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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
8
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.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Maximum Tolerated Dose (MTD) of Interleukin 15
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.
Time frame: First 28 days of treatment
Mean Progression Free Survival (PFS)
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.
Time frame: From study opening through May 2022 when the study was completed with a maximum follow up of approximately 2 years and 11 months for any participant.
Mean Event-free Survival (EFS)
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.
Time frame: From study opening through May 2022 when the study was completed with a maximum follow up of approximately 2 years and 11 months for any participant.
Mean Overall Survival (OS)
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.
Time frame: From study opening through May 2022 when the study was completed with a maximum follow up of approximately 2 years and 11 months for any participant.
Overall Response in Participants With Greater Than or Equal to 50% Programmed Death-ligand 1 (PD-L1) Expressing Tumor Cells
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.
Time frame: From the time the subject began protocol treatment until end of treatment, progression or start of another therapy or approximately 2 years
Number of Participants With Overall Best Response
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.
Time frame: 6 cycles (each cycle is 28 days) - approximately 168 days
Mean Duration of Response (DOR)
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.
Time frame: From the time that response to therapy is first documented until progressive disease is observed or the subject is lost to follow-up or approximately 2 years.
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