Know Cancer

forgot password

Autophagic Modulation With Anti-Angiogenic Therapy in Patients With Advanced Malignancies: A Phase I Trial of Sunitinib and Hydroxychloroquine

Phase 1
18 Years
Open (Enrolling)
Malignant Neoplasm

Thank you

Trial Information

Autophagic Modulation With Anti-Angiogenic Therapy in Patients With Advanced Malignancies: A Phase I Trial of Sunitinib and Hydroxychloroquine


I. To determine the MTD of the combination of sunitinib (Sutent), an oral tyrosine kinase
inhibitor with antiangiogenic activity that inhibits VEGFR2, c-kit and PDGFR, in combination
with hydroxychloroquine (HCQ), an inhibitor of autophagy, in patients with advanced solid
tumors that are refractory to standard chemotherapy.


I. Evaluating blocks of tissue from pre-treatment diagnostic biopsies and tissue from
biopsies taken during therapy, when available from enrolled patients, for expression of
markers Beclin1, LC3, p62 and GRp170 as indicators of autophagy potential.

II. Evaluating pre- and post- treatment PBMCs and tumor tissue, when available, for the
presence of autophagosomes by EM as indication of flux through the autophagy pathway.

III. Evaluating pre- and post- treatment peripheral blood mononuclear cells (PBMC) for
changes in the expression of LC3, p62 and GRp170 with the use of single agent sunitinib and
the use of the combination of sunitinib with hydroxychloroquine.

IV. Evaluating circulating tumor cells (CTCs) pre- and post- treatment with single agent
sunitinib and sunitinib + HCQ, and characterize these for markers of autophagy.
(exploratory) V. To determine whether the steady-state plasma concentration of HCQ
correlates with inhibition of autophagy and whether a pharmacokinetic interaction exists
between sunitinib and HCQ.

VI. To examine, when available, post treatment tumor biopsies for vascular markers to detect
decreased vascular proliferation by staining CD31, VEGF, Thrombospondin-1, and CD105
staining to monitor micro vessel density.

OUTLINE: This is a dose-escalation study of sunitinib malate.

Patients receive oral sunitinib malate once daily and oral hydroxychloroquine twice daily on
days 1-28. Treatment repeats every 42 days for 6 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 1 year.

Inclusion Criteria:

- Patients with histologically or cytologically proven advanced cancer

- Patients must have undergone treatment with at least one regimen of standard therapy,
either cytotoxic chemotherapy, an oral targeted agent or immunotherapy, or have a
form of cancer for which no standard therapy exists, or are not eligible for or
decline standard therapy; patients who have received prior therapy with sunitinib
will be allowed; patients with prostate cancer may continue on hormonal therapy if
they are currently receiving it

- Patients must have measurable or evaluable disease according to RECIST criteria

- Life expectancy > 12 weeks

- ECOG performance status =< 1

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9 g/dL

- Serum calcium ≤ 12.0 mg/dL

- Total serum bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal, unless the patient
has liver metastases, in which case both AST and ALT must be ≤ 5 X institutional
upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance ≥ 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- TSH within normal institutional limits is required for eligibility; free T3 and free
T4 values will also be obtained for baseline values should repeat parameters be
required later in the course of treatment, however these values will not be used to
determine eligibility

- CPK within normal institutional limits

- The following groups of patients are eligible provided they have New York Heart
Association class II (NYHA) cardiac function on baseline ECHO/MUGA:

- Those with a history of class II heart failure who are asymptomatic on treatment

- Those with prior anthracycline exposure

- Those who have received central thoracic radiation that included the heart in
the radiotherapy port

- Patients who require use of therapeutic doses of Coumadin-derivative anticoagulants
such as warfarin are excluded, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis; Note: Low molecular weight heparin is permitted provided
the patient's PT INR is ≤ 1.5

- Ejection fraction measured within institutional limits of normal by MUGA scan

- Patients with known brain metastases should be excluded because of their poor
prognosis and because they often develop progressive neurologic dysfunction that
would confound the evaluation of neurologic and other adverse events

- Women must: Have a negative serum or urine pregnancy test within 7 days prior to
study entry if she is a woman of child-bearing potential (WOCBP), OR

