This phase I trial studies the side effects and best dose of anti-inducible T-cell
co-stimulator (ICOS) monoclonal antibody MEDI-570 in treating patients with peripheral T-cell
lymphoma follicular variant or angioimmunoblastic T-cell lymphoma that has returned after a
period of improvement (relapsed) or has not responded to previous treatment (refractory).
Immunotherapy with monoclonal antibodies, such as anti-ICOS monoclonal antibody MEDI-570, may
induce changes in the body's immune system and may interfere with the ability of tumor cells
to grow and spread.
PRIMARY OBJECTIVE:
I. To determine the safety, maximum tolerated dose and recommended phase II dose (RP2D) of
anti-ICOS monoclonal antibody MEDI-570 (MEDI-570) in patients with refractory/relapsed
peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell
lymphoma (AITL), follicular lymphoma, mycosis fungoides (MF) and cutaneous T-cell lymphomas
(CTCL).
SECONDARY OBJECTIVES:
I. To evaluate the pharmacokinetic profile of MEDI-570. II. To evaluate the overall response
rate (ORR) and progression free survival (PFS) of MEDI-570 at all dose levels and in a
10-patient expansion cohort at the maximum tolerated dose (MTD).
III. To determine short and long term effects of MEDI-570 at all dose levels on the immune
system and on T-cell lymphocyte subsets.
IV. To determine the relationship between ICOS expression on tumor cells and response to
MEDI-570.
EXPLORATORY OBJECTIVE:
I. To evaluate biomarkers of response and resistance to MEDI-570 in the study population.
OUTLINE: This is a dose-escalation study.
Patients receive anti-ICOS monoclonal antibody MEDI-570 intravenously (IV) over 1-4 hours on
day 1. Treatment repeats every 21 days for up to 8 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6
weeks for 12 weeks.
Inclusion Criteria:
- Pathologic diagnosis of one of the following:
- For dose escalation:
- Confirmed diagnosis of peripheral T-cell lymphoma (PTCL) or
angioimmunoblastic T-cell lymphoma (AITL) that is refractory to at least one
line of therapy; anaplastic large cell lymphoma (ALCL) and natural killer
T-cell lymphoma nasal type (NKTCL) are excluded
- Advanced stage cutaneous T-cell lymphoma (CTCL), specifically CTCL NOS,
small/medium T-cell lymphoma (SMTCL) and mycosis fungoides (MF) stage IB,
IIA, IIB, III and IV that have relapsed after at least one specific prior
therapy (e.g. interferon, photopheresis, denileukin difitox, bexarotene,
etc); anaplastic cutaneous large cell lymphoma (ACLCL) and lymphomatoid
papulopsis are excluded
- Follicular lymphoma grade 1, 2 or 3A that meets the following criteria:
- Relapsed or refractory to at least 2 lines of therapy AND
- Relapsed or refractory post autologous cell transplantation (HCT)
- For dose expansion/dose confirmation phase:
- Patients with confirmed diagnosis of peripheral T-cell lymphoma (PTCL)
follicular type or angioimmunoblastic T-cell lymphoma (AITL) that is
refractory to at least one line of therapy
- At least 14 days from the last therapy dose or 5 half-lives (whichever is shorter),
and resolution of toxicity related to the last therapy, excluding grade 2 or less
peripheral neuropathy and alopecia; for radiation therapy, a minimum of 2 weeks and
resolution of all acute toxicity will be required
- Patients must have at least one measurable lesion that can be accurately measured with
spiral computed tomography (CT) scan, magnetic resonance imaging (MRI) scan, or
physical exam (by calipers only); (PTCL, AITL and follicular lymphoma patients will be
assessed on this study using the Lugano criteria for the evaluation of lymphomas; CTCL
and MF patients will be assessed using International Society for Cutaneous Lymphomas
[ISCL] and European Organization for Research and Treatment of Cancer [EORTC]
criteria)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Life expectancy of greater than 6 months
- Leukocytes >= 3,000/mcL
- Hemoglobin >= 80 d/L (or >= 8 g/dL)
- Patients must not have received a transfusion, with packed red blood cells,
within 2 weeks prior to sample being collected
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets (PLT) >= 50,000/mcL
- Absolute CD4 count > 100 cells/uL
- Total bilirubin < 1.5 upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
2.5 x institutional upper limit of normal
- Creatinine < 1.5 mg/dl (= 132 umol/L) or
- Creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal
- In patients with bone marrow involvement the minimum requirement is as follows:
- Leukocytes >= 2000/mcL
- ANC >= 1000/mcL
- PLT >= 50 000/mcL
- Availability of tissue for correlative studies; patients must have at least 6-8
unstained slides of archived formalin-fixed, paraffin-embedded tumor tissue available;
