PRIMARY OBJECTIVE:
I. To assess the antineoplastic efficacy of brentuximab vedotin in combination with
pembrolizumab in previously treated patients with PTCL, as measured by the overall objective
response rate (ORR).
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of brentuximab vedotin in combination with
pembrolizumab.
II. To assess efficacy using duration of objective response (DOR), time to response (TTR),
progression free survival (PFS), and overall survival (OS).
OUTLINE:
Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1, and
pembrolizumab IV over 30 minutes on day 3 of cycle 1, day 1 of subsequent cycles. Treatment
repeats every 21 days for up to 16 cycles in the absence of disease progression or
unacceptable toxicity. After 6 cycles of treatment, patients may discontinue treatment if
they experience disease progression, are eligible for stem cell transplant, or if they elect
to not undergo stem cell transplantation (SCT).
After completion of study treatment, patients are followed up to 5 years.
Inclusion Criteria:
- Patients must have a histologically-confirmed diagnosis of CD30- positive/expressing
peripheral T-cell lymphoma (PTCL). NOTE: All PTCL subtypes are eligible, except for
adult T-cell leukemia/Lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL); ATLL and
CTCL are excluded per exclusion criterion below. Examples of eligible subtypes include
but are not limited to the following:
- AITL: Angioimmunoblastic T-cell lymphoma
- EATL: Enteropathy-associated T-cell lymphoma
- ENKTL: Extranodal Natural Killer/T-cell Lymphoma
- FTCL: Follicular T-cell lymphoma
- HSTCL: Hepatosplenic T-cell lymphoma
- PTCL-NOS: Peripheral T-cell lymphoma, not otherwise specified
- PTCL-TFH: Nodal peripheral T-cell lymphoma with T-follicular helper phenotype
- SPTCL: Subcutaneous Panniculitis-like T-cell Lymphoma NOTE: CD30-positivity is
defined as >= 1% of cells expressing CD30 as detected by immunohistochemistry
(IHC) and determined by local review.
- Patients must have received at least one prior line of systemic therapy and must have
relapsed disease or secondary refractory disease meeting one of the below criteria:
- Disease that relapsed within > 6 months after completion of frontline therapy; or
- Disease that relapsed within any time after completion of secondary/subsequent
lines of therapy; or
- Disease that was refractory to secondary/subsequent lines of therapy NOTE:
Patients who have primary relapsed/refractory disease with relapse within 6
months of frontline treatment are not eligible. See exclusion criterion below
NOTE: Exclusions on receipt of prior brentuximab vedotin are described in
exclusion criterion below. Exclusions on receipt of prior immunotherapy are
described in exclusion criterion below.
- Patients must be >= 18 years of age
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Absolute neutrophil count (ANC) >= 1,000/mcL
- Platelets >= 50,000/mcL
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (without transfusion or
erythropoietin-dependency within =< 7 days prior to assessment)
- Measured or calculated creatinine clearance >= 60 mL/min
- Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 X upper limit of normal (ULN) OR direct bilirubin =< ULN
for patients with total bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for patients with liver metastases
- Female patients of reproductive potential must have a negative urine or serum
pregnancy test within 72 hours prior to registration. If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: In the
event that 72 hours have elapsed between the screening pregnancy test and the first
dose of study treatment, another pregnancy test (urine or serum) must be performed and
must be negative in order for the subject to start receiving study medication
- Female patients of reproductive potential must be willing to use an adequate method of
contraception starting >= 7 days prior to the first dose of study therapy and through
23 weeks after the last dose. Male patients of reproductive potential must agree to
use an adequate method of contraception starting >= 7 days prior to the first dose of
study therapy and through 31 weeks after the last dose. NOTE: Abstinence is acceptable
if this is the usual lifestyle and preferred contraception for the patient
- Patients must have an fludeoxyglucose F 18-positron emission tomography-computed
tomography (18FDG-PET-CT) scan (preferred) or CT scan of chest, abdomen, and pelvis
(and neck if clinically indicated) at baseline and must have measurable disease per
2014 Lugano Criteria. The same imaging modality should be used throughout the course
of study treatment to assess tumor response. NOTE: Imaging with contrast is preferred,
but imaging without contrast will be accepted if the use of contrast is not clinically
indicated
- Patients must have the ability to understand and the willingness to sign a written
informed consent form prior to registration on study
Exclusion Criteria:
- Patients who have received prior systemic anti-cancer therapy (including
investigational agents) within 4 weeks prior to registration are not eligible. NOTE:
Patients must have recovered from all adverse events due to previous therapies to =<
grade 1 or baseline to be eligible. (Exception: =< grade 2 alopecia is permitted).
