Clinical Trials /

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

NCT03905135

Description:

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. - CT or PET scans and 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 IL-15 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. ...

Related Conditions:
  • Anaplastic Large Cell Lymphoma
  • Anaplastic Large Cell Lymphoma, ALK-Negative
  • Mycosis Fungoides
  • Peripheral T-Cell Lymphoma, NOS
  • Sezary Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies
  • Official Title: A Phase 1 Study of Interleukin-15 in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies.

Clinical Trial IDs

  • ORG STUDY ID: 190076
  • SECONDARY ID: 19-C-0076
  • NCT ID: NCT03905135

Conditions

  • Peripheral T-cell Lymphoma-not Otherwise Specified
  • Mycosis Fungoides
  • Sezary Syndrome
  • ALK-negative Anaplastic Large Cell Lymphoma

Interventions

DrugSynonymsArms
rhIL-151- Experimental Treatment: Dose Escalation
Avelumab1- Experimental Treatment: Dose Escalation

Purpose

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. - CT or PET scans and 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 IL-15 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 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.

Detailed Description

      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 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 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) rhIL-15 administration in combination with standard
      intravenous (IV) avelumab treatment

      Eligibility:

        -  Age greater than or equal to 18 years of age

        -  ECOG performance status of less than or equal to 1

        -  Histologically or cytologically confirmed relapsed and/or refractory T-cell lymphoma of
           the following types: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS),
           mycosis fungoides/S(SqrRoot)(Copyright)zary syndrome or ALK-negative anaplastic large
           cell lymphoma

        -  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.
    

Trial Arms

NameTypeDescriptionInterventions
1- Experimental Treatment: Dose EscalationExperimentalIL-15 by 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 IV infusion at a dose of 10mg/kg on Day 8 and 22 of each cycle, to determine MTD
  • rhIL-15
  • Avelumab
2- Experimental Treatment: Dose ExpansionExperimentalIL-15 by civ infusion at the MTD on days 1- 5 of cycles 1-6 with avelumab at 10mg/kg on Day 8 and 22 ofeach cycle
  • rhIL-15
  • Avelumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have one of the following histologically or cytologically proven
             relapsed and/or refractory T-cell malignancies: confirmed by the Laboratory of
             Pathology, NCI, as follows: peripheral T-cell lymphoma NOS, mycosis
             fungoides/S(SqrRoot)(Copyright)zary syndrome, or ALK-negative anaplastic large cell
             lymphoma, for which no standard therapy exists or standard therapy has failed

          -  Patients with CD30+ MF/SS or CD30+ ALK-negative 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 RECIL 2017 or mSWAT
             criteria or have an abnormal clonal T-cell population detectable by peripheral blood
             flow cytometry

          -  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 will be eligible for future pediatric trials

          -  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

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

               -  Platelets greater than 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 m2 for patients with
                  creatinine levels greater than 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 4 months 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:

          -  Patients with other T-cell leukemias/lymphomas not specified in the inclusion 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 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 PD-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 10 mg/day of prednisone or
                  equivalent; or,

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          -  Patients with known 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 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 non-corticosteroid bronchodilator regimens are eligible

          -  Patients with active or history of any autoimmune disease

          -  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:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:28 days
Safety Issue:
Description:Frequency (number and percentage) of treatment-emergent adverse events

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • T-cell Lymphoproliferative Disorder
  • Cutaneous T Cell Lymphoma
  • Anti-PD-L1 monoclonal antibody
  • Antibody Dependent Cellular Cytotoxicity

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