Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Avelumab

Immunoglobulins

Antineoplastic Agents, Immunological

Interleukin 15 (IL-15) by continuous intravenous (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 intravenous (IV) infusion at a dose of 800mg on Day 8 and 22 of each cycle

Interleukin 15 (IL-15) by continuous intravenous (CIV) infusion at 4 mcg/kg/day on days 1-5 of each 28- day cycle (max 4 cycles) with avelumab by intravenous (IV) infusion at a dose of 800mg on Day 8 and 22 of each cycle

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.

rhIL-15

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

Kevin C Conlon, M.D.

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.

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 long term cluster of differentiation 8 (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 immunoglobulin G1 (IgG1) antibody that inhibits programmed cell death protein 1 (PD1)/PD-L1 interactions while leaving the PD1/Programmed cell death 1 ligand 2 (PD-L2) pathway intact and enhances immune activation against tumor cells. It has received United States (U.S.) Food and Drug Administration (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 additional mechanism 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 recombinant human Interleukin-15 (rhIL-15) - 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
* Eastern Cooperative Oncology Group (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 immunohistochemistry (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-cluster of differentiation 152 (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 continuous intravenous (CIV) interleukin-15 (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.

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

Phase II Trial of Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Response was assessed using the Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST)v1.1. Immune related complete response (irCR) is at least two radiographic determinations of complete response (CR - e.g., disappearance of all target lesions) at least 4 weeks apart and before Immune related progressive disease (irPD - defined as at least two consecutive radiographic determinations of progressive disease ((PD - e.g., appearance of one or more new lesions) at least 4 weeks apart). at least 4 weeks apart). Immune related partial response (irPR) is at least two radiographic determinations of partial response (PR - e.g., 30% decrease of target lesions) or better at least 4 weeks apart and before irPD (and not qualifying for an irCR).

Duration of response is defined as the time from the initial response (irCR, irPR or irSD) to progression or death, whichever comes first. Response was assessed using the Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST)v1.1. Immune related complete response (irCR) is at least two radiographic determinations of complete response (CR) at least 4 weeks apart and before Immune related progressive disease (irPD - defined as at least two consecutive radiographic determinations of progressive disease (PD) at least 4 weeks apart). Immune related partial response (irPR) is at least two radiographic determinations of partial response (PR) or better at least 4 weeks apart and before irPD (and not qualifying for an irCR). Immune related stable disease (irSD) is at least one radiographic assessment of stable disease (SD) (or better) ≥ 6 weeks after the first trial treatment administration and before irPD (and not qualifying for irCR or irPR).

Progression free survival is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever comes first. Progression was assessed using the Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST)v1.1. Immune related progressive disease (irPD) is defined as at least two consecutive radiographic determinations of progressive disease (PD - e.g., appearance of one or more new lesions) at least 4 weeks apart).

Overall survival is defined as the time from the date of study enrollment until time of death from any cause.

Adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse events.

National Cancer Institute (NCI)

Principal Investigator

Interleukin 15 (IL-15) by continuous intravenous (CIV) infusion at 2 mcg/kg/day on days 1-5 of each 28-day cycle (max 4 cycles) with avelumab by intravenous (IV) infusion at a dose of 800mg on Day 8 and 22 of each cycle

Arm 1- Safety Run-in Dose Level 1

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Kevin C. Conlon

Immune related complete response (irCR)

Immune related partial response (irPR)

Overall Response Rate (Complete Response + Partial Response)

Duration of Response

Progression-free Survival

Overall Survival

Grade 3

Grade 4

Grade 5

Number of Grade 3 Adverse Events Possibly, Probably or Definitely Related to Treatment of rhIL-15 + Avelumab

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Interleukin 15 (IL-15) by continuous intravenous (CIV) infusion at 4 mcg/kg/day on days 1-5 of each 28- day cycle (max 4 cycles) with avelumab by intravenous (IV) infusion at a dose of 800mg on Day 8 and 22 of each cycle to determine efficacy of treatment.

Arm 2-Dose Expansion

Overall Study

Symptoms and General Pathology

Blood and Lymph Conditions

Immune System Diseases

Infections

Syndrome

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Mycoses

Lymphoproliferative Disorders

Mycosis Fungoides

Lymphoma, T-Cell, Cutaneous

Sezary Syndrome

Lymphoma, Large-Cell, Anaplastic

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Communicable Diseases

Bacterial Infections

Bacterial Infections and Mycoses

Lymphosarcoma

Peripheral T-cell Lymphoma

Cutaneous T-cell Lymphoma

Anaplastic Large Cell Lymphoma

Interleukin-15 (IL-15) by continuous intravenous (civ) infusion at escalating doses of 1, 2, 3 and 4 mcg/kg/day on days 1-5 of each 28-day cycle (max 6 cycles) with avelumab by intravenous (IV) infusion at a dose of 10mg/kg on Day 8 and 22 of each cycle, to determine maximum tolerated dose (MTD)

Interleukin-15 (IL-15) by continuous intravenous (civ) infusion at the maximum tolerated dose (MTD) on days 1-5 of cycles 1-6 with avelumab at 10mg/kg on Day 8 and 22 of each cycle

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a starting dose level of 1 mcg/kg/day, a second dose level of 2 mcg/kg/day, a third dose level at 3 mcg/kg/day, and a fourth dose level at 4 mcg/kg/day on days 1-5 of each of six cycles.

