SELECT: The High-Dose Aldesleukin (IL-2) "Select" Trial for Patients With Metastatic Renal Cell Carcinoma

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00554515
• Collaborator: City of Hope National Medical Center (Other), Providence Cancer Center, Earle A. Chiles Research Institute (Other), Dartmouth-Hitchcock Medical Center (Other), Indiana University (Other), Loyola University (Other), Our Lady of Mercy Medical Center (Other), Roswell Park Cancer Institute (Other), University of California, Los Angeles (Other), University of Cincinnati (Other), University of Pittsburgh (Other), University of Virginia (Other), Vanderbilt University (Other), Wayne State University (Other)
• Enrollment: 123
• Location: 1
• Arm: 1
• Duration (Months): 84
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

High-dose interleukin 2 (Proleukin, Novartis) (IL-2) is approved by the U.S Food and Drug Administration (FDA) for the treatment of metastatic kidney cancer and is a standard treatment of this disease. At the present time, IL-2 is the only therapy for kidney cancer that can produce a remission of disease that lasts after treatment is completed. However, most patients who receive IL-2 do not benefit and all patients experience potentially dangerous side effects.

Recent research has suggested that certain patients may respond better to IL-2 than others. The Cytokine Working Group is currently conducting a clinical trial that aims to identify and confirm this research and narrow the application of IL-2 to those patients most likely to benefit.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Renal Cell Carcinoma	Drug: HD IL2	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine, in a prospective fashion, if the response rate to high-dose IL-2 for patients with metastatic renal cell carcinoma and "good" pathologic predictive features is significantly higher than a historical, unselected patient population.

Secondary

• To determine, in a prospective fashion, the response rate to high-dose IL-2 for patients with metastatic renal cell carcinoma and "poor" pathologic predictive features and to compare this response rate to the response rate of patients with "good" pathologic predictive features.

• To determine if components of other predictive and prognostic models (e.g MSKCI or UCLA criteria) can help to further define the optimal population to receive high-dose IL2 for metastatic renal cell carcinoma.

• To identify features of the baseline immune function (arginine, arginase, T cell zeta chain) of patients with metastatic renal cell carcinoma that are associated with response to high-dose IL-2.

• To identify new proteins or patterns of gene expression that might be associated with high-dose IL-2 responsiveness in order to further narrow the application of IL-2 therapy to those who will benefit the most.

Study Design

• Study Type: Interventional
• Actual Enrollment: 123 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The High-Dose Aldesleukin (IL-2) "Select" Trial: A Trial Designed to Prospectively Validate Predictive Models of Response to High Dose IL-2 Treatment in Patients With Metastatic Renal Cell Carcinoma
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Oct 31, 2013
• Actual Study Completion Date: Oct 31, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: HD IL2 Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.

Drug: HD IL2; Other Names: Proleukin Aldesleukin

Outcome Measures

Primary Outcome Measures

1. Objective Response in ISM Good Risk Group [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by investigator assessment of radiographs.

Secondary Outcome Measures

1. Objective Response Rate in ISM Poor Risk Group [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on treatment on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

2. Objective Response Rate (Independent Assessment) [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks.. Response status was determined by independent assessment of radiographs.

3. Overall Survival [Participants were followed for survival up to 7 years.]

   Overall survival based on the Kaplan-Meier method is defined as the time from treatment start to date of death or censored at the date of last documented contact.

4. 3-Year Progression-Free Survival Rate [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Long-term follow-up occurred every 3 m for 2 yrs, semi-annually for yr 3 and annually for yrs 4 and 5. Relevant for this endpoint was disease status at 3 y.]

   3-year progression-free survival rate is defined as the proportion of patients absent death or progression based on WHO criteria by 3 years since time of treatment start. PD is a >/=25% increase in the sum of products of the perpendicular diameters of all measurable lesions. Further, PD is the appearance of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions.

