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

• Sponsor: Leonard Appleman (Other)
• Overall Status: Completed
• CT.gov ID: NCT01550367
• Collaborator: Prometheus Laboratories (Industry)
• Enrollment: 30
• Locations: 7
• Arm: 1
• Duration (Months): 83.1
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Renal Cell Carcinoma	Drug: Hydroxychloroquine; Drug: IL-2	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Feb 6, 2018
• Actual Study Completion Date: Feb 1, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hydroxychloroquine + IL-2 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; 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.; Other Names: 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 Names: Aldesleukin

Outcome Measures

Primary Outcome Measures

1. Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at Either 1,200 mg/d or 600 mg/d) (All Patients) [Up to 3 years]

   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.

2. Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 1,200 mg/d [Up to 3 years]

   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.

3. Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 600 mg/d [Up to 3 years]

   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.

Secondary Outcome Measures

1. Overall Survival (OS) [Up to 3 years]

   Time from date of first protocol treatment until the date of death, or censored at date of last contact.

2. Progression-free Survival (PFS) [Up to 3 years]

   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.

3. Number of Doses of IL-2 + HCQ [Up to 3 years]

   Number of doses of IL-2 administered during the first course of therapy.

4. Frequency of Grade III and Grade IV Toxicities [Up to 3 years]

   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.

5. Worst Grade of Adverse Event Experienced [Up to 3 years]

   Number of participants who experienced Grade 2-5 adverse events.

6. Worst Grade of Adverse Event At Least Possibly Related to Treatment Experienced [Up to 3 years]

   Number of participants who experienced Grade 2-5 adverse events that were at least possibly related to study treatment.

7. Worst Grade of Adverse Event At Least Probably Related to Treatment Experienced [Up to 3 years]

   Number of participants who experienced Grade 2-5 adverse events that were at least probably related to study treatment.

8. Serum Lactate Dehydrogenase [Up to 2 years]

   Number of participants with either high serum lactate dehydrogenase (> 1.5 times upper limit of normal) or normal lactate dehydrogenase.

9. Hemoglobin Levels [Up to 3 years]

   Low hemoglobin levels (less than the lower limit of normal (13.2 g/dL)) are considered to be unfavorable.

10. Serum Calcium Levels (Corrected) [Up to 3 years]

    Number of patients with either normal or high serum calcium levels. High serum calcium levels are considered to be clinically unfavorable.

11. Prior Nephrectomy [Up to 3 years]

    Number of patients with history of a prior nephrectomy (surgical removal of a kidney) or no history of a prior nephrectomy.

12. Number of Participants With Low Karnofsky Performance Status [Up to 3 years]

    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.

13. Natural Killer (NK) Cells [Up to 3 years]

    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.

14. Myeloid Derived Suppressor Cell (MDSC) [Up to 3 years]

    Percentage of Myeloid Derived Suppressor Cell per ml of blood. MDSC immune cells originate from bone marrow stem cells and strongly expand in cancer.

15. Regulatory T Cells (Treg) [Up to 3 years]

    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.

16. Plasmacytoid Dendritic Cells (pDC) [Up to 3 years]

    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.

17. T-cell Lymphocytes [Up to 3 years]

    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.

18. Conventional Dendritic Cells (cDC) [Up to 3 years]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loyola University Chicago	Maywood	Illinois	United States	60153
2	Indiana University Simon Cancer Center	Indianapolis	Indiana	United States	46202
3	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
4	Dartmouth-Hitchcock Medical Center	Hanover	New Hampshire	United States	03755
5	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
6	Providence Health & Services	Portland	Oregon	United States	97213
7	University of Pittsburgh Cancer Institute / UPMC CancerCenter	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• Leonard Appleman
• Prometheus Laboratories

Investigators

• Principal Investigator: Leonard J Appleman, MD, PhD, University of Pittsburgh

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 5, 2019

More Information

Publications

None provided.

