Patient case: 45-year-old female with cervical cancer; genetic feature: ERBB2 (S310Y)

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

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.
  -  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.
  ...

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.

Eligibility: -  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

Relevance to patient case: not relevant