5. Objective Response Rate by MSKCC Risk Group [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

6. Objective Response Rate by UCLA SANI Score [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

7. Objective Response Rate by Tumor Type [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

8. Objective Response Rate by Clear Cell Histology Risk Group [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Response status was confirmed by an independent assessment of radiographs. Participants received up to 3 courses of 12 weeks duration each.]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks.

9. Objective Response Rate by CA-9 Score (CAIX Classification) [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

10. Objective Response Rate by PD-L1 Tumor [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

    The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

11. Objective Response Rate by B7-H3 Tumor [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

    The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

12. Objective Response Rate by CA-9 SNP [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).]

    The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.

13. Progression-Free Survival [Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Long-term follow-up occurred every 3 m for 2 yrs, semi-annually for yr 3 and annually for yrs 4 and 5. Median survival follow-up was X months (95% CI: ).]

    Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from treatment start to date of disease progression (PD) or death. Per WHO criteria: PD is a >/=25% increase in the sum of products of the perpendicular diameters of all measurable lesions. Further, PD is the appearance of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. Participants who were event-free were censored at the date of their last disease evaluation.

Other Outcome Measures

1. VHL Genotype Status [Determined from baseline sample.]

   VHL genotype status will be determined based on establish methods.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically confirmed renal cell carcinoma that is metastatic or unresectable.

• If patients have measurable disease restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.

• Patients must provide access to tissue blocks containing adequate tumor for interpretation and analysis.

• Patients must have measurable disease.

• Patients must have good performance status (ECOG 0 or 1; Karnofsky PS 100-80%).

• Patients must have adequate organ function.

• Patients must have no contraindication of vasopressor agents.

• Patients must be ≥ 18 years of age.

Exclusion Criteria:

• Patients who have received systemic therapy for metastatic disease.

• Patients with organ allografts.

• Patients who require or are likely to require systemic corticosteroid therapy for intercurrent illness.

• Patients with any significant medical disease other than the malignancy (e.g. COPD, patients with ascites or pleural effusions), which in the opinion of the investigator would significantly increase the risk of immunotherapy.

• Patients with a history of another malignancy within the past 5 years other than surgically cured non-melanoma skin cancer, carcinoma-in-situ or Stage I carcinoma of the cervix.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• City of Hope National Medical Center
• Providence Cancer Center, Earle A. Chiles Research Institute
• Dartmouth-Hitchcock Medical Center
• Indiana University
• Loyola University
• Our Lady of Mercy Medical Center
• Roswell Park Cancer Institute
• University of California, Los Angeles
• University of Cincinnati
• University of Pittsburgh
• University of Virginia
• Vanderbilt University
• Wayne State University

Investigators

• Study Chair: David F McDermott, MD, Beth Israel Deaconess Medical Center
• Principal Investigator: Kim Margolin, MD, City of Hope National Medical Center
• Principal Investigator: Walter Urba, MD, Chiles Cancer Center
• Principal Investigator: Marc Ernstoff, MD, Dartmouth-Hitchcock Medical Center
• Principal Investigator: Theodore Logan, MD, Indiana University
• Principal Investigator: Joseph Clark, MD, Loyola University
• Principal Investigator: Janice Dutcher, MD, Our Lady of Mercy Cancer Center
• Principal Investigator: Michael Wong, MD, Roswell Park Cancer Institute
• Principal Investigator: Allen Pantuck, MD, University of California, Los Angeles
• Principal Investigator: Leslie Oleksowicz, MD, University of Cincinnati
• Principal Investigator: Leonard Appleman, MD, University of Pittsburgh
• Principal Investigator: Geoffrey Weiss, MD, University of Virginia
• Principal Investigator: Jeffrey Sosman, MD, Vanderbilt University
• Principal Investigator: Ulka Vaishampayan, MD, Wayne State University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, Febbo P, Upton M, Lechpammer M, Signoretti S. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res. 2005 May 15;11(10):3714-21.
• McDermott DF. Update on the application of interleukin-2 in the treatment of renal cell carcinoma. Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):716s-720s. Review. Retraction in: Clin Cancer Res. 2018 Aug 1;24(15):3783.