• Responsible Party: Leonard Appleman, MD, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01550367
• Other Study ID Numbers: UPCI 11-080
• First Posted: Mar 12, 2012
• Last Update Posted: Jan 2, 2020
• Last Verified: Dec 1, 2019

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Hydroxychloroquine; Aldesleukin

Study Results

Participant Flow

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Period Title: Overall Study
STARTED	30
1200 mg/d HCQ	13
600 mg/d HCQ	17
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Overall Participants	30
Age (years) [Mean (Full Range) ]
1200 mg/d HCQ	58.2
600 mg/d HCQ	56.5
Sex: Female, Male (Count of Participants)
Female	4 13.3%
Male	9 30%
Female	4 13.3%
Male	13 43.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	30 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Karnofsky Performance Status (KPS) (Count of Participants)
KPS Score of 80	11 36.7%
KPS Score of 90	1 3.3%
KPS Score of 100	1 3.3%
KPS Score of 80	13 43.3%
KPS Score of 90	0 0%
KPS Score of 100	4 13.3%

Outcome Measures

1. Primary Outcome

Title	Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at Either 1,200 mg/d or 600 mg/d) (All Patients)
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine (HCQ at either 1,200 mg/d or 600 mg/d) who were evaluable for clinical response. Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, dosing was reduced to 600 mg/d.

Arm/Group Title	Hydroxychloroquine + IL-2
Arm/Group Description	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. Hydroxychloroquine: Continuous oral administration (at 600 mg/d) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, dose was reduced to 600 mg/d.
Measure Participants	29
Progressed Disease - All Patients	9 30%
Stable Disease - All Patients	14 46.7%
Partial Response - All Patients	3 10%
Complete Response - All Patients	3 10%

2. Primary Outcome

Title	Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 1,200 mg/d
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine (HCQ) 1,200 mg/d who were evaluable for clinical response.

Arm/Group Title	Hydroxychloroquine + IL-2
Arm/Group Description	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. Hydroxychloroquine: Continuous oral administration (at 1,200 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.
Measure Participants	12
Progressed Disease	5 16.7%
Stable Disease	6 20%
Partial Response	1 3.3%
Complete Response	0 0%

3. Primary Outcome

Title	Clinical Response - IL-2 Combined With Hydroxychloroquine (HCQ) at 600 mg/d
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine (HCQ) 600 mg/d who were evaluable for clinical response.

Arm/Group Title	Hydroxychloroquine + IL-2
Arm/Group Description	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. Hydroxychloroquine: Continuous oral administration (at 600 mg/d) was 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.
Measure Participants	17
Progressed Disease	4 13.3%
Stable Disease	8 26.7%
Partial Response	2 6.7%
Complete Response	3 10%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from date of first protocol treatment until the date of death, or censored at date of last contact.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine (HCQ).

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Measure Participants	30
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients with metastatic RCC treated with IL-2 combined with hydroxychloroquine (HCQ) at either 600 mg/d or 1,200 mg/d.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Measure Participants	30
Median (95% Confidence Interval) [months]	5.5

6. Secondary Outcome

Title	Number of Doses of IL-2 + HCQ
Description	Number of doses of IL-2 administered during the first course of therapy.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received at least one dose of study treatment (IL-2 + either 1,200 HCQ or 600 mg/d HCQ).

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Measure Participants	30
1200 mg/d HCQ	12.8
600 mg/d HCQ	13.2

7. Secondary Outcome

Title	Frequency of Grade III and Grade IV Toxicities
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received at least one dose (cycle) of study treatment (IL-2 + either 1,200 HCQ or 600 mg/d HCQ) and experienced specified categories of toxicities.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Measure Participants	30
Hypotension	5
Gastrointestinal	1
Hematologic	1
Pulmonary	1
Renal/electrolytes	4
Psychiatric	3

8. Secondary Outcome

Title	Worst Grade of Adverse Event Experienced
Description	Number of participants who experienced Grade 2-5 adverse events.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received at least one dose of study treatment (IL-2 + either 1,200 HCQ or 600 mg/d HCQ).

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Measure Participants	30
Grade 2 adverse event	1 3.3%
Grade 3 adverse event	4 13.3%
Grade 4 adverse event	7 23.3%
Grade 5 adverse event	1 3.3%
Grade 2 adverse event	0 0%
Grade 3 adverse event	4 13.3%
Grade 4 adverse event	13 43.3%
Grade 5 adverse event	0 0%

9. Secondary Outcome

Title	Worst Grade of Adverse Event At Least Possibly Related to Treatment Experienced
Description	Number of participants who experienced Grade 2-5 adverse events that were at least possibly related to study treatment.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received at least one dose of study treatment (IL-2 + either 1,200 HCQ or 600 mg/d HCQ).

