This phase Ib/II trial is aimed at studying the combination of a drug named Selinexor
(selective inhibitor of nuclear export) in combination with standard therapy for B cell
Non-Hodgkin's lymphoma called R-CHOP. The investigators will establish maximum tolerated dose
of Selinexor in combination with RCHOP and also study the efficacy of this combination for
therapy of B cell Non-Hodgkin's lymphoma. Giving Selinexor plus chemotherapy may work better
in treating patients with B cell non-Hodgkin lymphoma.
The study will be done in two phases namely phase 1B and phase 2.
In the phase 1B component the investigators intend to enroll patients in a 3+3 dose
escalation design. Newly diagnosed indolent and diffuse large cell lymphomas as well as
relapsed/refractory indolent B cell lymphomas are eligible for enrollment in the phase 1
component. The primary end-point for this component would be to establish the recommended
phase 2 dose (RP2D) for Selinexor in combination with standard dose RCHOP chemotherapy.
In the phase 2 part of the study the investigators will use recommended phase 2 dose of
Selinexor plus standard dose RCHOP combination to treat newly diagnosed DLBCL patients with
the primary end-point being 2 year Progression free survival.
Maintenance Phase: Patients with Follicular Lymphoma and Diffuse Large B cell lymphoma able
to achieve PR or better at the end of therapy scan will be put on maintenance Selinexor for a
total of one year. The dose of Selinexor in the maintenance phase would be similar to the
last dose used for that particular patient in the treatment phase 1 or 2.
Inclusion Criteria:
- Phase 1 Part: Patients with pathologically confirmed advanced stage B-cell NHL (Ann
Arbor stage 3 or 4) for whom R-CHOP is considered appropriate therapy; newly diagnosed
DLBCL, newly diagnosed low grade B cell NHL, and previously treated low grade B cell
NHL patients in first relapse after a prior treatment with non-anthracycline
containing chemotherapy are allowed; double hit and transformed diffuse large B cell
lymphoma are allowed
* Allowed low grade B cell lymphomas will include follicular lymphoma any grade,
marginal zone lymphoma including mucosa-associated lymphoid tissue (MALT) lymphoma,
indolent mantle cell lymphoma and Waldenstrom's macroglobulinemia
- Phase 2 Part: Patients with pathologically confirmed newly diagnosed diffuse large B
cell lymphoma (Ann Arbor stage 3 or 4); newly diagnosed double hit and transformed
diffuse large B cell lymphoma are allowed
- Patients must have measurable disease, defined as at least one lesion above and below
the diaphragm or stage 4 disease that can be accurately measured in at least one
dimension; lymph nodes should be considered abnormal if the long axis is > 1.5 cm,
regardless of the short axis
- Allowed prior therapy:
- Newly diagnosed DLBCL and low grade B cell lymphoma: No prior therapy is allowed
except steroids equivalent to maximum of prednisone 20 mg once daily for maximum
of seven days prior to registration
- Relapsed/refractory low grade B cell lymphoma (only allowed in phase I): A
minimum and maximum of one line of prior non-anthracycline containing therapy is
allowed; prior localized radiation therapy is not considered a line
- For patients who have had prior chemotherapy or immunotherapy, at least 2 weeks
must have elapsed between last dose and initial dose of RCHOP-selinexor; for
patients treated with radio-immunotherapy, at least 12 weeks
- All races and ethnic groups are eligible for this trial
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)
- Life expectancy of greater than 6 months
- Premenopausal female patients of child-bearing potential must agree to use dual
methods of contraception and have a negative serum pregnancy test at screening, and
male patients must use an effective barrier method of contraception if sexually active
with a female of child-bearing potential; acceptable methods of contraception are
condoms with contraceptive foam, oral, implantable or injectable contraceptives,
contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual
partner who is surgically sterilized or post-menopausal; for both male and female
patients, effective methods of contraception must be used throughout the study and for
three months following the last dose
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients with DLBCL who have received chemotherapy or immunotherapy (except one week
of steroids as described above) at any time point in the past for therapy of the
DLBCL; patients with low grade B cell lymphomas who have received more than one prior
line of chemotherapy or any anthracycline-containing therapy in the past for their low
grade B cell lymphoma; localized radiation therapy does not count as a line of therapy
- Patients who are receiving any other investigational agents
- Patients with known brain metastases are excluded
- History of severe allergic reactions (as determined by treating physician) attributed
to the drugs being used in the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, congestive heart failure (New York Heart Association [NYHA] class >= 3 or
left ventricular ejection fraction < 45%), unstable angina pectoris, myocardial
infarction within the last 3 months, clinically significant cardiac arrhythmia (i.e.,
ventricular tachycardia on anti-arrhythmia are excluded; 1st degree atrioventricular
[AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch
block [RBBB] permissible), or psychiatric illness/social situations that would limit
compliance with study requirements
- Pregnant and lactating women are excluded
- Human immunodeficiency virus (HIV)-positive patients regardless of treatment are
excluded; patients with evidence of active hepatitis B and hepatitis C infection with
positive real time polymerase chain reaction (qPCR) are also excluded but patients
with prior exposure to hepatitis B or C with negative qPCR are allowed
- Patients with severe intolerance to glucocorticoids
- Major surgery within 2 weeks of first dose of study drug
- Patients who are unable to swallow tablets, patients with malabsorption syndrome, or
any other gastrointestinal (GI) disease or GI dysfunction that could interfere with
absorption of study treatment
- Absolute neutrophil count (ANC) < 1500 cells/mm^3
- Platelet count < 100,000/mm^3
- Serum bilirubin > 1.5 times the upper limit of normal (ULN) (except patients with
Gilbert's syndrome: total bilirubin of > 3 x ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times ULN
- Estimated creatinine clearance of < 30 mL/min, calculated using the formula of
Cockroft and Gault