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion at the maximum tolerated dose (MTD) or maximum administered dose (MAD) on days 1-5 of each of six cycles

Avelumab (intravenous (IV) over 1 hour) will be administered at a dose of 10 mg/kg on days 8 and 22 of each of six cycles.

Background:

Some T-cell lymphomas and leukemias do not respond to standard treatment. Researchers hope to develop a treatment that works better than current treatments.

Objective:

To test if interleukin (IL-5) combined with avelumab is safe and effective for treating certain cancers.

Eligibility:

People ages 18 and older with relapsed T-cell leukemias and lymphomas for which no standard treatment exists or standard treatment has failed

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Blood, urine, heart, and lung tests
* Possible tumor biopsy
* Bone marrow biopsy: A small needle will be inserted into the hipbone to take out a small amount of marrow.
* Computed tomography (CT) or positron emission tomography (PET) scans and magnetic resonance imaging (MRI): Participants will lie in a machine that takes pictures of the body.

Participants will get the study drugs for 6 cycles of 28 days each. They will have a midline catheter inserted: A tube will be inserted into a vein in the upper chest. They will get Interleukin-15 (IL-5) as a constant infusion over the first 5 days of every cycle. They will get avelumab on days 8 and 22 of each cycle. They will be hospitalized for the first week of the first cycle.

Participants will have tests throughout the study:

* Blood and urine tests
* Another tumor biopsy if their disease gets worse
* Scans every 8 weeks
* Possible repeat MRI
* Another bone marrow biopsy at the end of treatment, if there was lymphoma in the bone marrow before treatment, and they responded to treatment everywhere else.

After they finish treatment, participants will have visits every 60 days for the first 6 months. Then visits will be every 90 days for 2 years, and then every 6 months for 2 years. Visits will include blood tests and may include scans.

Background:

Mature T-cell cancers are a phenotypically heterogeneous group of malignancies which constitute 10-15% of all non-Hodgkin lymphomas (NHL). Patients with relapsed/refractory T cell lymphomas have limited therapeutic options, making new therapeutic approaches extremely important.

The immunologic effects of recombinant human Interleukin-15 (rhIL-15), a stimulatory cytokine that promotes the differentiation and activation of NK cells, monocytes and long-term cluster of differentiation 8 (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 immunoglobulin G1 (IgG1) antibody that inhibits programmed cell death protein 1 (PD1)/PD-L1 interactions while leaving the PD1/programmed cell death ligand 2 (PD-L2) pathway intact and enhances immune activation against tumor cells. It has received United States (U.S.) Food and Drug Administration (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 additional mechanism of action. However, avelumab has not shown ADCC against normal immune cell subsets in humans.

A significant number of T-cell malignancies express PD-L1, and 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 these diseases.

Objectives:

To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of continuous intravenous infusion (civ) recombinant human interleukin-15 (rhIL-15) administration in combination with standard intravenous (IV) avelumab treatment

Eligibility:

Age \>= 18 years of age

Eastern Cooperative Oncology Group (ECOG) performance status of \<= 1

Histologically or cytologically confirmed relapsed and/or refractory T-cell lymphoma other than adult T-cell leukemia/lymphoma (ATLL), angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma T follicular helper phenotype (PTCL-TFH) and enteropathy-associated T-cell lymphoma (EATL).

Adequate organ and marrow function

Design:

Open-label, single-center, non-randomized Phase 1 study

Standard 3 + 3 design will be used to determine the MTD of dose-escalated rhIL-15 with fixed dose avelumab with a small expansion cohort at the MTD

Maximum 6 cycles (28-day cycle) of combination therapy

To explore all dose levels, including further evaluation in a dose expansion cohort, the accrual ceiling will be set at 30 patients.

Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies

A Phase 1 Study of Interleukin-15 in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

A dose-limiting toxicity (DLT) is defined as: any grade 3, 4, or 5 toxicity if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably or definitely related to interleukin-15 (IL-5) or avelumab by the principal investigator (PI) or designee during the first 28 days of treatment. Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.

