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

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
Investigator

- 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
use

- Must not have known G-6PD deficiency

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

- 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