• Responsible Party: David F. McDermott, MD, Principal Investigator, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT00554515
• Other Study ID Numbers: DFHCC 06-149; NCT00536757
• First Posted: Nov 7, 2007
• Last Update Posted: Jul 14, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by David F. McDermott, MD, Principal Investigator, Beth Israel Deaconess Medical Center: Kidney; Renal Cell; Metastatic; interleukin-2; select
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Aldesleukin

Study Results

Participant Flow

Recruitment Details	Participants enrolled from 13 institutions between November 2006 and November 2008.

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Period Title: Overall Study
STARTED	123
Treated	120
COMPLETED	5
NOT COMPLETED	118

Baseline Characteristics

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Overall Participants	120
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	35 29.2%
Male	85 70.8%
Region of Enrollment (participants) [Number]
United States	120 100%
MSKCC Risk Group (Count of Participants)
Favorable	23 19.2%
Intermediate	84 70%
Poor	13 10.8%
UCLA SANI Score (Count of Participants)
Low	10 8.3%
Intermediate	102 85%
High	8 6.7%
ISM Risk Group (Count of Participants)
Good	74 61.7%
Poor	43 35.8%
Unknown	3 2.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response in ISM Good Risk Group
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by investigator assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data for ISM analysis and classified as ISM good risk.

Arm/Group Title	ISM Good Risk Group
Arm/Group Description	ISM [Atkins et al CCR 2005]: Good predictive pathology OR the combination of intermediate predictive pathology and high CAIX staining Pathology [Upton et al. J Immunother 2005] Good predictive pathology: clear-cell histology AND no papillary features AND >50% alveolar features AND no granular features Intermediate predictive pathology: clear-cell histology AND no papillary features AND some (>0%) alveolar features AND 50% granular features CAIX [Bui et al. CCR 2003] High CAIX staining: >85% of CAIX positive tumor cells
Measure Participants	74
Number (95% Confidence Interval) [proportion of participants]	.23 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group
	Comments
	Type of Statistical Test	Superiority
	Comments	Comparison against historical control ORR of 14%.
Statistical Test of Hypothesis	p-Value	0.042
	Comments
	Method	exact binomial test
	Comments

2. Secondary Outcome

Title	Objective Response Rate in ISM Poor Risk Group
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on treatment on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data for ISM analysis and classified as ISM poor risk.

Arm/Group Title	ISM Poor Risk Group
Arm/Group Description	ISM [Atkins et al CCR 2005]: Poor predictive pathology OR the combination of intermediate predictive pathology and low CAIX staining Pathology [Upton et al. J Immunother 2005] Poor predictive pathology: non-clear-cell histology OR some (>0%) papillary features OR no alveolar features OR >50% granular features Intermediate predictive pathology: clear-cell histology AND no papillary features AND some (>0%) alveolar features AND 50% granular features CAIX [Bui et al. CCR 2003] Low CAIX staining: </=85% of CAIX positive tumor cells
Measure Participants	43
Number (95% Confidence Interval) [proportion of participants]	.23 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group
	Comments	Objective response rates were compared between ISM good and poor risk subgroups. ISM good risk ORR reported under primary endpoint.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Objective Response Rate (Independent Assessment)
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks.. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Measure Participants	120
Number (95% Confidence Interval) [proportion of participants]	.25 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group
	Comments	Test against the historical ORR was conducted in the overall study population as secondary analyses.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	exact binomial test
	Comments

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival based on the Kaplan-Meier method is defined as the time from treatment start to date of death or censored at the date of last documented contact.
Time Frame	Participants were followed for survival up to 7 years.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Measure Participants	120
Median (95% Confidence Interval) [months]	42.8