The MTD is the dose level at which no more than 1 of up to 6 participants experience a dose-limiting toxicity (DLT) during the DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) participants have DLT. A dose-limiting toxicity (DLT) is defined as: any grade 3, 4, or 5 toxicity, if not incontrovertibly due to disease progression or an extraneous cause, and deemed possibly, probably or definitely related to interleukin-15 (IL-5) by the principal investigator (PI) or designee during the first 28 days of treatment. Grade 3 is severe. Grade 4 is life threatening. Grade 5 is death related to adverse event.

PFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first. Disease relapse is Disease progression is \>20% increase in the sum of longest diameters of target lesions or appearance of a new lesion assessed by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria.

EFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), or death, whichever occurs first, and was estimated using Kaplan-Meier curves along with a 95% confidence interval. Disease relapse is Disease progression is \>20% increase in the sum of longest diameters of target lesions or appearance of a new lesion assessed by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria.

OS is defined as the time from the date of study enrollment until time of death from any cause and was estimated using Kaplan-Meier curves along with a 95% confidence interval.

Response was assessed by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria and reported along with a 95% confidence interval. Complete response is complete disappearance of all target lesions. Partial response is ≥30% decrease in the sum of longest diameters of target lesions but not a complete response. Minor response is ≥10% decrease in the sum of longest diameters of target lesions but not a partial response. Stable disease is \<10% decrease or ≤20% increase in the sum of longest diameters of target lesions. Disease progression is \>20% increase in the sum of longest diameters of target lesions or appearance of a new lesion.

OR is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Complete response is complete disappearance of all target lesions. Partial response is ≥30% decrease in the sum of longest diameters of target lesions but not a complete response. Minor response is ≥10% decrease in the sum of longest diameters of target lesions but not a partial response. Stable disease is \<10% decrease or ≤20% increase in the sum of longest diameters of target lesions. Disease progression is \>20% increase in the sum of longest diameters of target lesions or appearance of a new lesion assessed by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria.

DOR is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), death, or, in the absence of progressive disease (PD), date of last assessment. The response rate was assessed by the Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria and reported along with a 95% confidence interval. Complete response is complete disappearance of all target lesions. Partial response is ≥30% decrease in the sum of longest diameters of target lesions but not a complete response. Disease progression is \>20% increase in the sum of longest diameters of target lesions or appearance of a new lesion.

Three participants died from disease progression during the long-term survival follow-up phase of the study (they were only being called once every 3 months to check to see if they died and to learn of new cancer treatments). We were no longer tracking adverse events (AEs) at the time of death, thus only one death from progressive disease is listed in the serious adverse events table below.

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a starting dose level of 1 mcg/kg/day, a second dose level of 2 mcg/kg/day, a third dose level at 3 mcg/kg/day, and a fourth dose level at 4 mcg/kg/day on days 1-5 of each of six cycles.

Avelumab (intravenous (IV) over 1 hour) will be administered at a dose of 10 mg/kg on days 8 and 22 of each of six cycles.

Dose Escalation - Dose Level 1, 1mcg/kg Interleukin-15 With 10 mg Avelumab

Dose Level 2, 2mcg/kg Interleukin-15 With 10 mg Avelumab

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a starting dose level of 1 mcg/kg/day on days 1-5 of each of six cycles.

Avelumab (intravenous (IV) over 1 hour) will be administered at a dose of 10 mg/kg on days 8 and 22 of each of six cycles.

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a second dose level of 2 mcg/kg/day on days 1-5 of each of six cycles.

Avelumab (intravenous (IV) over 1 hour) will be administered at a dose of 10 mg/kg on days 8 and 22 of each of six cycles.

Total

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a starting dose level of 1 mcg/kg/day on days 1-5 of each of six cycles.

Interleukin-15 (IL-15) will be administered by continuous intravenous infusion in a dose-escalation fashion with a second dose level of 2 mcg/kg/day on days 1-5 of each of six cycles.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma	NCT04150562	Clear-Cell Rena...	rhIL-15 Avelumab	18 Years -	National Institutes of Health Clinical Center (CC)
Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies	NCT03905135	Peripheral T-ce... Mycosis Fungoid... Sezary Syndrome Anaplastic Larg...	rhIL-15 rhIL-15 Avelumab	18 Years -	National Institutes of Health Clinical Center (CC)
Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma	NCT04150562	Clear-Cell Rena...	rhIL-15 Avelumab	18 Years -	National Institutes of Health Clinical Center (CC)
Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies	NCT03905135	Peripheral T-ce... Mycosis Fungoid... Sezary Syndrome Anaplastic Larg...	rhIL-15 rhIL-15 Avelumab	18 Years -	National Institutes of Health Clinical Center (CC)

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