Interleukin-2 and Pembrolizumab for Metastatic Kidney Cancer

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02964078
• Collaborator: Merck Sharp & Dohme LLC (Industry), Prometheus Laboratories (Industry)
• Enrollment: 27
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 70.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The main purpose of this study is to evaluate the effects of the interleukin-2 given in combination with pembrolizumab.

Interleukin-2 (IL-2) is also called aldesleukin, or Proleukin™.

Pembrolizumab is also called Keytruda™, or anti-PD-1 antibody.

Condition or Disease	Intervention/Treatment	Phase
Kidney Cancer	Drug: Pembrolizumab; Drug: Interleukin-2	Phase 2

Detailed Description

The treatment is organized into blocks of 9 weeks, with pembrolizumab treatment planned for weeks 1, 4 and 7. On the second and third blocks, interleukin-2 is added, for 5 doses at a time, one dose every 8 hours, on a weekly schedule on the two weeks after the week 1 and the week 4 pembrolizumab doses.

There is no dose escalation portion: The dose and schedule of IL-2 is fixed, 600,000 IU/kg/dose, with a cap of 66 mIU/dose. Doses may be omitted for safety. The dose of pembrolizumab is fixed, flat dose 200 mg/dose.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Coordinated High Dose Interleukin-2 (Aldesleukin, Proleukin™) and Pembrolizumab (Anti-PD1, Keytruda™) for Therapy of Metastatic Kidney Cancer
• Actual Study Start Date: Apr 25, 2017
• Actual Primary Completion Date: Mar 26, 2019
• Anticipated Study Completion Date: Mar 1, 2023

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Pembrolizumab and Interleukin-2 Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.

Drug: Pembrolizumab; Pembrolizumab: 200 mg every 3 weeks, 12 doses planned. This is considered the investigational part of the combination. The infusion time is 1 hour.; Other Names: anti-PD-1 antibody Keytruda™ ; Drug: Interleukin-2; Interleukin-2: 8 admissions to hospital, each with 5 doses planned. This is considered the standard part of the combination. The standard interleukin-2 dose is 600,000 international units per kilogram per dose, with a maximum of 66,000,000 (for patients over 110 kg, which is 242 pounds). The dose is usually set at the start of the treatment and not adjusted. The infusion time is 15 minutes.; Other Names: aldesleukin Proleukin™ IL-2

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [Up to 24 months]

   Overall Response According to Immune-related response criteria (irRC). Overall response rate ORR is defined with confirmation of the response status Complete Response (CR) or Partial Response (PR) among the combination treatment population patients; the binomial estimate and its one-sided 95% confidence interval will be reported. CR: Disappearance of all lesions in two consecutive observation not less than 4 weeks apart. PR: ≥50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart.

Secondary Outcome Measures

1. Overall Survival (OS) of Intent to Treat (ITT) Population [Up to 24 months]

   Analysis: Overall Survival (OS) of ITT patients using Kaplan-Meier estimate, counting from the eligible date to death from any cause, or censored on end of known follow up, either within this study or in the Prometheus Laboratories sponsored PROCLAIM registry (PROCLAIM Registry to Evaluate the Treatment Patterns and Clinical Response in Malignancy, NCT01415167).

2. Progression Free Survival (PFS) [Up to 24 months]

   Progression-free survival (PFS) of ITT patients using Kaplan Meier estimate, from the confirmed eligible date to the first occurrence of disease progression or death, from any cause, or lost to follow up, whichever is earliest; or censored at last follow-up during study. Progressive Disease (PD): At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 weeks apart.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis/Condition for Entry into the Trial: Metastatic kidney cancer. Clear cell histology component from primary or metastatic lesion.

• Willing and able to provide written informed consent for the trial.

• Age over 18 on day of signing informed consent.

• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

• Willing to provide tissue from a newly obtained or archival tissue, if available.

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

• Demonstrate adequate organ function, as outlined in Table 1 of study protocol document.

• Females of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Females of childbearing potential must agree to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.