5. Secondary Outcome

Title	3-Year Progression-Free Survival Rate
Description	3-year progression-free survival rate is defined as the proportion of patients absent death or progression based on WHO criteria by 3 years since time of treatment start. PD is a >/=25% increase in the sum of products of the perpendicular diameters of all measurable lesions. Further, PD is the appearance of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Long-term follow-up occurred every 3 m for 2 yrs, semi-annually for yr 3 and annually for yrs 4 and 5. Relevant for this endpoint was disease status at 3 y.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Measure Participants	120
Number (95% Confidence Interval) [proportion of participants]	.108 0.1%

6. Secondary Outcome

Title	Objective Response Rate by MSKCC Risk Group
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	Favorable MSKCC Risk Group	Intermediate MSKCC Risk Group	Poor MSKCC Risk Group
Arm/Group Description	MSKCC developed a nomogram that is used to classify patients into 3 renal cell carcinoma (RCC) 5-year disease recurrence risk groups (low, intermediate, and high) using data from patients treated at MSK. The components of the nomogram include RCC histology, disease symptoms, pT stage, and tumor size.	MSKCC developed a nomogram that is used to classify patients into 3 renal cell carcinoma (RCC) 5-year disease recurrence risk groups (low, intermediate, and high) using data from patients treated at MSK. The components of the nomogram include RCC histology, disease symptoms, pT stage, and tumor size.	MSKCC developed a nomogram that is used to classify patients into 3 renal cell carcinoma (RCC) 5-year disease recurrence risk groups (low, intermediate, and high) using data from patients treated at MSK. The components of the nomogram include RCC histology, disease symptoms, pT stage, and tumor size.
Measure Participants	23	84	13
Number (95% Confidence Interval) [proportion of participants]	.22 0.2%	.25 NaN	.31 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group, Intermediate MSKCC Risk Group, Poor MSKCC Risk Group
	Comments	Objective response rates were compared between MSKCC subgroups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.89
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Objective Response Rate by UCLA SANI Score
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	Low UCLA SANI Score	Intermediate UCLA SANI Score	High UCLA SANI Score
Arm/Group Description	This tool predicts RCC patient's survival based on lymph node status, metastases, sarcomatoid feature, and TSH level. Patients are classified into 3 groups (low, intermediate, and high).	This tool predicts RCC patient's survival based on lymph node status, metastases, sarcomatoid feature, and TSH level. Patients are classified into 3 groups (low, intermediate, and high).	This tool predicts RCC patient's survival based on lymph node status, metastases, sarcomatoid feature, and TSH level. Patients are classified into 3 groups (low, intermediate, and high).
Measure Participants	10	102	8
Number (95% Confidence Interval) [proportion of participants]	.20 0.2%	.27 NaN	.00 NaN

8. Secondary Outcome

Title	Objective Response Rate by Tumor Type
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	Clear Cell Tumor Type	Non-clear Cell Tumor Type
Arm/Group Description
Measure Participants	114	5
Number (95% Confidence Interval) [proportion of participants]	.26 0.2%	.00 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group, Intermediate MSKCC Risk Group
	Comments	Objective response rates were compared between tumor type subgroups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.33
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Objective Response Rate by Clear Cell Histology Risk Group
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Response status was confirmed by an independent assessment of radiographs. Participants received up to 3 courses of 12 weeks duration each.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	Good Clear Cell Histology Risk Group	Intermediate Clear Cell Histology Risk Group	Poor Clear Cell Histology Risk Group
Arm/Group Description
Measure Participants	11	83	25
Number (95% Confidence Interval) [proportion of participants]	.27 0.2%	.24 NaN	.28 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group, Intermediate MSKCC Risk Group, Poor MSKCC Risk Group
	Comments	Objective response rates were compared between clear cell histology subgroups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.89
	Comments
	Method	Fisher Exact
	Comments

10. Secondary Outcome

Title	Objective Response Rate by CA-9 Score (CAIX Classification)
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	High CA-9 Score	Low CA-9 Score
Arm/Group Description	This score is based on the expression of the CA 9 protein (encoded by the CA9 gene) assessed from patient's tumor specimen. CA 9 expression score is quantified by immunohistochemical analysis using CA9 monoclonal antibody (M75); High is >85% of CAIX positive tumor cells.	This score is based on the expression of the CA 9 protein (encoded by the CA9 gene) assessed from patient's tumor specimen. CA 9 expression score is quantified by immunohistochemical analysis using CA9 monoclonal antibody (M75); Low is </=85% of CAIX positive tumor cells
Measure Participants	78	39
Number (95% Confidence Interval) [proportion of participants]	.33 0.3%	.22 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intermediate MSKCC Risk Group
	Comments	Objective response rates were compared between CA-9 score subgroups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.19
	Comments
	Method	Fisher Exact
	Comments

11. Secondary Outcome

Title	Objective Response Rate by PD-L1 Tumor
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	PD-L1 Tumor Negative	PD-L1 Tumor Positive
Arm/Group Description
Measure Participants	95	18
Number (95% Confidence Interval) [proportion of patients]	.19	.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group, Intermediate MSKCC Risk Group
	Comments	Objective response rates were compared between PD-L1 tumor subgroups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Fisher Exact
	Comments

12. Secondary Outcome

Title	Objective Response Rate by B7-H3 Tumor
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	Negative	Positive
Arm/Group Description
Measure Participants	29	86
Number (95% Confidence Interval) [proportion of participants]	.11 0.1%	.29 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group, Intermediate MSKCC Risk Group
	Comments	Objective response rates were compared between B7-H3 tumor subgroups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.08
	Comments
	Method	Fisher Exact
	Comments

13. Secondary Outcome

Title	Objective Response Rate by CA-9 SNP
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by independent assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients with available tumor tissue/data.

Arm/Group Title	CA-9 SNP Homozygous	CA-9 SNP Variant
Arm/Group Description	Patient's SNP (Single Nucleotide Polymorphism) status is determined by sequencing their tumor specimens. Patients are classified as homozygous or variant based on the observed nucleotide sequence.	Patient's SNP (Single Nucleotide Polymorphism) status is determined by sequencing their tumor specimens. Patients are classified as homozygous or variant based on the observed nucleotide sequence.
Measure Participants	66	12
Number (95% Confidence Interval) [proportion of participants]	.20 0.2%	.33 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ISM Good Risk Group, Intermediate MSKCC Risk Group
	Comments	Objective response rates were compared between CA-9 SNP subgroups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.28
	Comments
	Method	Fisher Exact
	Comments

14. Secondary Outcome

Title	Progression-Free Survival
Description	Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from treatment start to date of disease progression (PD) or death. Per WHO criteria: PD is a >/=25% increase in the sum of products of the perpendicular diameters of all measurable lesions. Further, PD is the appearance of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. Participants who were event-free were censored at the date of their last disease evaluation.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Long-term follow-up occurred every 3 m for 2 yrs, semi-annually for yr 3 and annually for yrs 4 and 5. Median survival follow-up was X months (95% CI: ).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Measure Participants	120
Median (95% Confidence Interval) [months]	4.2

15. Other Pre-specified Outcome

Title	VHL Genotype Status
Description	VHL genotype status will be determined based on establish methods.
Time Frame	Determined from baseline sample.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Post-Hoc Outcome

Title	Serum Arginine Levels
Description	Serum arginine levels will be determined based on establish immunohistochemical methods.
Time Frame	Determined from baseline sample.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Post-Hoc Outcome

Title	KIR Genotype Status
Description	Killer-immunoglobulin-like receptor (KIR) genotype status determined based on establish methods.
Time Frame	Determined from baseline sample.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Post-Hoc Outcome

