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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04150562
Recruitment Status : Recruiting
First Posted : November 4, 2019
Last Update Posted : October 30, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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 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.

Condition or disease Intervention/treatment Phase
Clear-Cell Renal Carcinoma Drug: rhIL-15 Biological: Avelumab Phase 2

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 PD-L1 in the tumor area 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Avelumab (Bavencio) With IL-15 in Subjects With Clear-cell Renal Carcinoma
Actual Study Start Date : May 26, 2020
Estimated Primary Completion Date : August 31, 2022
Estimated Study Completion Date : August 31, 2029


Arm Intervention/treatment
Experimental: 1- Experimental Treatment: Safety Run-in
IL-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
Drug: rhIL-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.

Biological: Avelumab
avelumab (800mg by IV) will be administered on days 8 and 22 of the 28- day cycle for four cycles

Experimental: 2-Experimental Treatment: Doe Expansion
IL-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
Drug: rhIL-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.

Biological: Avelumab
avelumab (800mg by IV) will be administered on days 8 and 22 of the 28- day cycle for four cycles




Primary Outcome Measures :
  1. Efficacy of rhIL-15 + avelumab [ Time Frame: one month after completion of treatment ]
    Overall response rate


Secondary Outcome Measures :
  1. Duration of response [ Time Frame: date clinical response is 1st identified until progression assessed - every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval.

  2. Progression-free survival [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval.

  3. Overall response rate [ Time Frame: 4 cycles ]
    The response rate will be determined and reported along with a 95% confidence interval.

  4. safety and tolerability of rhIL-15 + avelumab [ Time Frame: 4 cycles ]
    rate and severity of AEs will be summarized by grade and type of toxicity



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:
  • 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
    • 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 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
  • 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.

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): NCT04150562


Contacts
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Contact: NCI Medical Oncology Referral Office (240) 760-6050 NCIMO_Referrals@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kevin C Conlon, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04150562    
Other Study ID Numbers: 200007
20-C-0007
First Posted: November 4, 2019    Key Record Dates
Last Update Posted: October 30, 2020
Last Verified: October 13, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Antibody Dependent Cellular Cytotoxicity (ADCC)
Anti-PD-L1 monoclonal antibody
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Kidney Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases