20 mm with conventionaltechniques on either CT of MRI. Marker (CEA) elevation alone is insufficient for entry.
  • Patients may have had prior adjuvant treatment of advanced colorectal cancer. The prior treatment regimen must not have included bevacizumab but may have included oxaliplatin and the last dose of chemotherapy must have been 6 months prior to study entry. Patients with prior radiotherapy are acceptable. It must be at least 2 weeks since administration of radiation therapy and all signs of toxicty must have abated.
  • Patients must be 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 Urine Urine protein:creatinine ratio 1.0 at screening
  • Patients must not be pregnant or lactating as chemotherapy is thought to present substantial risk to the fetus/infant.
  • 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:

  • Major sugical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study. Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 0.
  • Patients with serious nonhealing wounds, ulcers, or bone fractures.
  • Patients with a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to Day 0
  • Patients with a history of myocardial infarction, unstable angina, or cerebrovascular accident 6 months prior to registration.
  • Patients with clinically significant peripheral vascular disease.
  • Patients with New York Heart Association Class II or greater congestive heart failure (class II is defined as symptoms of fatigue, dyspnea or other symptoms with ordinary physical activity).
  • Patients using oral or parenteral anticoagulation are not excluded provided they are on a stable dose of anticoagulant.
  • Patients with pre-existing hypertension should be on a stable antihypertensive regimen and have a blood pressure 150/100 mmHg at the time of enrollement.
  • Patients must not have known brain metastases because the study drug has not been adequately tested in this setting.
  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: NCT01206530

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   
Principal Investigator: Peter O'Dwyer, MD         
Sub-Investigator: Ravi Amaravadi, MD         
Sub-Investigator: Weijing Sun, MD         
Sub-Investigator: Bruce Giantonio, MD         
Sub-Investigator: Ursina Teitelbaum, MD         
Sub-Investigator: Mark Rosen, MD         
Sub-Investigator: Daniel Pryma, MD         
Sub-Investigator: Chaitanya Divgi, MD         
Sub-Investigator: Stephen Hahn, MD         
Sponsors and Collaborators
Abramson Cancer Center of the University of Pennsylvania
Investigators
Principal Investigator: Peter J. 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: NCT01206530     History of Changes
Other Study ID Numbers: UPCC 07210
Study First Received: September 16, 2010
Last Updated: February 25, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Abramson Cancer Center of the University of Pennsylvania:
histologically documented
advanced
metastatic
adenocarcinoma
colon
rectum

Additional relevant MeSH terms:
Colorectal Neoplasms
Adenocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Bevacizumab
Fluorouracil
Hydroxychloroquine
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents

ClinicalTrials.gov processed this record on September 16, 2014