Study of Hydroxychloroquine and Aldesleukin in Renal Cell Carcinoma Patients (RCC)

The rationale for combining the high dose bolus aldesleukin with hydroxychloroquine includes
potential positive interactions on the immune regulatory side, non-overlapping toxicities,
and potential for prolongation and increased number of responses based on murine studies
conducted at the University of Pittsburgh. This study is a multi-center phase II study
designed to estimate the efficacy of combination therapy of standard high dose bolus IL-2 and
various doses of hydroxychloroquine therapy in metastatic RCC patients.

Inclusion Criteria:

- Histologically confirmed metastatic renal cell carcinoma with predominantly clear cell
histology.

- Have measurable disease by RECIST 1.1 criteria. For example, this would include tumor
in the lung, liver, and retroperitoneum. Bone disease is difficult to follow and
quantify and as a sole site would not be acceptable.

- Patients must be at least 4 weeks from radiation or surgery and recovered from all ill
effects.

- Age ≥18 years.

- Karnofsky Performance Status ≥80%.

- Adequate end organ function:

1. Hematologic: ANC ≥ 1000cells/uL, platelets ≥ 100,000/uL, hemoglobin ≥ 9g/dl (pre
transfusion values used for prognostic factor, can be transfused or use
recombinant erythropoietin growth factors but must not have active bleeding).

2. Liver: AST ≤ 2 x ULN (upper limit of normal), serum total bilirubin ≤ 2 x ULN
(except for patients with Gilbert's Syndrome).

3. Renal: serum creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60ml/min
using Cockcroft-Gault estimation using the formula per protocol.

4. Pulmonary: FEV1 ≥ 2.0 liters or ≥ 75% of predicted for height and age. (PFTs are
required for patients over 50 or with significant pulmonary or smoking history
defined as >20 pack years or history of COPD/emphysema).

5. Cardiac: No evidence of congestive heart failure, symptoms of coronary artery
disease, myocardial infarction less than one year prior to entry, serious cardiac
arrhythmias, or unstable angina. Patients who are over 40 or have had previous
cardiac disease will be required to have a negative or low probability cardiac
stress test for cardiac ischemia.

- Women should not be lactating and, if of childbearing age, have a negative pregnancy
test within two weeks of entry to the study.

- Appropriate contraception in both genders.

- The patient must be competent and have signed informed consent.

- CNS: No history of cerebrovascular accident, transient ischemic attacks, central
nervous system or brain metastases.

Exclusion Criteria:

- Patients who have previously received IL-2 are NOT eligible. Patients on HCQ in
neoadjuvant protocols or in the past for clinical indications ARE eligible, as are
patients who have previously received CTLA-4 and/or PD-1/PD-L1 antibodies.

- Concomitant second malignancy except for non-melanoma skin cancer, and non-invasive
cancer such as cervical CIS, superficial bladder cancer without local recurrence or
breast CIS.

- In patients with a prior history of invasive malignancy, less than five years in
complete remission.

- Positive serology for HIV, hepatitis B or hepatitis C.

- Significant co-morbid illness such as uncontrolled diabetes or active infection that
would preclude treatment on this regimen.

- Use of corticosteroids or other immunosuppression (if patient had been taking
steroids, at least 2 weeks must have passed since the last dose).

- History of inflammatory bowel disease or other serious autoimmune disease. (Not
including thyroiditis and rheumatoid arthritis). Patients already on
hydroxychloroquine for such disorders are not eligible.

- Patients with organ allografts.

- Uncontrolled hypertension (BP >150/100 mmHg).

- Proteinuria dipstick > 3+ or ≥ 2gm/24 hours.

- Urine protein:creatinine ratio ≥ 1.0 at screening.

- Major surgery, open biopsy, significant traumatic injury within 28 days of starting
treatment or anticipation of need for major surgical procedure during the course of
the study.

- Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
prior to starting treatment. Central venous catheter placements are permitted.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to starting treatment.

- Serious, non-healing wound, ulcer, or bone fracture.

- History of tumor-related or other serious hemorrhage, bleeding diathesis, or
underlying coagulopathy.

- History of deep venous thrombosis, clinically significant peripheral vascular disease,
or other thrombotic event.

- Inability to comply with study and/or follow-up procedures.

- Individuals with known history of glucose 6 phosphate deficiency are excluded from the
trial (possible issue with HCQ tolerance).

- Patients with previously documented macular degeneration or diabetic retinopathy are
excluded from the trial.

- Baseline EKG with QTc > 470 msec (including subjects on medication). Subjects with
ventricular pacemaker for whom QT interval is not measurable will be eligible on a
case-by-case basis.