Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma
Condition: Clear-Cell Renal Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms
Intervention: rhIL-15; Avelumab
Intervention description: Recombinant human Interleukin-15 (rhIL-15) will be administered by continuous intravenous infusion (CIV) at a starting dose of 2 mcg/kg/day for the first dose level followed by a second dose level of 4mcg/kg/day on days 1-5 of the 28-day cycle of each of four cycles.; avelumab (800mg by intravenous (IV) will be administered on days 8 and 22 of the 28- day cycle for four cycles
Intervention MeSH terms: Avelumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Antibody Dependent Cellular Cytotoxicity (ADCC); Anti-PD-L1 monoclonal antibody

Summary:

      Background:

      -Clear-cell renal cell carcinoma (ccRCC) is a kind of kidney cancer. The drug avelumab may
      help direct the immune response to the tumors and can prolong the immune response. The drug
      Interleukin-15 (IL-15) stimulates certain kinds of white blood cells that have the potential
      to attack the cancer.

      Objective:

      -To test whether IL-15 and avelumab administered together are safe and effective at treating
      ccRCC.

      Eligibility:

      -People ages 18 and older with relapsed, metastatic biopsy proven clear cell renal cell
      carcinoma (ccRCC) that has not responded to standard treatments

      Design:

      Participants will be screened with:

        -  Medical history

        -  Physical exam

        -  Blood, urine, heart, and lung tests

        -  Computed tomography (CT) and positron emission tomography (PET) scans and possible MRI:
           Participants will lie in a machine that takes pictures of the body. For the CT scan,
           they may receive an oral contrast agent by mouth and normally receive IV contrast
           through a vein to improve the x-ray images.

        -  Tumor sample to confirm expression of avelumab target: If one is not available,
           participants will require a new biopsy that is generally obtained by a needle that is
           inserted into the tumor.

      Participants will get the study drugs by vein for up to four 28-day cycles. The IL-15 will be
      given through a vein continuously for the first 5 days (120 hours) of each cycle. They
      avelumab will be given through a vein over about 1 hour on days 8 and 22 of each cycle.
      Participants will be hospitalized for their 1st week of IL-15 cycle and may be able to
      receive their subsequent IL-15 treatment as an outpatient depending on their side effects.
      Participants who receive the infusion as an outpatient will return to the hospital each day
      for a new bag of IL-15. Participants who cannot or do not want to be treated as an outpatient
      will be treated in the hospital during their 5-day IL-15 infusions.

        -  Participants will need a midline venous catheter which is longer than a standard venous
           catheter but is still inserted into a peripheral vein in their arm.

        -  Participants will have repeats of blood tests to monitor the blood counts and chemistry
           throughout the study.

        -  Participants will have follow-up visits 30 days after their last treatment, every 60
           days for the first 6 months, every 90 days for 2 years, then every 6 months.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically proven metastatic clear cell renal carcinoma with
             greater than or equal to 5% expression of programmed death-ligand 1 (PD-L1) on the
             tumor cells confirmed by immunohistochemistry (IHC) in the national Cancer Institute
             (NCI) Lab of Pathology. Archival tumor sample may be used but if archival tissue is
             not available or is not adequate, tissue biopsy will be required.

          -  Patients must have failed or relapsed and have progressive disease after at least 2
             prior therapies that include multityrosine kinase inhibitor (mTKI) like axitinib or
             sunitinib and an anti-Programmed cell death protein 1 (PD1) or PD-L1 (ICI) therapy
             like nivolumab which could have been administered in combination with an anti-cluster
             of differentiation 152 (CTLA4) agent like ipilimumab. Patients who received an immune
             checkpoint inhibitor (ICI) in combination with a mTKI would be eligible for the trial
             if they received another appropriate treatment. Adjuvant or neoadjuvant with either
             type of agent would not fulfill this requirement only treatment for metastatic disease
             will be considered to satisfy this criterion.

          -  Disease must be measurable with at least one measurable lesion by the Response
             Evaluation Criteria in Solid Tumors (Recist) v1.1 criteria that is different from the
             lesion biopsied.

          -  Age >=18 years

        NOTE: Because no dosing or adverse event data are currently available on the use of
        recombinant human Interleukin-15 (rhIL-15) in combination with avelumab in patients <18
        years of age, children are excluded from this study, but may be eligible for future
        pediatric trials

          -  Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >=80%)

          -  Adequate organ and marrow function as defined below:

               -  absolute neutrophil count greater than or equal to 1,500/mcL

               -  absolute lymphocyte count greater than or equal to 500/mcL

               -  Hemoglobin greater than or equal to 10 g/dL

               -  Platelets greater than or equal to 100,000/mcL

               -  total bilirubin less than or equal to 1.5 X institutional upper limit of normal
                  (ULN)

               -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase
                  (SGOT)/Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT)
                  less than or equal to 2.5 X institutional ULN

               -  Serum creatinine less than or equal to 1.5 X institutional ULN

        OR

          -  Creatinine clearance greater than or equal to 50 mL/min/1.73 m^2 for patients with
             creatinine levels >1.5 institutional ULN

          -  Negative serum or urine pregnancy test at screening for women of childbearing
             potential (WOCBP).

        NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone
        successful surgical sterilization or who is not postmenopausal. WOCBP must have a negative
        pregnancy test (human chorionic gonadotropin (HCG) blood or urine) during screening.

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and 1 month after completion of rhIL-15 and
             avelumab administration. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          -  Chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C).

          -  Persisting toxicity related to prior therapy of grade > 1, with the exception of the
             following: alopecia, sensory neuropathy grade <= 2, or other grade <= 2 not
             constituting a safety risk based on investigator's judgement.

          -  Patients who are receiving any other investigational agents

          -  Current use of immunosuppressive medication, EXCEPT for the following:

               -  Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
                  intra-articular injection)

               -  Systemic corticosteroids at physiologic doses <= 10 mg/day of prednisone or
                  equivalent; or,

               -  Steroids as premedication for hypersensitivity reactions (e.g., computed
                  tomography (CT) scan premedication).

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  Patients with previous malignant disease other than the target malignancy within the
             last 5 years with the exception of basal or squamous cell carcinoma of the skin or
             cervical carcinoma in situ.

          -  Patients with history of any organ transplantation

          -  Vaccination within 4 weeks of the first dose of avelumab. Vaccination with a live
             vaccine while on trial is prohibited.

        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.

          -  Patients with history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to rhIL-15 or avelumab.

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection requiring systemic therapy, or psychiatric illness/social
             situations that would limit compliance with study requirements.

          -  Inability or refusal to practice effective contraception during therapy or the
             presence of pregnancy or active breastfeeding. Based on its mechanism of action,
             avelumab can cause fetal harm when administered to a pregnant woman. Animal studies
             have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk
             of immune-mediated rejection of the developing fetus resulting in fetal death. These
             potential risks may also apply to other agents used in this study.

          -  Patients with active bacterial infections, documented human immunodeficiency virus
             (HIV) infection or positive screening serology, polymerase chain reaction (PCR)
             evidence for active or chronic hepatitis B or hepatitis C, or positive screening
             hepatitis B virus (HBV)/hepatitis C virus (HCV) serology without documentation of
             successful curative treatment

          -  Patients with active or history of any autoimmune disease, including asthma requiring
             chronic inhaled or oral corticosteroids, or with history of asthma requiring
             mechanical ventilation; patients with a history of mild asthma that are on or can be
             switched to non-corticosteroid bronchodilator regimens are eligible

          -  Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease:
             cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial
             infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure
             (greater than or equal to New York Heart Association Classification Class II), or
             serious cardiac arrhythmia requiring medication

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.