Title	Objective Response Rate (Investigator Assessment)
Description	The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on World Health Organization (WHO) criteria. [Miller et al. Cancer 1981] Per WHO, evaluation of tumor measurements of measurable lesions centers on the percent change from baseline in the sum of the perpendicular diameters. Complete Response (CR) is disappearance of all clinical and laboratory evidence of disease; Partial Response (PR) is a >/= 50% decrease. PR status also requires no simultaneous increase in the size of any metastatic lesion, absence of one or more new metastatic lesions and/or unequivocal progression of existing non-target lesions. CR and PR status needs confirmation within 4 weeks. Response status was determined by investigator assessment of radiographs.
Time Frame	Disease was evaluated radiologically at baseline and during weeks 8 and 12 of each course. Participants received up to 3 courses of 12 weeks duration each. Median (range) days on treatment: 20 (1-262).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all treated patients.

Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
Measure Participants	120
Number (95% Confidence Interval) [proportion of participants]	0.283 0.2%

Adverse Events

Time Frame	Adverse events were assessed continuously throughout treatment. Treatment duration was a median of 3 courses (duration of 12 weeks each) in this study cohort. Note: one grade 2 serious adverse event (SAE), one grade 3 other adverse event (OAE) and one grade 4 OAE are missing from the tables because codes/description of these events are unknown but these patients are included in the overall number affected.
Adverse Event Reporting Description	Serious AEs: AE that results in death; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly or birth defect; or is an important medical event when, based upon appropriate medical judgment, it may jeopardize the participant and require medical or surgical intervention to prevent one of the above outcomes. Other AEs: Remaining AEs (max grade) with trt-attribution of possibly, probably or definitely.
Arm/Group Title	HD IL2
Arm/Group Description	Participants received high-dose (HD) IL2, 600,000 IU/kg/dose (Prometheus Laboratories Inc.) i.v. every 8 hours for 5 days (maximum of 14 doses) beginning on day 1 and again on day 15. One course generally consisted of 5 days of treatment, 9 days of rest, 5 more days of treatment, and 9 weeks of rest, followed by up to two additional courses of HD IL2 for patients who benefited and tolerated most of the planned IL2 doses. A treatment delay of up to 4 weeks was allowed for resolution of side effects between courses. Patients were eligible to receive a maximum of three courses of treatment.
All Cause Mortality
	HD IL2
	Affected / at Risk (%)	# Events
Total	3/120 (2.5%)
Serious Adverse Events
	HD IL2
	Affected / at Risk (%)	# Events
Total	15/120 (12.5%)
Blood and lymphatic system disorders
Hemoglobin	1/120 (0.8%)
Cardiac disorders
Cardiac-ischemia	1/120 (0.8%)
Pericardial effusion (non-malignant)	1/120 (0.8%)
Cardiac-other	2/120 (1.7%)
General disorders
Fatigue	3/120 (2.5%)
Fever w/o neutropenia	1/120 (0.8%)
Constitutional, other	1/120 (0.8%)
Hepatobiliary disorders
Liver dysfunction/failure	1/120 (0.8%)
Injury, poisoning and procedural complications
Fracture	1/120 (0.8%)
Investigations
Lymphopenia	2/120 (1.7%)
Platelets	1/120 (0.8%)
Bilirubin	3/120 (2.5%)
Creatinine	3/120 (2.5%)
Metabolism and nutrition disorders
Hypocalcemia	1/120 (0.8%)
Hypophosphatemia	1/120 (0.8%)
Hyponatremia	2/120 (1.7%)
Psychiatric disorders
Confusion	1/120 (0.8%)
Renal and urinary disorders
Renal failure	2/120 (1.7%)
Respiratory, thoracic and mediastinal disorders
Edema, larynx	1/120 (0.8%)
Skin and subcutaneous tissue disorders
Rash/desquamation	1/120 (0.8%)
Vascular disorders
Hypotension	2/120 (1.7%)
Other (Not Including Serious) Adverse Events
	HD IL2
	Affected / at Risk (%)	# Events
Total	2/120 (1.7%)
Eye disorders
Uveitis	1/120 (0.8%)
Renal and urinary disorders
Renal failure	1/120 (0.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.