NOTE: If a patient underwent a major surgery, he/she must have recovered adequately
from the toxicity and/or complications from the surgical intervention prior to
starting study treatment
- Patients who have received prior radiotherapy within =< 2 weeks prior to registration
are not eligible. EXCEPTION: A >= 1-week washout is permitted for palliative radiation
(=< 2 weeks of radiotherapy) to non-central nervous system [CNS] disease. NOTE:
Patients must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis
- Patients with adult T-cell leukemia/lymphoma (ATLL) or cutaneous T-cell lymphoma are
not eligible
- Patients with a history of (non-infectious) pneumonitis that required steroids,
evidence of interstitial lung disease, or active, non-infectious pneumonitis are not
eligible
- Patients with a history of allogeneic stem cell transplant or graft-versus
host-disease (GvHD) within =< 5 years prior to registration are not eligible
- Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2
agent, or with an agent directed to another stimulatory or co-inhibitory T-cell
receptor (e.g., CTLA-4, OX40, CD137) are not eligible
- Patients with known, active central nervous system (CNS) metastases and/or
carcinomatous meningitis are not eligible. NOTE: Patients with previously treated
brain metastases may participate, provided they are stable (without evidence of
progression by imaging for at least four weeks prior to the first dose of trial
treatment and any neurologic symptoms have returned to baseline), have no evidence of
new or enlarging brain metastases, and are not using steroids for at least 7 days
prior to trial treatment. This exception does not include carcinomatous meningitis,
which is excluded regardless of clinical stability
- Patients with a diagnosis of immunodeficiency or who are receiving systemic steroid
therapy or any other form of immunosuppressive therapy within =< 7 days prior to the
first dose of trial treatment are not eligible. EXCEPTIONS: Short term steroid
preparation prior to tumor imaging is permitted for prophylaxis (e.g., contrast dye
allergy)
- Patients with active autoimmune disease that has required systemic treatment (i.e.,
with the use of disease modifying agents, corticosteroids or immunosuppressive drugs)
within =< 2 years prior to registration are not eligible. Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Patients with a history of progressive multifocal leukoencephalopathy (PML) are not
eligible
- Patients with a history of pancreatitis are not eligible
- Patients with pre-existing >= grade 2 peripheral neuropathy are not eligible
- Patients who have a known, additional, active malignancy that is progressing or that
requires active treatment are not eligible. Exceptions include basal cell carcinoma of
the skin or squamous cell carcinoma of the skin that has undergone potentially
curative therapy and in situ cervical cancer
- Patients with a known human immunodeficiency (HIV) infection or active Bacillus
Tuberculosis (TB) are not eligible. NOTE: No testing for HIV or TB is required, unless
mandated by a local health authority
- Patients with a known history of Hepatitis B (defined as Hepatitis B surface antigen
[HBsAg] reactive) or a known, active Hepatitis C virus infection (defined as HCV
ribonucleic acid [RNA] [qualitative] is detected) are not eligible.
NOTE: No testing for Hepatitis B or Hepatitis C is required, unless mandated by a local
health authority
- Patients with a known hypersensitivity to pembrolizumab, brentuximab vedotin, or any
of their excipients are not eligible
- Patients who have received a live vaccine within =< 30 days prior to registration are
not eligible. 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 who are pregnant, breastfeeding or expecting to conceive or father children
within the projected duration of the trial, starting >= 7 days prior to the first dose
of study therapy and through 23 weeks after the last dose (for females) or through 31
weeks after the last dose (for males) are not eligible
- Patients who are unwilling or unable to comply with the protocol or have a known
psychiatric illness or substance abuse disorder that would interfere with cooperation
with the requirements of the trial are not eligible
- Patients who have an uncontrolled intercurrent illness, as determined by treating
investigator judgement, including but not limited to any of the following, are not
eligible:
- Hypertension that is not controlled on medication,
- Ongoing or active infection requiring systemic treatment within ≤ 3 days prior to
registration (other than uncomplicated urinary tract infection),
- Severe cardiac disease, such as symptomatic congestive heart failure,
unstable/uncontrolled angina pectoris, and unstable/uncontrolled cardiac
arrhythmia,
- Severe renal impairment,
- Moderate or severe hepatic impairment (e.g., Child-Pugh B or C)
- History or current evidence of any other illness, condition, therapy, or
laboratory abnormality that the treating investigator feels would interfere with
study compliance, would compromise the patient's safety or study endpoints, would
not be in the best interest of the patient, would confound the results of the
trial, or would interfere with the patient's participation for the full duration
of the trial
- Patients who have primary relapsed/refractory disease with relapse within 6 months of
receipt of frontline treatment are not eligible
- Patients who were refractory to a prior brentuximab vedotin-containing regimen are not
eligible. (Note: Patients who previously received a brentuximab vedotin-containing
regimen and who experienced stable disease for >= 3 months or better as best response
are eligible)
