Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, Nivolumab In Metastatic Clear Cell Renal Cell Cancer

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02989714
• Collaborator: (none)
• Enrollment: 13
• Locations: 4
• Arm: 1
• Actual Duration (Months): 39.3
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This will be a single arm, multi-site phase Ib/II clinical trial of standard doses of High Dose Interleukin-2 (HD IL2) (600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart) in IL-2 eligible clear cell metastatic RCC (Renal Cell Carcinoma) subjects in combination with Nivolumab.

Investigators hypothesize that concurrent PD-1 inhibition synergistically enhances the anti-tumor immune response to HD IL-2 in metastatic clear cell RCC. Investigators postulate that the combination of the two therapies would result in an increase in the overall response rate, complete response rate, and improved survival outcomes compared to either of the individual therapies.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Interleukin-2; Drug: Nivolumab	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, Nivolumab In Metastatic Clear Cell Renal Cell Cancer
• Actual Study Start Date: Mar 16, 2017
• Actual Primary Completion Date: Feb 25, 2019
• Actual Study Completion Date: Jun 23, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HD IL2 and Nivolumab	Drug: Interleukin-2; 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart; Other Names: High Dose Interleukin-2 ; Drug: Nivolumab; Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression

Outcome Measures

Primary Outcome Measures

1. The Number of Patients With Grade 3 and Grade 4 Adverse Events of Interest [28 days from the first dose of Nivolumab]

   This is the primary outcome for the Phase Ib portion of the trial. Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.

2. The Number of Patients That Respond to Treatment [12 Weeks]

   This is the primary outcome for the Phase II portion of the trial. Includes complete response (CR) + partial response (PR), measured by computerized tomography (CT) or magnetic resonance imaging (MRI) scan and assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Secondary Outcome Measures

1. Number of Grade 3-5 Adverse Events of Interest [For the duration of the therapy plus 60 days post treatment]

   Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.

2. Overall Survival at 24 Months [24 Months]

   Overall survival at 24 months following the first dose of study therapy; 24 month estimates were reported using the product limit method of Kaplan and Meier along with 95% confidence intervals.

3. Progression Free Survival (PFS) at 24 Months [24 Months]

   PFS is defined as the time from start of study therapy with Nivolumab until progression or death; up to 24 months. Progressive disease is defined as At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects must have a histologic diagnosis of clear cell renal cell carcinoma (pure or mixed) with radiologic or histologic or cytologic evidence of metastatic disease.

• Subjects may have received up to 2 prior lines of systemic therapy (excluding any neoadjuvant/adjuvant therapy) including anti-VEGF or VEGFR inhibitor (e.g. sorafenib, pazopanib, sunitinib, bevacizumab, axitinib) or mTOR inhibitor (e.g. everolimus or temsirolimus) for metastatic disease.

• Age ≥ 18 years at the time of consent.

• ECOG (Eastern Cooperative Oncology Group) performance status (an attempt to quantify cancer patients' general well-being and activities of daily life. The score ranges from 0 to 5 where 0 is asymptomatic and 5 is death.) of 0 or 1

• Adequate organ and marrow function

• Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to prior to registration. Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. All others are considered women of child bearing potential.

• Females and males of childbearing potential must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 6 months after treatment discontinuation.

• Subjects must have measurable disease on physical exam or imaging

• An archived tissue block with the subject's renal cell carcinoma must be identified prior to registration.

• Subjects must be considered appropriate candidates for HD IL-2 by one of the treating investigators listed on the protocol. HD IL-2 candidacy evaluation is per institutional guidelines at each site and should include a dobutamine stress echocardiogram or equivalent. Subjects with a positive stress test for cardiac ischemia would be excluded from this trial.

• No clinically significant infections or any other medical condition(s) that render the subject ineligible for high dose IL-2 therapy as judged by the treating investigator.

• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Prior interferon or interleukin-2 therapy is NOT allowed.

• Prior anti-PD-1/PD-L1 targeted therapy is NOT allowed. Prior CTLA-4 therapy or CD40/CD40L targeted therapy is allowed.

• Prior systemic treatment must be completed at least 14 calendar days prior to registration and the subject must have recovered from the toxicities of treatment to grade 1 or better.

• Prior radiation therapy is allowed if completed at least 14 calendar days prior to registration.

• Treatment with any investigational agent or on an interventional clinical trial within 30 days prior to registration.

• No prior or concurrent malignancy is allowed except for: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localized or locally advanced prostate cancer definitively treated without recurrence or with biochemical recurrence only, or any other cancer fully treated or from which the subject has been disease-free for at least 2 years.

• Current untreated brain metastasi(e)s. If treated history of CNS (central nervous system) metastases, should have completed radiation or surgery at least 12 weeks prior and off systemic corticosteroids.

• Autoimmune diseases such as rheumatoid arthritis are NOT allowed. Vitiligo, mild psoriasis (topical therapy only) or hypothyroidism are allowed.

