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Aldesleukin and Pembrolizumab in Treating Patients With Advanced or Metastatic Kidney Cancer

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ClinicalTrials.gov Identifier: NCT03260504
Recruitment Status : Recruiting
First Posted : August 24, 2017
Last Update Posted : November 5, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Washington

Brief Summary:
This phase I trial studies the side effects and best dose of aldesleukin when given together with pembrolizumab in treating patients with kidney cancer that has spread to other parts of the body. Aldesleukin may stimulate white blood cells to kill kidney cancer cells. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving aldesleukin and pembrolizumab may work better in treating patients with kidney cancer.

Condition or disease Intervention/treatment Phase
Clear Cell Renal Cell Carcinoma Stage III Renal Cell Cancer Stage IV Renal Cell Cancer Biological: Aldesleukin Biological: Pembrolizumab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of aldesleukin (IL-2) combined with pembrolizumab (MK-3475) in patients with metastatic clear cell renal cell carcinoma (RCC).

SECONDARY OBJECTIVES:

I. To assess preliminary antitumor activity of pembrolizumab in combination with IL-2.

EXPLORATORY OBJECTIVES:

I. To investigate the association of PD-L1 protein expression by pretreatment tumor with response to treatment.

II. To investigate the association of regulatory T cell (Treg) frequency and Treg to effector T cell (Teff) ratios in peripheral blood and tumor tissue with response to therapy.

III. To investigate the association of de novo serological and cellular responses against the ubiquitous RCC tumor antigen 5T4 with response to therapy.

IV. To investigate the association of tumor infiltrating lymphocyte (TIL) repertoire clonality with response to therapy and to assess the detection of dominant TIL clones within peripheral blood over time in responding patients.

V. To investigate the association of whole genome copy number alterations measured on pretreatment archived, formalin fixed, paraffin embedded (FFPE) tumor with response to therapy.

OUTLINE: This is a dose-escalation study of aldesleukin.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also receive aldesleukin subcutaneously (SC) weekly on days 1-5 of courses 1 and 2 or aldesleukin IV on days 2-6 of courses 1 and 2. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for every 3 months for up to 1 year.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Interleukin-2 (Aldesleukin) and Pembrolizumab Combination Therapy for Patients With Advanced Renal Cell Carcinoma
Actual Study Start Date : August 28, 2018
Estimated Primary Completion Date : March 17, 2021
Estimated Study Completion Date : March 17, 2021


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, aldesleukin)
Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive aldesleukin SC weekly on days 1-5 of courses 1 and 2 or aldesleukin IV on days 2-6 of courses 1 and 2. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Biological: Aldesleukin
Given SC or IV
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 1 year ]
    Assessed by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE)


Secondary Outcome Measures :
  1. Anti-tumor activity [ Time Frame: At baseline and every 3 months for up to 1 year ]
    Tumor imaging post-treatment compared to baseline imaging; assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

  2. Overall response rate (ORR) [ Time Frame: At baseline and every 3 months for up to 1 year ]
    Assessed by RECIST 1.1

  3. Disease control rate (DCR) [ Time Frame: At baseline and every 3 months for up to 1 year ]
    Assessed by RECIST 1.1.

  4. Progression free survival (PFS) [ Time Frame: Up to 1 year ]
    PFS will be evaluated using the method of Kaplan-Meier. Median PFS times and associated 95% confidence interval will also be calculated

  5. Change in performance status [ Time Frame: At baseline and every 3 months for up to 1 year ]
    Assessed by Eastern Cooperative Oncology Group (ECOG) Performance Scale


Other Outcome Measures:
  1. Absolute numbers of effector T cells (Teff) [ Time Frame: Up to 1 year ]
    Will assess the ratio of Treg and Teff. Analyses of T cell subsets will be correlated with clinical outcomes.

  2. Absolute numbers of regulatory T cells (Treg) [ Time Frame: Up to 1 year ]
    Will assess the ratio of Treg and effector T cells. Analyses of T cell subsets will be correlated with clinical outcomes.

  3. Chromosomal copy number alterations [ Time Frame: Up to 1 year ]
    OncoScan chromosomal array analyses will be carried out on archived tumor for RCC patients treated with IL-2 and pembrolizumab and chromosomal numerical abnormalities (CNAs) correlated to objective response rate.

  4. De novo 5T4 specific humoral and/or cellular immune responses [ Time Frame: Up to 1 year ]
    Will be analyzed as a potential marker of "on target" effective anti-tumor immunity and correlated with clinical response.

  5. PD-L1 expression [ Time Frame: Up to 1 year ]
    Will be assessed by immunohistochemistry.

  6. Tumor infiltrating lymphocytes (TIL) clonality score [ Time Frame: Up to 1 year ]
    TIL clonality score will be correlated with clinical outcomes of renal cell carcinoma (RCC) patients treated with IL-2 plus pembrolizumab.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be willing and able to provide written informed consent for the trial
  • Have histologic confirmation of RCC with a clear cell component
  • Have advanced (not amenable to potentially curative surgery) or metastatic RCC
  • Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Available tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500 /mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) >= 40 mL/min for subject with creatinine levels > 1.5 X institutional ULN; creatinine clearance should be calculated by Cockcroft-Gault
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) >= 65% of predicted (patients >= 40 years old)
  • Left ventricular ejection fraction (LVEF) >= 50% measured by multigated acquisition (MUGA) scan, echo, or stress test study with myocardial perfusion imaging
  • Normal/negative cardiac stress testing with myocardial perfusion imaging OR cardiac catheterization with non-significant angiogram findings reviewed by a cardiology consultant (dose level 3 and >= 40 years old)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy test 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
  • Female subjects of childbearing potential should be willing 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; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male subjects should 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

Exclusion Criteria:

  • (Dose levels 1 and 2) - may have received one or more systemic treatments or regimens for metastatic RCC; (dose level 3) - cannot have received prior systemic treatment for RCC
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Has received prior therapy with IL-2 or other investigational systemic cytokine therapy signaling through a common gamma-chain cytokine receptor including IL-7, IL-15 or IL-21
  • Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
  • Has had a prior monoclonal antibody 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: 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 locally curable cancers such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ of the cervix or breast that has undergone potentially curative therapy
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis

    • (Dose level 1) subjects 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
    • (Dose Level 2 and 3) subjects may not have any history of or current CNS metastases; baseline imaging of the brain is required within 28 days prior to the start of study treatments
  • 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 an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study
  • Has history of (non-infectious) pneumonitis that required steroids or active, non-infectious pneumonitis
  • Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the corrected QT interval defined as > 450 msec for males and > 470 msec for female
  • History of any of the following cardiovascular conditions within 6 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, class III or IV congestive heart failure as defined by the New York Heart Association, symptomatic peripheral vascular disease, cerebrovascular accident, or transient ischemic attack
  • 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 the subject's participation for the full duration of the trial, or is not in the best interest of the subject 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 a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days prior to the first dose of trial treatment; 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03260504


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Scott S. Tykodi    206-667-3799    stykodi@fredhutch.org   
Principal Investigator: Scott S. Tykodi         
Sponsors and Collaborators
University of Washington
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Scott Tykodi Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT03260504     History of Changes
Other Study ID Numbers: 9611
NCI-2017-01416 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9611 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: August 24, 2017    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Aldesleukin
Pembrolizumab
Interleukin-2
Antineoplastic Agents, Immunological
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents