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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Inhibiting the Systemic Autophagic Syndrome - A Phase I/II Study of Hydroxychloroquine and Aldesleukin in Renal Cell Carcinoma Patients (RCC). A Cytokine Working Group (CWG) Study

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: IL-2


Participation Criteria
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Eligibility Criteria
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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: 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). Liver: AST ≤ 2 x ULN (upper limit of normal), serum total bilirubin ≤ 2 x ULN (except for patients with Gilbert's Syndrome). Renal: serum creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60ml/min using Cockcroft-Gault estimation using the formula per protocol. 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine + IL-2<br>One course of treatment (84 days) will consist of high dose (600,000 IU/kg) bolus IL-2 administered intravenously every 8 hours on days 1-5 and 15-19 (maximum 14 doses/5 days of administration) and hydroxychloroquine (HCQ) orally started two weeks prior to IL-2 infusions and continued while able to take oral medication for up to 3 courses. | Drug: Hydroxychloroquine<br>* Continuous oral administration (at 600 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.<br>* Other names: Plaquenil;Drug: IL-2<br>* 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<br>* Other names: Aldesleukin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at Either 1,200 mg/d or 600 mg/d) (All Patients) | Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 3 years | 
| Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 1,200 mg/d | Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 3 years | 
| Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 600 mg/d | Clinical Response: per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from date of first protocol treatment until the date of death, or censored at date of last contact. | Up to 3 years | 
| Progression-free Survival (PFS) | 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. Per RECIST 1.1, Progressive Disease (PD) is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 3 years | 
| Number of Doses of IL-2 + HCQ | Number of doses of IL-2 administered during the first course of therapy. | Up to 3 years | 
| Frequency of Grade III and Grade IV Toxicities | Number of specified categories of grade III and IV or unexpected or rare toxicities occurring during the first course (up until the end of cycle 1) of IL-2 treatment. | Up to 3 years | 
| Worst Grade of Adverse Event Experienced | Number of participants who experienced Grade 2-5 adverse events. | Up to 3 years | 
| Worst Grade of Adverse Event At Least Possibly Related to Treatment Experienced | Number of participants who experienced Grade 2-5 adverse events that were at least possibly related to study treatment. | Up to 3 years | 
| Worst Grade of Adverse Event At Least Probably Related to Treatment Experienced | Number of participants who experienced Grade 2-5 adverse events that were at least probably related to study treatment. | Up to 3 years | 
| Serum Lactate Dehydrogenase | Number of participants with either high serum lactate dehydrogenase (> 1.5 times upper limit of normal) or normal lactate dehydrogenase. | Up to 2 years | 
| Hemoglobin Levels | Low hemoglobin levels (less than the lower limit of normal (13.2 g/dL)) are considered to be unfavorable. | Up to 3 years | 
| Serum Calcium Levels (Corrected) | Number of patients with either normal or high serum calcium levels. High serum calcium levels are considered to be clinically unfavorable. | Up to 3 years | 
| Prior Nephrectomy | Number of patients with history of a prior nephrectomy (surgical removal of a kidney) or no history of a prior nephrectomy. | Up to 3 years | 
| Number of Participants With Low Karnofsky Performance Status | Karnofsky performance status is a standard way of measuring the ability of cancer patients to perform ordinary tasks. The Karnofsky Performance Status scores range from 0 to 100. A higher score means the patient is better able to carry out daily activities. Karnofsky Performance Status may be used to determine a patient's prognosis, to measure changes in a patient's ability to function, or to decide if a patient should be included in the trial. A low Karnofsky performance status (<80%) is considered to be unfavorable. | Up to 3 years | 
| Natural Killer (NK) Cells | Percentage of Natural Killer (NK) cells per ml of blood. NK cells are lymphocytes with the ability to kill tumor cells without deliberate immunization or activation. | Up to 3 years | 
| Myeloid Derived Suppressor Cell (MDSC) | Percentage of Myeloid Derived Suppressor Cell per ml of blood. MDSC immune cells originate from bone marrow stem cells and strongly expand in cancer. | Up to 3 years | 
| Regulatory T Cells (Treg) | Percentage of Regulatory T cells per ml of blood. High levels of Tregs in the tumor microenvironment are associated with poor prognosis in many cancers by suppressing the body's anti-tumor immune response. | Up to 3 years | 
| Plasmacytoid Dendritic Cells (pDC) | Percentage of Plasmacytoid dendritic cells per ml of blood. In cancer, pDC are malignant immune cells that demonstrate an impaired response that can contribute to the establishment of an immunosuppressive tumor microenvironment. | Up to 3 years | 
| T-cell Lymphocytes | Percentage of T-cell lymphocytes in blood as cells per ml. T-cells are a subtype of white blood cells which play a key role in the immune system and fighting cancer. | Up to 3 years | 
| Conventional Dendritic Cells (cDC) | Percentage of Conventional Dendritic Cells (cDC) per ml of blood. cDC reside in tissues and once activated, migrate to draining lymph nodes to promote adaptive immune responses. | Up to 3 years |