• Medical need for systemic corticosteroids >10mg prednisone daily or equivalent alternative steroid (except physiologic dose for adrenal replacement therapy) or other immunosuppressive agents (such as cyclosporine or methotrexate) Topical and inhaled corticosteroids are allowed if medically needed.

• History of allergic reaction to interleukin-2 or nivolumab

• Prior history of psychiatric disorder or seizure disorders which could be exacerbated by Interleukin-2 as judged by the treating investigator. 3.2.12 Evidence of significant cardiovascular disease including history of recent (< 6 months prior) myocardial infarction, congestive heart failure, primary cardiac arrhythmias (not due to electrolyte disorder or drug toxicity, for example) beyond occasional PVC's (premature ventricular contractions), angina, positive low-level stress test, or cerebrovascular accident. All patients should have baseline pulmonary function tests. Adequate pulmonary function should be documented (FEV1 >2 liters or ≥75% of predicted for height and age) prior to initiating therapy.

• Any history of HIV or hepatitis B infection

• Any other medical or surgical condition or disease that, in the judgment of the treating physician, renders subject ineligible for High Dose Interleukin-2 therapy.

• Any history of organ allografts

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
2	University of Minnesota	Minneapolis	Minnesota	United States	55455
3	University Hospitals Seidman Cancer Center	Cleveland	Ohio	United States	44106
4	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Ajjai Alva, M.D., University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 23, 2018

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT02989714
• Other Study ID Numbers: UMCC 2016.103; HUM00120502
• First Posted: Dec 12, 2016
• Last Update Posted: Jul 13, 2021
• Last Verified: Jun 1, 2021

• 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
• Additional relevant MeSH terms: Carcinoma, Renal Cell; Nivolumab; Interleukin-2

Study Results

Participant Flow

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
Period Title: Overall Study
STARTED	13
Started Nivolumab	12
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
Overall Participants	13
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	3 23.1%
Male	10 76.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 100%
Unknown or Not Reported	0 0%
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	2 15.4%
White	11 84.6%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	The Number of Patients With Grade 3 and Grade 4 Adverse Events of Interest
Description	This is the primary outcome for the Phase Ib portion of the trial. Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.
Time Frame	28 days from the first dose of Nivolumab

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 dose of Nivolumab and Interleukin-2

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
Measure Participants	12
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	The Number of Patients That Respond to Treatment
Description	This is the primary outcome for the Phase II portion of the trial. Includes complete response (CR) + partial response (PR), measured by computerized tomography (CT) or magnetic resonance imaging (MRI) scan and assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 dose of Nivolumab and Interleukin-2

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
Measure Participants	12
Count of Participants [Participants]	2 15.4%

3. Secondary Outcome

Title	Number of Grade 3-5 Adverse Events of Interest
Description	Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.
Time Frame	For the duration of the therapy plus 60 days post treatment

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 dose of Nivolumab and Interleukin-2

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
Measure Participants	12
Number [events]	7

4. Secondary Outcome

Title	Overall Survival at 24 Months
Description	Overall survival at 24 months following the first dose of study therapy; 24 month estimates were reported using the product limit method of Kaplan and Meier along with 95% confidence intervals.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 dose of Nivolumab and Interleukin-2

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart. Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression.
Measure Participants	12
Number (95% Confidence Interval) [percentage of participants]	77.1 593.1%

5. Secondary Outcome

Title	Progression Free Survival (PFS) at 24 Months
Description	PFS is defined as the time from start of study therapy with Nivolumab until progression or death; up to 24 months. Progressive disease is defined as At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 dose of Nivolumab and Interleukin-2

Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart. Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression.
Measure Participants	12
Number (95% Confidence Interval) [percentage of participants]	43.6 335.4%