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Grade 2 adverse event	1 3.3%
Grade 3 adverse event	5 16.7%
Grade 4 adverse event	7 23.3%
Grade 2 adverse event	0 0%
Grade 3 adverse event	4 13.3%
Grade 4 adverse event	13 43.3%

10. Secondary Outcome

Title	Worst Grade of Adverse Event At Least Probably Related to Treatment Experienced
Description	Number of participants who experienced Grade 2-5 adverse events that were at least probably related to study treatment.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received at least one dose of study treatment (IL-2 + either 1,200 HCQ or 600 mg/d HCQ).

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Grade 2 adverse event	1 3.3%
Grade 3 adverse event	5 16.7%
Grade 4 adverse event	7 23.3%
Grade 2 adverse event	2 6.7%
Grade 3 adverse event	4 13.3%
Grade 4 adverse event	11 36.7%

11. Secondary Outcome

Title	Serum Lactate Dehydrogenase
Description	Number of participants with either high serum lactate dehydrogenase (> 1.5 times upper limit of normal) or normal lactate dehydrogenase.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom LDH was able to be measured from clinical samples and determined to be either normal or high.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ, but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d.
Measure Participants	30
1200 mg/d HCQ	11 36.7%
600 mg/d HCQ	17 56.7%
1200 mg/d HCQ	2 6.7%
600 mg/d HCQ	0 0%

12. Secondary Outcome

Title	Hemoglobin Levels
Description	Low hemoglobin levels (less than the lower limit of normal (13.2 g/dL)) are considered to be unfavorable.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patient that received study treatment for whom hemoglobin levels were able to be measured from clinical samples and determined to be either normal or low.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
1200 mg/d HCQ	6 20%
600 mg/d HCQ	3 10%
1200 mg/d HCQ	7 23.3%
600 mg/d HCQ	14 46.7%

13. Secondary Outcome

Title	Serum Calcium Levels (Corrected)
Description	Number of patients with either normal or high serum calcium levels. High serum calcium levels are considered to be clinically unfavorable.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom serum calcium levels were able to be measured from clinical samples and determined to be either normal or high.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
1200 mg/d HCQ	13 43.3%
600 mg/d HCQ	14 46.7%
1200 mg/d HCQ	0 0%
600 mg/d HCQ	3 10%

14. Secondary Outcome

Title	Prior Nephrectomy
Description	Number of patients with history of a prior nephrectomy (surgical removal of a kidney) or no history of a prior nephrectomy.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment, with or without a history of nephrectomy (surgical removal of a kidney).

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
600 mg/d HCQ	3 10%
1200 mg/d HCQ	0 0%
600 mg/d HCQ	14 46.7%
1200 mg/d HCQ	13 43.3%

15. Secondary Outcome

Title	Number of Participants With Low Karnofsky Performance Status
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patient that received study treatment for whom Karnofsky performance status was able to be assessed.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
1200 mg/d HCQ	0 0%
600 mg/d HCQ	0 0%

16. Secondary Outcome

Title	Natural Killer (NK) Cells
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom Natural Killer (NK) cells were able to be measured.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Mean (Full Range) [percentage of cells]	38.4

17. Secondary Outcome

Title	Myeloid Derived Suppressor Cell (MDSC)
Description	Percentage of Myeloid Derived Suppressor Cell per ml of blood. MDSC immune cells originate from bone marrow stem cells and strongly expand in cancer.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom MDSC were able to be measured.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Mean (Full Range) [percentage of cells/mL]	11.3

18. Secondary Outcome

Title	Regulatory T Cells (Treg)
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom Regulatory T cells (Treg) were able to be measured.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Mean (Full Range) [percentage of cells/mL]	10.5

19. Secondary Outcome

Title	Plasmacytoid Dendritic Cells (pDC)
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom Plasmacytoid dendritic Cells (pDC) were able to be measured.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Mean (Full Range) [percentage of cells/mL]	0.3

20. Secondary Outcome

Title	T-cell Lymphocytes
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom T-Cells were able to be measured.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Mean (Full Range) [percentage of cells/mL]	63.9

21. Secondary Outcome

Title	Conventional Dendritic Cells (cDC)
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients that received study treatment for whom Conventional Dendritic Cells (cDC) were able to be measured.

Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d or 600 mg/d) + IL-2
Arm/Group Description	One course of treatment (84 days) consisted 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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d for initial (13) patients, then 600 mg/d for next (17) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
Measure Participants	30
Mean (Full Range) [percentage of cells/mL]	0.6

Adverse Events

Time Frame	Up to 3 years for cohort.
Arm/Group Title	Hydroxychloroquine (HCQ) (1,200 mg/d ) + IL-2		Hydroxychloroquine (HCQ) (600 mg/d) + IL-2
Arm/Group Description	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. Hydroxychloroquine: Continuous oral administration (at 1,200 mg/d (initial (13) patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).		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. Hydroxychloroquine: Continuous oral administration at 600 mg/d (17 patients) was 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. 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 Note: Patients were initially treated at 1200 mg/d HCQ (13 patients), but after several unexpected adverse events, the dose of HCQ was reduced to 600 mg/d (17 patients).
All Cause Mortality
	Hydroxychloroquine (HCQ) (1,200 mg/d ) + IL-2		Hydroxychloroquine (HCQ) (600 mg/d) + IL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/13 (69.2%)		2/17 (11.8%)
Serious Adverse Events
	Hydroxychloroquine (HCQ) (1,200 mg/d ) + IL-2		Hydroxychloroquine (HCQ) (600 mg/d) + IL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/13 (92.3%)		17/17 (100%)
Blood and lymphatic system disorders
Anemia	1/13 (7.7%)	1	2/17 (11.8%)	4
Cardiac disorders
Atrial fibrillation	1/13 (7.7%)	1	0/17 (0%)	0
Cardiac disorders - Other, specify	2/13 (15.4%)	2	0/17 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/13 (7.7%)	1	0/17 (0%)	0
Diarrhea	0/13 (0%)	0	1/17 (5.9%)	1
Mucositis oral	1/13 (7.7%)	2	1/17 (5.9%)	1
Nausea	1/13 (7.7%)	1	1/17 (5.9%)	1
General disorders
Death NOS	1/13 (7.7%)	1	0/17 (0%)	0
Hepatobiliary disorders
Bile duct stenosis	1/13 (7.7%)	1	0/17 (0%)	0
Investigations
Alanine aminotransferase increased	1/13 (7.7%)	1	0/17 (0%)	0
Alkaline phosphatase increased	1/13 (7.7%)	1	0/17 (0%)	0
Blood bilirubin increased	2/13 (15.4%)	2	1/17 (5.9%)	1
Investigations - Other, specify	0/13 (0%)	0	1/17 (5.9%)	2
Lipase increased	2/13 (15.4%)	8	1/17 (5.9%)	1
Lymphocyte count decreased	6/13 (46.2%)	37	13/17 (76.5%)	66
Neutrophil count decreased	0/13 (0%)	0	2/17 (11.8%)	2
Platelet count decreased	3/13 (23.1%)	4	1/17 (5.9%)	1
Serum amylase increased	3/13 (23.1%)	4	0/17 (0%)	0
Urine output decreased	1/13 (7.7%)	1	0/17 (0%)	0
White blood cell decreased	1/13 (7.7%)	1	0/17 (0%)	0
Metabolism and nutrition disorders
Hypercalcemia	0/13 (0%)	0	1/17 (5.9%)	1
Hyperkalemia	0/13 (0%)	0	1/17 (5.9%)	1
