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

• Complete response (CR), overall survival (OS) and time to progression (TTP) of patients with metastatic RCC treated with IL-2 + HCQ to the historical data of patients treated with high dose IL-2 alone in the CWG data base. [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: No ]

  CR (target lesions): Disappearance of all target lesions CR (non-target lesions): Disappearance of all non-target lesions and normalization of tumor marker level

  Survival: date of first protocol treatment to the date of death, or censored at date of last contact.

  TTP: time from the date of first protocol treatment until the date disease progression criteria are met (in responding patients progression criteria uses the reference of the smallest measurements recorded since the treatment started) or is censored at date of last disease assessment for those who have not progressed.

• Safety/toxicity of IL-2 + HCQ compared to CWG database of metastatic RCC patients treated with IL-2 alone: # doses IL-2 during 1st course; toxicity after scheduled 9th dose IL-2; frequency grade III and IV or unexpected or rare toxicities [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: Yes ]
  Number of doses of IL-2 administered during the first course of therapy; toxicity after the scheduled 9th dose of IL-2; frequency of grade III and IV or unexpected or rare toxicities
• Baseline laboratory parameters outlined under "description" (to be correlated with toxicity, response, and survival). [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: Yes ]
  Baseline laboratory parameters include: miRNAs pre- and post-IL-2; KIR genotyping; T and NK cell enumeration and activation in the peripheral blood; circulating mDC and pDC frequency and DC function, TCR-zeta chain expression in T and NK cells, arginase or arginine levels; circulating cytokines, chemokines, growth factors and angiogenesis mediators
• Known prognostic criteria for RCC patients (Motzer criteria, performance status, prior nephrectomy, presence of liver and/or bone metastases categories) on clinical outcome. [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: No ]

• Compare the complete response, overall survival and time to progression of patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine to the historical data of patients treated with high dose IL-2 alone in the CWG data base. [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: No ]
• Safety/toxicity of IL-2 + HCQ compared to CWG database of metastatic RCC patients treated with IL-2 alone: # doses IL-2 during 1st course; toxicity after scheduled 9th dose IL-2; frequency grade III and IV or unexpected or rare toxicities [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: Yes ]
• Correlate baseline laboratory parameters with toxicity, response, and survival. [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: Yes ]
  Baseline laboratory parameters include: miRNAs pre- and post-IL-2; KIR genotyping; T and NK cell enumeration and activation in the peripheral blood; circulating mDC and pDC frequency and DC function, TCR-zeta chain expression in T and NK cells, arginase or arginine levels; circulating cytokines, chemokines, growth factors and angiogenesis mediators
• Evaluate the utility of known prognostic criteria for RCC patients (Motzer criteria, performance status, prior nephrectomy, presence of liver and/or bone metastases categories) on clinical outcome. [ Time Frame: up to 3 years to accrue and assess outcome ] [ Designated as safety issue: No ]

The main goal of the research study is to determine whether treating renal cell cancer patients with the study drug, hydroxychloroquine, along with IL-2, a standard treatment of kidney cancer that has spread to other parts of the body, can make the cancer easier to kill and eliminate. Another goal is to see how the study drug affects the body's immune cells which fight cancer cells.

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.

• Drug: Hydroxychloroquine
  Continuous oral administration (at 600 mg/d or 1200 mg/d) will be initiated prior to the first dose (day -14) given 14 days prior to initiation of the first dose of IL-2 and then daily or twice a day throughout all three treatment courses.
  Other Name: Plaquenil
• Drug: IL-2
  600,000 IU/kg IV bolus q 8 hrs x days 1-5 and 15-19 (maximum 28 doses - 14 per 5 day cycle) of each 84-day course
  Other Name: Aldesleukin

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 received prior systemic therapy for metastatic RCC or have previously received IL-2 are not eligible. Patients on HCQ in neoadjuvant protocols or in the past for clinical indications ARE eligible.
• 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.