• Males must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

• Cardiac testing with either exercise stress test or thallium stress test, within 3 months of start of the first treatment day. Atrial fibrillation that is rate controlled is allowed. Note - the first treatment day is about 9 weeks before the first IL-2 treatment day. If a cardiologist's evaluation determines that this is superfluous based on other assessments, then this may be omitted.

• Pulmonary function test is required, within 3 months of start.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

• Has a known history of active Bacillus Tuberculosis (TB).

• Has hypersensitivity to pembrolizumab or any of its excipients.

• The number of prior therapies is restricted as follows: (a) Zero or one prior therapies during the preceding one year. This serves to limit the treatment cohort to patients with either only slowly progressive disease, or up to one prior therapy. (b) No prior PD-1 or PD-L1 antibody therapies are allowed. (c) Prior IL-2 is allowed, if it finished more than 1 year prior. (d) The following are not counted as medical therapies: nephrectomy, radiation therapy, other energy-ablative techniques, or metastasectomy.

• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Potential participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment that would be exclusionary.

• Has known history of, or any evidence of active, non-infectious pneumonitis.

• Has an active infection requiring systemic therapy.

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).

• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

• Myocardial infarction, stroke, coronary artery bypass surgery, coronary stent, or unstable angina within one year.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Merck Sharp & Dohme LLC
• Prometheus Laboratories

Investigators

• Principal Investigator: Jad Cuahoud, MD, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 16, 2020

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT02964078
• Other Study ID Numbers: MCC-18536; MISP# 52587; IIT15PLK02
• First Posted: Nov 15, 2016
• Last Update Posted: Jun 23, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Kidney Disease; Metastatic; Antibody
• Additional relevant MeSH terms: Kidney Neoplasms; Carcinoma, Renal Cell; Aldesleukin; Pembrolizumab; Interleukin-2

Study Results

Participant Flow

Arm/Group Title	Pembrolizumab and Interleukin-2
Arm/Group Description	Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.
Period Title: Overall Study
STARTED	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pembrolizumab and Interleukin-2
Arm/Group Description	Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 63%
>=65 years	10 37%
Sex: Female, Male (Count of Participants)
Female	5 18.5%
Male	22 81.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 7.4%
Not Hispanic or Latino	25 92.6%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	25 92.6%
More than one race	0 0%
Unknown or Not Reported	1 3.7%
Region of Enrollment (participants) [Number]
United States	27 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response According to Immune-related response criteria (irRC). Overall response rate ORR is defined with confirmation of the response status Complete Response (CR) or Partial Response (PR) among the combination treatment population patients; the binomial estimate and its one-sided 95% confidence interval will be reported. CR: Disappearance of all lesions in two consecutive observation not less than 4 weeks apart. PR: ≥50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab and Interleukin-2
Arm/Group Description	Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.
Measure Participants	27
Median (90% Confidence Interval) [percentage of participants]	70.4 260.7%

2. Secondary Outcome

Title	Overall Survival (OS) of Intent to Treat (ITT) Population
Description	Analysis: Overall Survival (OS) of ITT patients using Kaplan-Meier estimate, counting from the eligible date to death from any cause, or censored on end of known follow up, either within this study or in the Prometheus Laboratories sponsored PROCLAIM registry (PROCLAIM Registry to Evaluate the Treatment Patterns and Clinical Response in Malignancy, NCT01415167).
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab and Interleukin-2
Arm/Group Description	Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.
Measure Participants	27
Number (95% Confidence Interval) [proportion of participants]	1 3.7%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression-free survival (PFS) of ITT patients using Kaplan Meier estimate, from the confirmed eligible date to the first occurrence of disease progression or death, from any cause, or lost to follow up, whichever is earliest; or censored at last follow-up during study. Progressive Disease (PD): At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 weeks apart.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab and Interleukin-2
Arm/Group Description	Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.
Measure Participants	27
Number (95% Confidence Interval) [proportion of participants]	.630 2.3%