Hypoalbuminemia	5/13 (38.5%)	8	3/17 (17.6%)	6
Hypocalcemia	2/13 (15.4%)	2	0/17 (0%)	0
Hypokalemia	1/13 (7.7%)	1	0/17 (0%)	0
Hyponatremia	2/13 (15.4%)	2	2/17 (11.8%)	3
Hypophosphatemia	6/13 (46.2%)	19	15/17 (88.2%)	41
Nervous system disorders
Akathisia	1/13 (7.7%)	1	0/17 (0%)	0
Psychiatric disorders
Agitation	1/13 (7.7%)	1	0/17 (0%)	0
Anxiety	1/13 (7.7%)	2	2/17 (11.8%)	2
Confusion	1/13 (7.7%)	1	0/17 (0%)	0
Delirium	0/13 (0%)	0	1/17 (5.9%)	1
Renal and urinary disorders
Renal and urinary disorders - Other, specify	2/13 (15.4%)	2	0/17 (0%)	0
Urinary retention	5/13 (38.5%)	10	3/17 (17.6%)	6
Respiratory, thoracic and mediastinal disorders
Apnea	1/13 (7.7%)	1	0/17 (0%)	0
Dyspnea	2/13 (15.4%)	2	1/17 (5.9%)	1
Hypoxia	1/13 (7.7%)	1	0/17 (0%)	0
Pulmonary edema	1/13 (7.7%)	1	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders - Other, specify	1/13 (7.7%)	1	0/17 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/13 (0%)	0	1/17 (5.9%)	1
Vascular disorders
Hypertension	1/13 (7.7%)	1	1/17 (5.9%)	1
Hypotension	6/13 (46.2%)	9	2/17 (11.8%)	2
Other (Not Including Serious) Adverse Events
	Hydroxychloroquine (HCQ) (1,200 mg/d ) + IL-2		Hydroxychloroquine (HCQ) (600 mg/d) + IL-2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		17/17 (100%)
Blood and lymphatic system disorders
Anemia	8/13 (61.5%)	41	13/17 (76.5%)	50
Blood and lymphatic system disorders - Other, specify	1/13 (7.7%)	1	0/17 (0%)	0
Cardiac disorders
Atrial fibrillation	1/13 (7.7%)	1	0/17 (0%)	0
Cardiac disorders - Other, specify	4/13 (30.8%)	6	5/17 (29.4%)	10
Heart failure	0/13 (0%)	0	1/17 (5.9%)	1
Myocarditis	1/13 (7.7%)	1	0/17 (0%)	0
Sinus bradycardia	0/13 (0%)	0	1/17 (5.9%)	1
Sinus tachycardia	7/13 (53.8%)	14	6/17 (35.3%)	8
Endocrine disorders
Hypothyroidism	1/13 (7.7%)	1	0/17 (0%)	0
Eye disorders
Blurred vision	0/13 (0%)	0	1/17 (5.9%)	1
Eye disorders - Other, specify	1/13 (7.7%)	1	0/17 (0%)	0
Flashing lights	0/13 (0%)	0	1/17 (5.9%)	1
Photophobia	1/13 (7.7%)	1	1/17 (5.9%)	1
Gastrointestinal disorders
Abdominal pain	3/13 (23.1%)	6	3/17 (17.6%)	3
Ascites	1/13 (7.7%)	1	0/17 (0%)	0
Constipation	4/13 (30.8%)	4	1/17 (5.9%)	1
Diarrhea	11/13 (84.6%)	27	13/17 (76.5%)	28
Dry mouth	2/13 (15.4%)	3	1/17 (5.9%)	1
Dyspepsia	3/13 (23.1%)	5	1/17 (5.9%)	1
Gastroesophageal reflux disease	0/13 (0%)	0	1/17 (5.9%)	1
Gastrointestinal disorders - Other, specify	2/13 (15.4%)	2	2/17 (11.8%)	3
Mucositis oral	6/13 (46.2%)	10	7/17 (41.2%)	11
Nausea	12/13 (92.3%)	30	14/17 (82.4%)	40
Oral pain	1/13 (7.7%)	2	0/17 (0%)	0
Pancreatitis	3/13 (23.1%)	4	0/17 (0%)	0
Vomiting	9/13 (69.2%)	21	11/17 (64.7%)	25
General disorders
Chills	9/13 (69.2%)	16	8/17 (47.1%)	17
Death NOS	1/13 (7.7%)	1	0/17 (0%)	0
Edema face	0/13 (0%)	0	2/17 (11.8%)	2
Edema limbs	9/13 (69.2%)	19	10/17 (58.8%)	18
Fatigue	9/13 (69.2%)	28	12/17 (70.6%)	34
