Clinical Trials /

Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma

NCT04150562

Description:

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 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 - CT and 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 be 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.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Trial of Avelumab (Bavencio (R)) With IL-15 in Subjects With Clear-Cell Renal Carcinoma
  • Official Title: Phase II Trial of Avelumab (Bavencio (R)) With IL-15 in Subjects With Clear-Cell Renal Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 200007
  • SECONDARY ID: 20-C-0007
  • NCT ID: NCT04150562

Conditions

  • Clear-Cell Renal Carcinoma

Interventions

DrugSynonymsArms
rhIL-151- Experimental Treatment: Safety Run-in
Avelumab1- Experimental Treatment: Safety Run-in

Purpose

Background: - Clear-cell renal cell carcinoma (ccRCC) is among the 10 most frequent diagnostic cancers in the United States with more than an estimated 62,000 new cases in 2016. The prognosis for patients with metastatic disease is poor with survival rates of 8%. - The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory cytokine that promotes the differentiation and activation of NK cells, monocytes and longterm CD8+ memory T-cells, has been assessed in several Phase 1 trials in cancer patients. - Avelumab is an anti-programmed death ligand-1 (PD-L1) fully human IgG1 antibody that inhibits PD1/PD-L1 interactions while leaving the PD1/PD-L2 pathway intact and enhances immune activation against tumor cells. It has received U.S. FDA accelerated approval for the treatment of patients with metastatic Merkel cell carcinoma (MCC) and urothelial carcinoma. - Unlike other approved anti-PD-L1/PD1 antibodies, avelumab induces lysis of tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC), indicating an additionalmechanism of action. However, avelumab has not shown ADCC against normal immune cell subsets in humans. - More than 50% of ccRCC is PD-L1+ with higher expression in unfavorable prognostic tumors. Since the anti-PD-L1 antibody avelumab has shown ADCC activity in vitro, agents that may enhance ADCC by increasing number and activity of Fc-binding effector cells -such as rhIL15 - could improve efficacy of avelumab in this disease. Objectives: -Determine the efficacy of combined continuous intravenous infusion (CIV) rhIL-15 and avelumab treatment in patients with anti-PD-1/PD-L1 refractory metastatic clear cell renal carcinoma (ccRCC) by assessing the overall response rate Eligibility: - Age greater than or equal to 18 years of age - ECOG performance status of less than or equal to 1 - Histologically proven metastatic clear cell renal carcinoma with greater than or equal to 5% expression of PDL1 on the tumor cells confirmed by IHC - Patients must have failed or relapsed and have progressive disease after at least 2 prior therapies that include multityrosine kinase inhibitor like axitinib or sunitinib and an anti-PD1 or PD-L1 immune checkpoint inhibitor therapy like nivolumab which could have been administered in combination with an anti-CTLA4 agent like ipilimumab - Adequate organ and marrow function Design: - Open-label, single-center, non-randomized Phase II study - Safety Run-in Cohort with 3-6 patients at dose level 2mcg/kg and 4mcg/kg CIV IL-15 (recommended phase II dose) will ensure safety of recommended phase II dose rhIL-15 with fixed dose avelumab with Dose Expansion Cohort at 4mcg/kg dose level - Efficacy of the combination will be assessed in a Simon two-stage phase II design with 9 or 17 patients depending on demonstration of clinical activity in the initial group of 9 patients - Maximum 4 cycles (28-day cycle) of combination therapy - To explore both Safety Run-in Cohort and further evaluation in a Dose Expansion Cohort,the accrual ceiling will be set at 25 patients.

Detailed Description

      Background:

        -  Clear-cell renal cell carcinoma (ccRCC) is among the 10 most frequent diagnostic cancers
           in the United States with more than an estimated 62,000 new cases in 2016. The prognosis
           for patients with metastatic disease is poor with survival rates of 8%.

        -  The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory
           cytokine that promotes the differentiation and activation of NK cells, monocytes and
           longterm CD8+ memory T-cells, has been assessed in several Phase 1 trials in cancer
           patients.