Adverse Events

Time Frame	Adverse events recorded from Cycle 1 day 1 through 30 days after cessation of treatment
Arm/Group Title	Pembrolizumab and Interleukin-2
Arm/Group Description	Outpatient Intravenous (IV) infusion of Pembrolizumab and Inpatient IV infusion of Interleukin-2.
All Cause Mortality
	Pembrolizumab and Interleukin-2
	Affected / at Risk (%)	# Events
Total	0/27 (0%)
Serious Adverse Events
	Pembrolizumab and Interleukin-2
	Affected / at Risk (%)	# Events
Total	17/27 (63%)
Blood and lymphatic system disorders
Anemia	1/27 (3.7%)	2
Leukocytosis	5/27 (18.5%)	10
Cardiac disorders
Atrial fibrilation	3/27 (11.1%)	3
Atrial flutter	1/27 (3.7%)	1
Supraventricular tachycardia	2/27 (7.4%)	2
Ventricular tachycardia	2/27 (7.4%)	2
Gastrointestinal disorders
Nausea	1/27 (3.7%)	1
Vomiting	2/27 (7.4%)	2
Abdominal Pain	2/27 (7.4%)	2
General disorders
Flu like symptoms	1/27 (3.7%)	1
Infusion related reaction	1/27 (3.7%)	1
Fatigue	1/27 (3.7%)	1
Pain	1/27 (3.7%)	1
Investigations
Creatinine increased	3/27 (11.1%)	3
Blood bilirubin increased	3/27 (11.1%)	4
Alanine aminotransferase increased	1/27 (3.7%)	1
Aspartate aminotransferase increased	1/27 (3.7%)	1
Lymphocyte count decreased	7/27 (25.9%)	19
Electrocardiogram QT corrected interval prolonged	2/27 (7.4%)	2
Metabolism and nutrition disorders
Hypocalcemia	1/27 (3.7%)	1
Hyponatremia	4/27 (14.8%)	8
Hypophosphatemia	8/27 (29.6%)	14
Hypermagnesemia	1/27 (3.7%)	1
Hypoalbuminemia	1/27 (3.7%)	1
Hypokalemia	2/27 (7.4%)	3
Hyperglycemia	1/27 (3.7%)	2
Dehydration	1/27 (3.7%)	1
Hyperuricemia	1/27 (3.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	3/27 (11.1%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	3/27 (11.1%)	4
Nervous system disorders
Edema cerebral	2/27 (7.4%)	2
Headache	2/27 (7.4%)	2
Intracranial hemorrhage	1/27 (3.7%)	1
Nervous system disorders - Other	2/27 (7.4%)	4
Intracranial hemorrhage	2/27 (7.4%)	2
Nystagmus	1/27 (3.7%)	1
Renal and urinary disorders
Acute kidney injury	6/27 (22.2%)	6
Renal and urinary disorders - Other	8/27 (29.6%)	9
Renal and urinary disorders - Other	8/27 (29.6%)	8
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/27 (11.1%)	3
Hypoxia	1/27 (3.7%)	1
Adult respiratory distress syndrome	1/27 (3.7%)	1
Vascular disorders
Capillary leak syndrome	1/27 (3.7%)	1
Hypotension	7/27 (25.9%)	12
Hypertension	3/27 (11.1%)	6
Vascular disorders - Other	2/27 (7.4%)	3
Capillary leak syndrome	2/27 (7.4%)	2
Other (Not Including Serious) Adverse Events
	Pembrolizumab and Interleukin-2
	Affected / at Risk (%)	# Events
Total	25/27 (92.6%)
Blood and lymphatic system disorders
Leukocytosis	6/27 (22.2%)	10
Anemia	1/27 (3.7%)	2
Cardiac disorders
Sinus tachycardia	8/27 (29.6%)	10
Atrial fibrillation	4/27 (14.8%)	5
Chest pain - cardiac	2/27 (7.4%)	2
Ventricular tachycardia	2/27 (7.4%)	2
Asystole	1/27 (3.7%)	1