Fever	3/13 (23.1%)	4	7/17 (41.2%)	23
Gait disturbance	1/13 (7.7%)	1	0/17 (0%)	0
General disorders and administration site conditions - Other, specify	8/13 (61.5%)	18	9/17 (52.9%)	18
Localized edema	0/13 (0%)	0	1/17 (5.9%)	2
Malaise	3/13 (23.1%)	3	0/17 (0%)	0
Non-cardiac chest pain	1/13 (7.7%)	1	1/17 (5.9%)	1
Pain	1/13 (7.7%)	1	5/17 (29.4%)	6
Hepatobiliary disorders
Bile duct stenosis	1/13 (7.7%)	1	0/17 (0%)	0
Immune system disorders
Allergic reaction	0/13 (0%)	0	3/17 (17.6%)	3
Infections and infestations
Mucosal infection	0/13 (0%)	0	1/17 (5.9%)	1
Sinusitis	0/13 (0%)	0	1/17 (5.9%)	1
Skin infection	1/13 (7.7%)	1	0/17 (0%)	0
Soft tissue infection	0/13 (0%)	0	1/17 (5.9%)	1
Tooth infection	0/13 (0%)	0	1/17 (5.9%)	1
Upper respiratory infection	1/13 (7.7%)	1	1/17 (5.9%)	3
Urinary tract infection	0/13 (0%)	0	2/17 (11.8%)	2
Injury, poisoning and procedural complications
Fall	0/13 (0%)	0	1/17 (5.9%)	1
Investigations
Activated partial thromboplastin time prolonged	0/13 (0%)	0	1/17 (5.9%)	1
Alanine aminotransferase increased	6/13 (46.2%)	9	8/17 (47.1%)	12
Alkaline phosphatase increased	8/13 (61.5%)	26	6/17 (35.3%)	16
Aspartate aminotransferase increased	7/13 (53.8%)	10	8/17 (47.1%)	9
Blood bilirubin increased	8/13 (61.5%)	23	9/17 (52.9%)	22
CPK increased	3/13 (23.1%)	5	1/17 (5.9%)	1
Cardiac troponin I increased	1/13 (7.7%)	1	0/17 (0%)	0
Creatinine increased	7/13 (53.8%)	39	12/17 (70.6%)	64
INR increased	0/13 (0%)	0	4/17 (23.5%)	5
Investigations - Other, specify	5/13 (38.5%)	9	11/17 (64.7%)	15
Lipase increased	4/13 (30.8%)	21	6/17 (35.3%)	12
Lymphocyte count decreased	6/13 (46.2%)	43	13/17 (76.5%)	76
Neutrophil count decreased	2/13 (15.4%)	3	4/17 (23.5%)	6
Platelet count decreased	8/13 (61.5%)	25	12/17 (70.6%)	45
Serum amylase increased	4/13 (30.8%)	18	2/17 (11.8%)	7
Urine output decreased	1/13 (7.7%)	1	1/17 (5.9%)	1
Weight gain	5/13 (38.5%)	6	8/17 (47.1%)	12
Weight loss	2/13 (15.4%)	3	3/17 (17.6%)	4
White blood cell decreased	5/13 (38.5%)	8	6/17 (35.3%)	13
Metabolism and nutrition disorders
Acidosis	1/13 (7.7%)	1	0/17 (0%)	0
Anorexia	6/13 (46.2%)	11	6/17 (35.3%)	13
Hypercalcemia	1/13 (7.7%)	2	2/17 (11.8%)	5
Hyperglycemia	0/13 (0%)	0	4/17 (23.5%)	4
Hyperkalemia	6/13 (46.2%)	13	4/17 (23.5%)	10
Hypermagnesemia	1/13 (7.7%)	1	3/17 (17.6%)	6
Hypertriglyceridemia	1/13 (7.7%)	1	0/17 (0%)	0
Hyperuricemia	0/13 (0%)	0	1/17 (5.9%)	1
Hypoalbuminemia	8/13 (61.5%)	61	14/17 (82.4%)	77
Hypocalcemia	7/13 (53.8%)	14	12/17 (70.6%)	30
Hypoglycemia	2/13 (15.4%)	2	1/17 (5.9%)	1
Hypokalemia	3/13 (23.1%)	3	6/17 (35.3%)	9
Hypomagnesemia	11/13 (84.6%)	28	16/17 (94.1%)	48
Hyponatremia	9/13 (69.2%)	28	13/17 (76.5%)	36
Hypophosphatemia	10/13 (76.9%)	37	16/17 (94.1%)	75
Metabolism and nutrition disorders - Other, specify	2/13 (15.4%)	4	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/13 (0%)	0	1/17 (5.9%)	1
