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A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Rectal Cancer, Colon Cancer, Metastasis, Adenocarcinoma

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Trial Information

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, 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.

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.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Primary Purpose: Treatment

Outcome Measure:

Response Rate

Outcome Description:

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.

Safety Issue:


Principal Investigator

Peter J. O'Dwyer, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Abramson Cancer Center of the University of Pennsylvania


United States: Institutional Review Board

Study ID:

UPCC 07210



Start Date:

September 2010

Completion Date:

September 2013

Related Keywords:

  • Rectal Cancer
  • Colon Cancer
  • Metastasis
  • Adenocarcinoma
  • histologically documented
  • advanced
  • metastatic
  • adenocarcinoma
  • colon
  • rectum
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms
  • Neoplasm Metastasis



Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283