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

NCT03905135 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 19007619-C-0076
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Peripheral T-cell Lymphoma NOS; Mycosis Fungoides; Sezary Syndrome; Anaplastic Large Cell Lymphoma

Keywords

T-cell Lymphoproliferative Disorder; Cutaneous T-Cell Lymphoma; Anti-PD-L1 monoclonal antibody; Antibody Dependent Cellular Cytotoxicity (ADCC)

Outcome Measures

Primary Outcomes (1)

• 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.

  First 28 days of treatment

Secondary Outcomes (6)

• Mean Progression Free Survival (PFS)

  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)

  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)

  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

  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

  6 cycles (each cycle is 28 days) - approximately 168 days

Other Outcomes (2)

• Number of Participants With a Dose-limiting Toxicity (DLT)

  First 28 days of treatment

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

  Date treatment consent signed to date off study, approximately 21 months and 18 days for the dose level 1 and 3 months and 19 days for the dose level 2.

Study Arms (2)

1- Experimental Treatment: Dose Escalation

EXPERIMENTAL

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)

Drug: rhIL-15; Biological: Avelumab

2- Experimental Treatment: Dose Expansion

EXPERIMENTAL

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

Drug: rhIL-15; Biological: Avelumab

Interventions

rhIL-15 DRUG

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.

Also known as: Recombinant human Interleukin-15

1- Experimental Treatment: Dose Escalation

Avelumab BIOLOGICAL

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.

Also known as: Bavencio

1- Experimental Treatment: Dose Escalation; 2- Experimental Treatment: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically proven relapsed/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), or enteropathy-associated T-cell lymphoma (EATL), confirmed by the Laboratory of Pathology, National Cancer Institute (NCI)
• Patients with CD30 (also known as TNFRSF8) + mycosis fungoides/Sezary syndrome (MF/SS) or CD30+ anaplastic large cell lymphoma (ALCL) must have relapsed after or become intolerant to treatment with brentuximab vedotin.
• A formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be available for performance of correlative studies. NOTE: Patients must be willing to have a tumor biopsy if prior tissue or adequate archival tissue is not available (i.e., post-enrollment and prior to treatment).
• Disease must be measurable with at least one measurable lesion by response evaluation criteria in lymphoma (RECIL) 2017 or Modified Severity-Weighted Assessment Tool (mSWAT) criteria or have an abnormal clonal T-cell population detectable by peripheral blood flow cytometry
• Age greater than or equal to 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 will be eligible for future pediatric trials
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
• Adequate organ and marrow function as defined:
• Absolute neutrophil count greater than 1,000/mcL
• Absolute lymphocyte count greater than or equal to 500/mcL
• Hemoglobin greater than or equal to 9 g/dL
• Platelets greater than 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

You may not qualify if:

• Patients with the following T-cell leukemias/lymphomas: 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).
• Chemotherapy and anti-tumor antibodies within 4 weeks (6 weeks for nitrosoureas or mitomycin C); other tumor-directed systemic therapy and radiation therapy within 2 weeks.
• Persisting toxicity related to prior therapy of grade \> 1, with the exception of the following: alopecia, sensory neuropathy grade less than or equal to 2, or other grade less than or equal to 2 not constituting a safety risk based on investigator's judgment
• Patients who are receiving any other investigational agents
• Patients who have had prior therapy with any antibody/drug targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) Tcell coregulatory proteins (immune checkpoints)
• 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 less than or equal to 10 mg/day of prednisone or equivalent; or,
• Steroids as premedication for hypersensitivity reactions (e.g., computed tomography (CT) scan premedication)
• Patients with known central nervous system (CNS) involvement 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
• Received a live vaccine 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 recombinant human Interleukin-15 (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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Dubois SP, Miljkovic MD, Fleisher TA, Pittaluga S, Hsu-Albert J, Bryant BR, Petrus MN, Perera LP, Muller JR, Shih JH, Waldmann TA, Conlon KC. Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies. J Immunother Cancer. 2021 Apr;9(4):e002193. doi: 10.1136/jitc-2020-002193.

  PMID: 33883258 DERIVED

• Waldmann TA, Dubois S, Miljkovic MD, Conlon KC. IL-15 in the Combination Immunotherapy of Cancer. Front Immunol. 2020 May 19;11:868. doi: 10.3389/fimmu.2020.00868. eCollection 2020.

  PMID: 32508818 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, T-Cell; Mycosis Fungoides; Sezary Syndrome; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell, Cutaneous

Interventions

Interleukin-15; avelumab

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Kevin C. Conlon
• Organization: National Cancer Institute

conlonkc@mail.nih.gov

240-858-3570

Study Officials

• Kevin C Conlon, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 3, 2019
• First Posted: April 5, 2019
• Study Start: June 7, 2019
• Primary Completion: March 25, 2021
• Study Completion: May 17, 2022
• Last Updated: September 13, 2022
• Results First Posted: September 13, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be available during the study and indefinitely. Genomic data will be available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data will be made available via database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)