Arthritis	1/13 (7.7%)	2	2/17 (11.8%)	2
Back pain	2/13 (15.4%)	2	2/17 (11.8%)	2
Chest wall pain	1/13 (7.7%)	1	0/17 (0%)	0
Musculoskeletal and connective tissue disorder - Other, specify	2/13 (15.4%)	3	2/17 (11.8%)	4
Myalgia	0/13 (0%)	0	2/17 (11.8%)	2
Neck pain	0/13 (0%)	0	1/17 (5.9%)	1
Pain in extremity	0/13 (0%)	0	3/17 (17.6%)	3
Nervous system disorders
Akathisia	1/13 (7.7%)	2	2/17 (11.8%)	2
Dizziness	1/13 (7.7%)	1	3/17 (17.6%)	3
Dysgeusia	3/13 (23.1%)	4	3/17 (17.6%)	6
Headache	4/13 (30.8%)	4	4/17 (23.5%)	5
Nervous system disorders - Other, specify	3/13 (23.1%)	3	3/17 (17.6%)	6
Paresthesia	1/13 (7.7%)	1	0/17 (0%)	0
Peripheral sensory neuropathy	1/13 (7.7%)	1	1/17 (5.9%)	1
Tremor	1/13 (7.7%)	1	0/17 (0%)	0
Psychiatric disorders
Agitation	2/13 (15.4%)	2	1/17 (5.9%)	1
Anxiety	5/13 (38.5%)	14	11/17 (64.7%)	17
Confusion	3/13 (23.1%)	4	2/17 (11.8%)	2
Delirium	0/13 (0%)	0	2/17 (11.8%)	2
Hallucinations	1/13 (7.7%)	1	4/17 (23.5%)	4
Insomnia	5/13 (38.5%)	6	5/17 (29.4%)	5
Psychiatric disorders - Other, specify	2/13 (15.4%)	2	1/17 (5.9%)	1
Restlessness	0/13 (0%)	0	1/17 (5.9%)	1
Renal and urinary disorders
Acute kidney injury	3/13 (23.1%)	3	0/17 (0%)	0
Hematuria	2/13 (15.4%)	2	0/17 (0%)	0
Proteinuria	6/13 (46.2%)	8	4/17 (23.5%)	11
Renal and urinary disorders - Other, specify	2/13 (15.4%)	2	4/17 (23.5%)	5
Urinary retention	6/13 (46.2%)	12	5/17 (29.4%)	10
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/13 (23.1%)	4	1/17 (5.9%)	1
Apnea	1/13 (7.7%)	1	0/17 (0%)	0
Cough	2/13 (15.4%)	5	7/17 (41.2%)	7
Dyspnea	10/13 (76.9%)	15	7/17 (41.2%)	8
Epistaxis	0/13 (0%)	0	1/17 (5.9%)	1
Hiccups	1/13 (7.7%)	1	0/17 (0%)	0
Hoarseness	1/13 (7.7%)	1	0/17 (0%)	0
Hypoxia	3/13 (23.1%)	3	0/17 (0%)	0
Pleural effusion	0/13 (0%)	0	1/17 (5.9%)	1
Pulmonary edema	1/13 (7.7%)	1	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders - Other, specify	2/13 (15.4%)	3	5/17 (29.4%)	8
Wheezing	3/13 (23.1%)	3	0/17 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/13 (0%)	0	1/17 (5.9%)	1
Dry skin	7/13 (53.8%)	10	9/17 (52.9%)	20
Erythema multiforme	2/13 (15.4%)	2	0/17 (0%)	0
Pruritus	11/13 (84.6%)	22	10/17 (58.8%)	21
Rash acneiform	2/13 (15.4%)	2	1/17 (5.9%)	1
Rash maculo-papular	0/13 (0%)	0	3/17 (17.6%)	5
Skin and subcutaneous tissue disorders - Other, specify	3/13 (23.1%)	3	4/17 (23.5%)	4
Skin hyperpigmentation	0/13 (0%)	0	1/17 (5.9%)	1
Urticaria	0/13 (0%)	0	1/17 (5.9%)	1
Vascular disorders
Capillary leak syndrome	0/13 (0%)	0	4/17 (23.5%)	4
Flushing	8/13 (61.5%)	15	8/17 (47.1%)	19
Hot flashes	0/13 (0%)	0	1/17 (5.9%)	1
Hypertension	1/13 (7.7%)	1	4/17 (23.5%)	6
Hypotension	11/13 (84.6%)	26	12/17 (70.6%)	29
Superficial thrombophlebitis	0/13 (0%)	0	1/17 (5.9%)	1
Thromboembolic event	0/13 (0%)	0	2/17 (11.8%)	2
Vascular disorders - Other, specify	1/13 (7.7%)	1	1/17 (5.9%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.