Atrial flutter	1/27 (3.7%)	1
Cardiac disorders - Other	1/27 (3.7%)	1
Sinus bradycardia	2/27 (7.4%)	2
Supraventricular tachycardia	1/27 (3.7%)	1
Endocrine disorders
Hyperthyroidism	1/27 (3.7%)	1
Eye disorders
Blurred vision	1/27 (3.7%)	1
Gastrointestinal disorders
Diarrhea	2/27 (7.4%)	3
Nausea	2/27 (7.4%)	2
Vomiting	2/27 (7.4%)	2
Abdominal pain	1/27 (3.7%)	2
Constipation	1/27 (3.7%)	1
Dry mouth	1/27 (3.7%)	1
Dysphagia	1/27 (3.7%)	1
General disorders
Fatigue	3/27 (11.1%)	3
Fever	3/27 (11.1%)	4
Edema limbs	2/27 (7.4%)	2
Pain	2/27 (7.4%)	2
Chills	1/27 (3.7%)	1
Flu like symptoms	1/27 (3.7%)	1
General disorders and administration site conditions -Other	1/27 (3.7%)	1
Infections and infestations
Infections and Infestations - Other	1/27 (3.7%)	1
Upper respiratory infection	1/27 (3.7%)	1
Investigations
Creatinine increased	7/27 (25.9%)	12
Lymphocyte count decreased	7/27 (25.9%)	19
Blood bilirubin increased	5/27 (18.5%)	6
Urine output decreased	3/27 (11.1%)	4
Alanine aminotransferase increased	2/27 (7.4%)	2
Electrocardiogram QT corrected interval prolonged	2/27 (7.4%)	2
Investigations - Other	2/27 (7.4%)	2
Aspartate aminotransferase increased	1/27 (3.7%)	1
Weight gain	1/27 (3.7%)	1
Metabolism and nutrition disorders
Hypophosphatemia	8/27 (29.6%)	14
Hyponatremia	5/27 (18.5%)	9
Hypokalemia	2/27 (7.4%)	3
Anorexia	1/27 (3.7%)	1
Dehydration	1/27 (3.7%)	1
Hyperglycemia	1/27 (3.7%)	2
Hypermagnesemia	1/27 (3.7%)	1
Hyperuricemia	1/27 (3.7%)	1
Hyperalbuminemia	1/27 (3.7%)	2
Hypocalcemia	1/27 (3.7%)	1
Hypoglycemia	1/27 (3.7%)	1
Obesity	1/27 (3.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	4/27 (14.8%)	7
Myalgia	1/27 (3.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	2/27 (7.4%)	2
Nervous system disorders
Headache	4/27 (14.8%)	5
Intracranial hemorrhage	2/27 (7.4%)	2
Dizziness	1/27 (3.7%)	1
Facial muscle weakness	1/27 (3.7%)	1
Lethargy	1/27 (3.7%)	1
Nervous system disorders - Other	1/27 (3.7%)	1
Nystagmus	1/27 (3.7%)	1
Tremor	1/27 (3.7%)	1
Renal and urinary disorders
Renal and urinary disorders - Other	6/27 (22.2%)	7
Acute kidney injury	6/27 (22.2%)	6
Reproductive system and breast disorders
Dyspareunia	1/27 (3.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/27 (22.2%)	6
Adult respiratory distress syndrome	1/27 (3.7%)	1
Hypoxia	1/27 (3.7%)	1
Pneumonitis	1/27 (3.7%)	1
Respiratory, thoracic and mediastinal disorders - Other	1/27 (3.7%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	6/27 (22.2%)	9
Dry skin	3/27 (11.1%)	3
Pruritus	3/27 (11.1%)	4
Skin and subcutaneous tissue disorders -Other	2/27 (7.4%)	2
Vascular disorders
Hypotension	4/27 (14.8%)	6
Hypertension	4/27 (14.8%)	8
Capillary leak syndrome	3/27 (11.1%)	3
Vascular disorders - Other	2/27 (7.4%)	2

Limitations/Caveats

[Not Specified]

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.