        -  Avelumab is an anti-programmed death ligand-1 (PD-L1) fully human IgG1 antibody that
           inhibits PD1/PD-L1 interactions while leaving the PD1/PD-L2 pathway intact and enhances
           immune activation against tumor cells. It has received U.S. FDA accelerated approval for
           the treatment of patients with metastatic Merkel cell carcinoma (MCC) and urothelial
           carcinoma.

        -  Unlike other approved anti-PD-L1/PD1 antibodies, avelumab induces lysis of tumor cells
           via antibody-dependent cell-mediated cytotoxicity (ADCC), indicating an
           additionalmechanism of action. However, avelumab has not shown ADCC against normal
           immune cell subsets in humans.

        -  More than 50% of ccRCC is PD-L1+ with higher expression in unfavorable prognostic
           tumors. Since the anti-PD-L1 antibody avelumab has shown ADCC activity in vitro, agents
           that may enhance ADCC by increasing number and activity of Fc-binding effector cells
           -such as rhIL15 - could improve efficacy of avelumab in this disease.

      Objectives:

      -Determine the efficacy of combined continuous intravenous infusion (CIV) rhIL-15 and
      avelumab treatment in patients with anti-PD-1/PD-L1 refractory metastatic clear cell renal
      carcinoma (ccRCC) by assessing the overall response rate

      Eligibility:

        -  Age greater than or equal to 18 years of age

        -  ECOG performance status of less than or equal to 1

        -  Histologically proven metastatic clear cell renal carcinoma with greater than or equal
           to 5% expression of PDL1 on the tumor cells confirmed by IHC

        -  Patients must have failed or relapsed and have progressive disease after at least 2
           prior therapies that include multityrosine kinase inhibitor like axitinib or sunitinib
           and an anti-PD1 or PD-L1 immune checkpoint inhibitor therapy like nivolumab which could
           have been administered in combination with an anti-CTLA4 agent like ipilimumab

        -  Adequate organ and marrow function

      Design:

        -  Open-label, single-center, non-randomized Phase II study

        -  Safety Run-in Cohort with 3-6 patients at dose level 2mcg/kg and 4mcg/kg CIV IL-15
           (recommended phase II dose) will ensure safety of recommended phase II dose rhIL-15 with
           fixed dose avelumab with Dose Expansion Cohort at 4mcg/kg dose level

        -  Efficacy of the combination will be assessed in a Simon two-stage phase II design with 9
           or 17 patients depending on demonstration of clinical activity in the initial group of 9
           patients

        -  Maximum 4 cycles (28-day cycle) of combination therapy

        -  To explore both Safety Run-in Cohort and further evaluation in a Dose Expansion
           Cohort,the accrual ceiling will be set at 25 patients.
    

Trial Arms

NameTypeDescriptionInterventions
1- Experimental Treatment: Safety Run-inExperimentalIL-15 by CIV infusion at escalating doses of 2 and 4 mcg/kg/day on days 1-5 of each 28-day cycle (max 4 cycles) with avelumab by IV infusion at a dose of 800mg on Day 8 and 22 of each cycle
  • rhIL-15
  • Avelumab
2-Experimental Treatment: Doe ExpansionExperimentalIL-15 by CIV infusion at 4 mcg/kg/day on days 1-5 of each 28- day cycle (max 4 cycles) with avelumab by IV infusion at a dose of 800mg on Day 8 and 22 of each cycle
  • rhIL-15
  • Avelumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically proven metastatic clear cell renal carcinoma with
             greater than or equal to 5% expression of PD-L1 on the tumor cells confirmed by IHC in
             the 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-PD1 or PD-L1 (ICI) therapy like nivolumab which could have been
             administered in combination with an anti-CTLA4 agent like ipilimumab. Patients who
             received an 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 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 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

          -  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

               -  Leukocytes greater than or equal to 3,000/mcL

               -  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)

               -  AST(SGOT)/ALT(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 (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 or Legally Authorized Representative (LAR) 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., 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, including allogenic stem cell
             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 HIV infection or positive
             screening serology, PCR evidence for active or chronic hepatitis B or hepatitis C, or
             positive screening HBV/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 noncorticosteroid 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy of rhIL-15 + avelumab
Time Frame:one month after completion of treatment
Safety Issue:
Description:Overall response rate

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Antibody Dependent Cellular Cytotoxicity (ADCC)
  • Anti-PD-L1 monoclonal antibody

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