PRIMARY OBJECTIVE:
I. To evaluate the maximum tolerated dose (MTD) of choline salicylate (CS) that can be
combined with selinexor twice weekly in patients with relapsed/refractory diffuse large B
cell lymphoma (DLBCL) or mantle cell lymphoma (MCL).
SECONDARY OBJECTIVE:
I. To evaluate the response (overall response rate [ORR], clinical benefit rate [CBR] and
duration of response [DOR]) of selinexor and CS in patients with relapsed/refractory DLBCL or
MCL.
CORRELATIVE RESEARCH OBJECTIVE:
I. To determine if CRM1 expression in malignant lymphoma cells from patients treated on this
study have a predictive role.
OUTLINE: This is a dose-escalation study.
Patients receive selinexor orally (PO) twice a week (BIW) on days 1, 3, 8, 10, 15, 17, 22,
and 24, and choline salicylate PO three times daily (TID) on days 1-28. Patients undergoing
pharmacokinetic analysis receive choline salicylate beginning on day 3 of cycle 1 (D3C1) and
beginning on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles
in the absence of disease progression or unacceptable toxicity. Patents who achieve >= stable
disease continue treatment for an additional 6 cycles (maximum of 12 cycles) at the
discretion of the treating physician and patient.
Inclusion Criteria:
- Biopsy-proven relapsed and/or refractory DLBCL (including double/triple hit or
transformed large B-cell lymphomas) or MCL. Relapsed is defined as a relapse that
occurred after having a response to the last therapy that lasted > 26 weeks.
Refractory is no response (stable disease or progressive disease while on therapy) or
relapse within 6 months. Refractoriness to autologous stem cell transplant will be
defined as disease progression within 52 weeks following transplant.
- Most recent tumor biopsy must be < 26 weeks prior to registration
- Measurable or assessable disease: Measurable disease is defined as measurable by
computed tomography (CT) (dedicated CT or the CT portion of a positron emission
tomography [PET]/CT) or magnetic resonance imaging [MRI]: To be considered measurable,
there must be at least one lesion that has a single diameter of >= 1.5 cm. NOTE: Skin
lesions can be used if the area is >= 1.5cm in at least one diameter and photographed
with a ruler. Patients with assessable disease by PET/CT are also eligible as long as
the assessable disease is biopsy proven lymphoma
- Patients must have previously been treated with at least 2 lines of therapy
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
- Absolute neutrophil count (ANC) >= 1,000/mm^3 (obtained =< 21 days prior to
registration)
- Platelet count >= 100,000/mm^3 (obtained =< 21 days prior to registration)
- Hemoglobin >= 8.5 g/dL (may be transfused to reach criteria) (obtained =< 21 days
prior to registration)
- Total bilirubin < 2 x upper limit of normal (ULN) (or total bilirubin =< 3.0 x ULN
with direct bilirubin =< 1.5 x ULN in patients with well-documented Gilbert's
Syndrome) (obtained =< 21 days prior to registration)
- Aspartate transaminase (AST) =< 2.5 x ULN and alanine aminotransferase (ALT) =< 2.5 x
ULN (obtained =< 21 days prior to registration)
- Calculated creatinine clearance must be >= 35 ml/min using the Cockcroft Gault formula
(obtained =< 21 days prior to registration)
- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only
- Female of childbearing potential (FCBP*) must commit to take highly effective
contraceptive precautions** without interruption during the study and continue for at
least 12 weeks after the last dose of selinexor and CS. FCBP must refrain from
breastfeeding and donating oocytes during the course of the study. Males must use an
effective barrier method of contraception without interruption during the study and
continue for at least 12 weeks after the last dose of selinexor and CS. They must
refrain from donating sperm during the study participation.
- *FCBP defined as sexually mature women who have not undergone bilateral tubal
ligation, bilateral oophorectomy, or hysterectomy; or who have not been
postmenopausal (i.e., who have not menstruated at all) for at least 1 year
- Highly effective forms of birth control are methods that achieve a failure
rate of less than 1% per year when used consistently and correctly. Highly
effective forms of birth control include: hormonal contraceptives (oral,
injectable, patch, and intrauterine devices), male partner sterilization, or
total abstinence from heterosexual intercourse, when this is the preferred
and usual lifestyle of the patient NOTE: The double-barrier method (e.g.,
synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream,
or gel), periodic abstinence (such as calendar, symptothermal,
post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea
method, and spermicide-only are not acceptable as highly effective methods
of contraception
- Provide written informed consent
- Willing to return to enrolling institution for follow-up (during the Active Monitoring
Phase of the study)
- Willingness to provide mandatory blood specimens per protocol for Pharmacokinetics
(PKs) and banking, and mandatory tissue samples for correlative research. NOTE: If an
institution is not able to provide the tissue, it does not cause the patient to be
ineligible; however, the collection of these tissues is strongly recommended
Exclusion Criteria:
- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:
- Pregnant women
- Nursing women
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
- Patients known to have active hepatitis B, or C infection, or known to be positive for
hepatitis C virus (HCV) ribonucleic acid (RNA) or hepatitis B surface antigen (HBsAg)
(hepatitis B virus [HBV] surface antigen). Patients known to be human immunodeficiency
virus (HIV) positive, except those with CD4+ T-cell (CD4+) counts >= 350 cells/uL and
on an established antiretroviral therapy (ART) for at least twelve weeks and have an
HIV viral load less than 400 copies/mL prior to enrollment
- 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
- Life expectancy of < 6 months
- Active gastrointestinal (GI) dysfunction interfering with the ability to swallow
tablets, or any GI dysfunction that could interfere with absorption of study treatment
- Known intolerance to or contraindications for choline salicylate therapy. Patients
with known allergy to acetylsalicylic acid (ASA) are not eligible
- Prior exposure to a selective inhibitors of nuclear export (SINE) compound, including
selinexor
- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm
- Active second malignancy requiring treatment that would interfere with the assessment
of the response of the lymphoma to this protocol therapy. Patients with treated
malignancies on hormonal therapy (for example breast or prostate cancer) are eligible
- History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
- Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =< 2 weeks
prior to registration. NOTE: Exception: patients on any BTK inhibitor (ibrutinib,
zanabrutinib, acalabrutinib, etc), or venetoclax, or corticosteroids (any dose) may
continue therapy up until the new regimen has started at investigator discretion.
After the start of protocol therapy, corticosteroids can be used at investigator's
discretion and tapered to lowest possible dose
- Active graft versus (vs.) host disease (after allogeneic stem cell transplantation) at
registration
- Major surgery (including bowel resection) =< 3 weeks prior to registration
- Must not be currently eligible or have declined high-dose therapy with autologous stem
cell transplantation rescue or chimeric antigen receptor (CAR)-T cell therapy
- Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
- Known active central nervous system (CNS) lymphoma. Patients with previous CNS
involvement can enroll if the CNS component is inactive
- Patients who are on active anticoagulant therapy with direct oral anticoagulants
(DOACs), aspirin or warfarin are not eligible due to potential bleeding. EXCEPTIONS:
Patients who are on aspirin (81 mg) for primary prevention of cardiovascular disease
can enroll, but the ASA needs to be held while on this protocol therapy