Adverse Events

Time Frame	60 days after end of treatment (Up to 14 months)
Arm/Group Title	HD IL2 and Nivolumab
Arm/Group Description	Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
All Cause Mortality
	HD IL2 and Nivolumab
	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)
Serious Adverse Events
	HD IL2 and Nivolumab
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Gastrointestinal disorders
Pancreatitis	1/13 (7.7%)	1
Colitis	1/13 (7.7%)	1
General disorders
Fatigue	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Fracture	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	HD IL2 and Nivolumab
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anemia	11/13 (84.6%)	25
Leukocytosis	1/13 (7.7%)	1
Thrombotic thrombocytopenic purpura	1/13 (7.7%)	2
Cardiac disorders
Sinus tachycardia	4/13 (30.8%)	5
Ventricular tachycardia	1/13 (7.7%)	1
Ear and labyrinth disorders
Tinnitus	1/13 (7.7%)	1
Endocrine disorders
Hyperthyroidism	1/13 (7.7%)	1
Hypothyroidism	2/13 (15.4%)	2
Eye disorders
Eye disorders - Other	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal pain	3/13 (23.1%)	3
Bloating	1/13 (7.7%)	1
Colitis	2/13 (15.4%)	2
Constipation	2/13 (15.4%)	2
Diarrhea	9/13 (69.2%)	18
Dry mouth	2/13 (15.4%)	2
Hemorrhoids	1/13 (7.7%)	1
Mucositis oral	2/13 (15.4%)	2
Nausea	9/13 (69.2%)	16
Oral pain	2/13 (15.4%)	2
Vomiting	8/13 (61.5%)	14
General disorders
Chills	10/13 (76.9%)	18
Edema face	1/13 (7.7%)	1
Edema limbs	6/13 (46.2%)	6
Fatigue	11/13 (84.6%)	14
Fever	3/13 (23.1%)	4
Infusion related reaction	1/13 (7.7%)	1
Infusion site extravasation	1/13 (7.7%)	1
Localized edema	1/13 (7.7%)	1
Pain	2/13 (15.4%)	2
Immune system disorders
Allergic reaction	2/13 (15.4%)	2
Infections and infestations
Papulopustular rash	4/13 (30.8%)	4
Skin infection	1/13 (7.7%)	1
Vaginal infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Fall	3/13 (23.1%)	3
Fracture	1/13 (7.7%)	1
Vascular access complication	1/13 (7.7%)	1
Wound dehiscence	1/13 (7.7%)	1
Investigations
Alanine aminotransferase increased	11/13 (84.6%)	36
Alkaline phosphatase increased	8/13 (61.5%)	16
Aspartate aminotransferase increased	11/13 (84.6%)	33
Blood bilirubin increased	9/13 (69.2%)	18
Cardiac troponin T increased	1/13 (7.7%)	1
CPK increased	1/13 (7.7%)	3
Creatinine increased	9/13 (69.2%)	35
Lymphocyte count decreased	8/13 (61.5%)	32
Lymphocyte count increased	5/13 (38.5%)	10
Neutrophil count decreased	2/13 (15.4%)	3
Platelet count decreased	8/13 (61.5%)	20
Urine output decreased	3/13 (23.1%)	5
Weight loss	2/13 (15.4%)	2
White blood cell decreased	4/13 (30.8%)	10
Metabolism and nutrition disorders
Anorexia	5/13 (38.5%)	5
Dehydration	1/13 (7.7%)	1
Hypercalcemia	1/13 (7.7%)	2
Hyperglycemia	7/13 (53.8%)	42
Hyperkalemia	6/13 (46.2%)	11
Hypoalbuminemia	10/13 (76.9%)	35
Hypocalcemia	9/13 (69.2%)	34
Hypoglycemia	1/13 (7.7%)	1
Hypokalemia	4/13 (30.8%)	6
Hypomagnesemia	2/13 (15.4%)	2
Hyponatremia	7/13 (53.8%)	12
Hypophosphatemia	2/13 (15.4%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	1/13 (7.7%)	1
Arthritis	2/13 (15.4%)	2
Back pain	3/13 (23.1%)	3
Chest wall pain	1/13 (7.7%)	1
Muscle weakness left-sided	1/13 (7.7%)	1
Pain in extremity	2/13 (15.4%)	2
Nervous system disorders
Dizziness	4/13 (30.8%)	4
Dysphasia	1/13 (7.7%)	1
Encephalopathy	1/13 (7.7%)	1
Extrapyramidal disorder	1/13 (7.7%)	1
Paresthesia	1/13 (7.7%)	1
Peripheral sensory neuropathy	1/13 (7.7%)	1
Presyncope	3/13 (23.1%)	3
Psychiatric disorders
Confusion	2/13 (15.4%)	2
Insomnia	1/13 (7.7%)	1
Renal and urinary disorders
Acute kidney injury	2/13 (15.4%)	2
Chronic kidney disease	1/13 (7.7%)	4
Hematuria	1/13 (7.7%)	1
Urinary tract obstruction	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/13 (15.4%)	2
Cough	4/13 (30.8%)	4
Epistaxis	1/13 (7.7%)	1
Hypoxia	1/13 (7.7%)	1
Nasal congestion	1/13 (7.7%)	1
Pneumonitis	1/13 (7.7%)	1
Postnasal drip	1/13 (7.7%)	1
Productive cough	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders - Other	1/13 (7.7%)	2
Sneezing	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Dry skin	4/13 (30.8%)	4
Pruritus	11/13 (84.6%)	20
Rash maculo-papular	4/13 (30.8%)	5
Skin and subcutaneous tissue disorders - Other	2/13 (15.4%)	2
Vascular disorders
Flushing	1/13 (7.7%)	1
Hypotension	10/13 (76.9%)	16
Superficial thrombophlebitis	1/13 (7.7%)	1

Limitations/Caveats

The trial did not meet criteria for continuation to the second stage.

More Information

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.