- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01206530
FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer
April 16, 2019 updated by: Abramson Cancer Center of the University of Pennsylvania
A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer
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.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
50
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Abramson Cancer Center of the University of Pennsylvania
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
---|---|
Response Rate
|
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
Outcome Measure |
Measure Description |
---|---|
Progression-free survival
|
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
|
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
|
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.
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Peter J. O'Dwyer, MD, Abramson Cancer Center of the University of Pennsylvania
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
September 1, 2010
Primary Completion (Actual)
September 1, 2017
Study Completion (Actual)
September 1, 2017
Study Registration Dates
First Submitted
September 16, 2010
First Submitted That Met QC Criteria
September 20, 2010
First Posted (Estimate)
September 22, 2010
Study Record Updates
Last Update Posted (Actual)
April 18, 2019
Last Update Submitted That Met QC Criteria
April 16, 2019
Last Verified
April 1, 2019
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Adenocarcinoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Protective Agents
- Antineoplastic Agents, Immunological
- Angiogenesis Inhibitors
- Angiogenesis Modulating Agents
- Growth Substances
- Growth Inhibitors
- Micronutrients
- Vitamins
- Antiprotozoal Agents
- Antiparasitic Agents
- Antidotes
- Vitamin B Complex
- Antimalarials
- Fluorouracil
- Oxaliplatin
- Bevacizumab
- Leucovorin
- Hydroxychloroquine
Other Study ID Numbers
- UPCC 07210
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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