KPT-330 Plus RICE for Relapsed/Refractory Aggressive B-Cell Lymphoma

Although aggressive B-cell lymphomas are potentially curable with front-line chemotherapy, at
least one-third of patients experience progression or relapse. Second-line regimens such as
rituximab, ifosfamide, carboplatin, and etoposide (RICE) are administered with the goal of
cytoreduction prior to autologous stem cell transplantation (ASCT) in eligible patients.
However, half of patients who receive salvage treatment and ASCT are still not cured.

Selinexor is a Selective Inhibitor of Nuclear Export / SINE compound, which is a new class of
molecule. SINE compounds have been shown to induce apoptotic cell death in pre-clinical
models of AML, CLL, T-ALL, and Ph+ ALL as well as B and T-cell non-Hodgkin lymphomas.
Preliminarily, selinexor has demonstrated promising single-agent clinical activity in
patients with previously treated NHL including DLBCL, warranting further investigation. Based
on promising preclinical and clinical data, selinexor is currently under evaluation in
combination with chemotherapy for solid tumors.

The investigators hypothesize that the combination of selinexor plus RICE will be
well-tolerated and clinically active in participants with previously treated aggressive
B-cell lymphomas and propose a phase I trial to evaluate this combination. Moreover,
Investigators will evaluate primary patient samples before and after selinexor to investigate
the mechanisms of action of selinexor, including the mechanisms by which selinexor sensitizes
cells to chemotherapy, and evaluate other novel drug combinations in aggressive B-cell
lymphomas.

Inclusion Criteria:

- Patients must have histologically confirmed aggressive B-cell non-Hodgkin lymphomas:

- DLBCL including ABC, GCB or PMBCL subtypes

- Double/triple hit lymphomas

- Indolent lymphomas transformed to aggressive lymphomas

- Follicular lymphomas grade 3B

- Patients must have received at least two cycles of anthracycline based chemotherapy
administered with curative intent and one of the following:

- failed to have achieve at least a partial response after 2 or more cycles

- failed to achieve a complete response after 6 or more cycles

- progressed after an initial response

- Patients must be age ≥18 years.

- Patients must have at least one site of measurable disease, 1.5 cm in diameter or
greater.

- Patients must have ECOG performance status of 0-2.

- Patients must have laboratory test results within these ranges:

- Absolute neutrophil count ≥ 1500/mm³

- Platelet count ≥ 100,000/mm³

- Serum creatinine clearance ≥40 mL/min

- Total bilirubin ≤ 1.5x ULN. Higher levels are acceptable if these can be
attributed to active hemolysis or ineffective erythropoiesis.

- AST (SGOT) and ALT (SGPT) ≤ 2x ULN

- Women of childbearing potential must agree to use dual methods of contraception and
have a negative serum pregnancy test prior to selinexor treatment. 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.

- Patients must be able to understand and willing to sign a written informed consent
document.

- Patients must be able to adhere to the study visit schedule and other protocol
requirements.

- Patients must not have any serious medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from signing the informed consent
form.

- Patients must not have any condition, including the presence of laboratory
abnormalities, which places the subject at unacceptable risk if he/she were to
participate in the study or confounds the ability to interpret data from the study.

Exclusion Criteria:

- Patients with hyperuricemia or other potential signs of tumor lysis syndrome

- Patients with more than minimally symptomatic disease (i.e. > grade 1), high tumor
burden, or other indication for urgent treatment.

- Patients who have had prior malignancies (other than B-cell lymphomas) for ≤5 years
with exception of currently treated basal cell, squamous cell carcinoma of the skin,
or carcinoma "in situ" of the cervix or breast.

- Patients who have had other anti-cancer therapy, including radiation or experimental
drug or therapy, within 28 days of enrollment.

- Patients with known HIV, active hepatitis B, active hepatitis C.

- Patients with known central nervous system involvement by lymphoma.