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 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 >= 18 years of age
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.
- INCLUSION CRITERIA:
- 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, NCI
- Patients with CD30+ mycosis fungoides/S(SqrRoot)(Copyright)zary 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 RECIL 2017 or 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
- 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)
- 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 30 days 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 to understand and the willingness to sign a written informed
consent document
EXCLUSION CRITERIA:
- 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 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 less than or equal to 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, unrelated to their
malignancy, 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
- 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