- Be at least one year post-menopausal, OR

- Be surgically sterile

- Patients of childbearing or child fathering potential must be willing to use an
acceptable method of birth control prior to study entry and for the duration of the
study; acceptable methods of contraception include hormonal, barrier methods,
intrauterine device, tubal ligation/vasectomy or abstinence; women should not breast
feed while on treatment with sunitinib and HCQ

- Patients must not have a history of any condition (social or medical) that, in the
opinion of the investigator, might interfere with the patient's ability to comply
with the protocol or pose additional or unacceptable risk to the patient

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow and retain sunitinib tablets are excluded

- Approval for HCQ treatment by an eye doctor, based on a screening eye exam; examples
of disqualifying baseline conditions include macular degeneration and other retinal
disease, see exclusion criteria

- Patients must be able to understand and sign informed consent

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy or biologic agents within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who
have not recovered from adverse events due to agents administered more than 4 weeks
earlier; at least 4 weeks must have elapsed since any major surgery

- Patients on treatment for rheumatoid arthritis or systemic lupus erythematosus

- Patients receiving any disease-modifying anti-rheumatic drug (DMARD)

- Active clinically significant infection requiring antibiotics, antivirals or
antifungals; these medications may be allowed for instances of prophylaxis or
treatment felt to not be clinically significant at the discretion of the Principal

- Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg or
higher or diastolic blood pressure of 90 mmHg or higher) are ineligible

- Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid
function in the normal range with medication are ineligible

- Diagnosis or history of central nervous system (CNS) disease (i.e. primary brain
tumor, malignant seizures, untreated CNS metastases or carcinomatous meningitis or
CNS metastases)

- Patient must not have ongoing ventricular cardiac dysrhythmias of grade = 2 as
described by the CTEP Active Version of the NCI CTCAE; patients with a history of
serious ventricular arrhythmia (VT or VF > 3 beats in a row) are also excluded;
additionally, patients with ongoing atrial fibrillation are not eligible

- QTc interval ≥ 500 msec on baseline EKG

- Any of the following within 6 months prior to first dose of treatment: myocardial
infarction, symptomatic coronary artery disease (severe or unstable angina), artery
bypass graft, uncontrolled arrhythmias, symptomatic congestive heart failure,
cerebrovascular accident or transient ischemic attack, or pulmonary embolus

- Patients with known HIV are excluded due to possibility of unknown side effects on
the immune system by these agents; the potential impact of pharmacokinetic
interactions of retroviral therapy with sunitinib is unknown; appropriate studies may
be undertaken in patients with HIV and those receiving combination anti-retroviral
therapy in the future

- Because sunitinib is metabolized primarily by the CYP3A4 liver enzyme, the
eligibility of patients taking medications that are potent inducers or inhibitors of
that enzyme will be determined following a review of their case by the Principal
Investigator; every effort should be made to switch patients taking such agents or
substances to other medications

- Must not have psoriasis or porphyria

- Must not have known hypersensitivity to 4-aminoquinoline compound

- Must not have retinal or visual field changes from prior 4-aminoquinoline compound

- Must not have known G-6PD deficiency

- Patients must not have any known GI pathology that would interfere with drug

- Patients must not have known prior hypersensitivity to sunitinib or
hydroxychloroquine or any of their components

- Must not be taking hydroxychloroquine for treatment or prophylaxis of malaria

- Patients must not have a clinically significant bleeding or clotting disorder

- Patients requiring medication with aurothioglucose (contraindicated with concurrent
administration of antimalarials)

- History of gastrointestinal perforation, or intra-abdominal abscess within the
previous 28 days

- Serious, non-healing infection, bone fracture or nonhealing ulcer or wound

- Current treatment on another clinical trial; participation in non-therapeutic
clinical trials is permissible

- Patients with nephrotic syndrome

- Cataracts that would interfere with required funduscopic examinations, or severe
baseline visual impairment including macular degeneration, retinopathy or visual
field changes, or having only one functional eye; all patients must undergo a
screening eye exam prior to enrollment

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD), as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Outcome Time Frame:

Up to 42 days

Safety Issue:


Principal Investigator

Janice Mehnert

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer Institute of New Jersey


United States: Food and Drug Administration

Study ID:




Start Date:

January 2010

Completion Date:

Related Keywords:

  • Malignant Neoplasm
  • Neoplasms



Dana-Farber Cancer Institute Boston, Massachusetts  02115
Cancer Institute of New Jersey New Brunswick, New Jersey  08901