if not enough archived tissue is available, a fresh tumor biopsy prior to study
initiation is mandatory; for patients who have undergone a fresh baseline biopsy at
baseline, the archived tissue is not mandatory
- The effects of MEDI-570 on the developing human fetus are unknown; for this reason,
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, during
the study participation, and for 3 months after the last dose of the drug; 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; men
treated or enrolled on this protocol must have either had a prior vasectomy or agree
to use effective contraception prior to the study, during the study, and for 3 months
after the last dose of the drug; males should avoid fathering children during and for
at least three months after therapy is completed
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who are receiving any other investigational agents
- Patients with known brain metastases 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
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MEDI-570 or history of anaphylaxis to any biological component
- Any history or evidence of opportunistic infection within 6 months of screening
including tuberculosis, severe cytomegalovirus (CMV) or herpetic infections (such as
disseminated herpes, herpes encephalitis, ophthalmic herpes)
- Evidence of active infection by hepatitis B and/or C; active viral infection by
hepatitis B and hepatitis C could be associated with cytopenias (due to hypersplenism
or due to the active virus itself), which could add further risk when a potential
immunosuppressive medication is used; for patients with hepatitis B treated with
anti-virals to undetectable viral load, and for patients with hepatitis C with
undetectable ribonucleic acid (RNA) levels and no evidence of liver damage, enrollment
may be considered and should discuss first with study's principal investigator
- History of human immunodeficiency virus (HIV) infection; the human immunodeficiency
virus (HIV) depletes CD4 T-cells and could also have a role in T-cell anergy; since
MEDI-570 preferentially affects CD4 T-cell numbers and function, and the resultant
immunosuppression by this agent can be prolonged, exposing HIV patients to MEDI-570
will place them in an unnecessary risk of developing infections due to an underlying
acquired cellular immunity defect
- History of primary immunodeficiency
- Receipt of live or live attenuated vaccine within 12 weeks prior to enrollment
- All potential patients must undergo a tuberculosis (TB) test prior to study entry to
rule out active or latent tuberculosis (either purified protein derivative [PPD] or
QuantiFERON-TB Gold, whichever is preferred and available at the institution);
patients with a history of TB (even if treated), or evidence of active or latent TB,
are excluded; the diagnosis of active TB is defined per current guidelines; patients
with a positive TB test (e.g. PPD or QuantiFERON-TB Gold) will be excluded; patients
with history of Bacille-Calmette-Guerin (BCG) vaccination will be tested with
QuantiFERON-TB Gold test in order to rule out exposure to TB
- Patients who have undergone allogeneic stem cell transplantation
- Patients who have undergone autologous stem cell transplantation within 3 months from
study entry
- Major surgery within 30 days prior or during the study period
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study due to the potential toxicity in
pre-clinical reproductive studies; in addition, there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
MEDI-570; breastfeeding should be discontinued if the mother is treated with MEDI-570
- Patients with active, known, or suspected autoimmune disease, except in these
conditions:
- Participants with well-controlled asthma and/or mild allergic rhinitis (seasonal
allergies) are eligible
- Participants with the following disease conditions are also eligible:
- Vitiligo,
- Type 1 diabetes mellitus
- Residual hypothyroidism due to autoimmune condition only requiring hormone
replacement
- Euthyroid participants with a history of Grave's disease (participants
suspected autoimmune thyroid disorders must be negative for thyroglobulin
and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin
prior to first dose of study drug)
- For patients with ITP (idiopathic thrombocytopenic purpura) or AIHA
(autoimmune hemolytic anemia), a case by case discussion with study
principal investigator (PI) may be considered
- Patients not receiving systemic therapy (i.e., systemic steroids or biologic
therapy with disease modifying anti-rheumatic drugs [DMARDs]) within 2 years
can be also eligible
- Patients with a weight of < 39 kg
