- Escalation: Identify the maximum tolerated dose(s) (MTD) and recommended phase 2 dose(s)
(RP2D) of SEL-VEN combination therapy in patients with diffuse large B-cell lymphoma
(DLBCL) and acute myeloid leukemia (AML).
- Expansion: Determine the overall response rate of SEL-VEN combination therapy in
patients with relapsed/refractory hematologic malignancies.
- To explore biomarkers of response to SEL-VEN therapy.
- To determine the progression free survival (PFS) and overall survival (OS) of SEL-VEN
OUTLINE: This is a dose-escalation study.
Patients receive venetoclax orally (PO) once daily (QD) on days 1-28. Patients with DLBCL
receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Patients with venetoclax-naive
AML are treated with selinexor on days 8, 15, and 22 of cycle 1, followed by days 1, 8, 15,
and 22 of subsequent cycles. Venetoclax-refractory AML patients begin both drugs on cycle 1
day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable
After completion of study treatment, patients are followed up at 28 days and every 3 months
for 2 years.
- Written informed consent in accordance with federal, local, and institutional
guidelines. The patient must provide informed consent prior to the first screening
- Age ≥ 18 years
- Life expectancy > 12 weeks.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Histologically confirmed diagnosis of one of the following, in accordance with WHO
- Diffuse Large B-cell Lymphoma (DLBCL, including primary mediastinal large B cell
lymphoma, T cell rich B cell lymphoma, and high-grade B cell lymphoma NOS).
Patients with Burkitt's, lymphoblastic lymphoma, follicular lymphoma, and mantle
cell lymphoma are not included. OR
- Acute Myeloid Leukemia (AML)
- Diffuse Large B-cell Lymphoma and acute myeloid leukemia as above.
- VEN Refractory expansion cohort: Patients must have previously received and
failed venetoclax therapy (either monotherapy or combination) during their
treatment course (i.e., patients may receive non-VEN therapy immediately prior to
enrollment on this study). Treatment failure is defined as evidence of disease
progression after ≥ 1 cycle (four weeks) of full-intensity venetoclax-based
therapy (i.e., 28 days exclusive of ramp-up. Patients that require dose
reductions due to intolerance may be considered for this cohort after discussion
with the sponsor.)
- Patients with CLL/SLL and Mantle Cell Lymphoma are excluded from the VEN
- Relapsed or refractory following ≥ 1 line(s) of prior therapy and subjects are
refractory to, intolerant of, or ineligible for therapies known to provide clinical
- Patients that relapse ≥ 3 months after allogeneic hematopoietic cell transplantation
(HCT) are eligible.
- Female patients of childbearing potential must agree to use two methods of
contraception (including one highly effective and one effective method of
contraception) and have a negative serum pregnancy test at Screening. Male patients
must use an effective barrier method of contraception if sexually active with a female
of childbearing potential. For both male and female patients, effective methods of
contraception must be used throughout the study and for 3 months following the last
dose of study treatment.
- For leukemia and DLBCL with known or suspected marrow involvement, patients must have
at least 10-15 mL of bone marrow aspirate material obtained within 14 days of
beginning treatment on this study. Patients with DLBCL must have 3-5 unstained slides,
or tissue block, available for evaluation within 14 days of study enrollment in the
expansion cohorts. DLBCL patients enrolled during the escalation phase must have
blocks available for submission within 28 days of beginning treatment.
- CBC testing must confirm adequate marrow reserve, as demonstrated by:
- DLBCL: Hgb ≥ 10g/dL, platelets ≥ 75,000 cells/mm3 , ANC ≥ 1,000 cells/mm3
- Adequate organ function, as demonstrated by:
- Total bilirubin < 1.5 x upper limit of normal (ULN) (except patients with
Gilbert's syndrome (hereditary indirect hyperbilirubinemia), who must have a
total bilirubin of < 3 x ULN, and
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to < 2
- Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula).
- Patients who are pregnant or lactating
- Patients who received any systemic anticancer therapy including investigational agents
or radiation ≤3 weeks (or ≤5 half-lives of the drug [whichever is shorter]) prior to
C1D1. Hydroxyurea is permitted for up to 14 days in AML patients
- Inadequate recovery from toxicity attributed to prior anti-cancer therapy. With the
exception of alopecia or fatigue, patients must have recovered to baseline or ≤ Grade
1 (NCI-CTCAE v4.03) residual toxicity prior to first dose of protocol-indicated
- Participation in another clinical trial with any investigational drug within 14 days
prior to study enrollment.
- Patients included in the VEN refractory cohort that have discontinued venetoclax
therapy (either monotherapy or combination) due to toxicity or hypersensitivity,
including prior history of grade 3/4 TLS during prior VEN exposure
- In dose expansion cohorts, except venetoclax relapsed cohort, no prior treatment with
SINE compounds, another XPO1 inhibitor, or BCL-2 inhibitors.
- Active GVHD requiring calcineurin inhibitors or steroid dosing ≥ 10mg/day prednisone
(or equivalent) or < 3 months from allogenic hematopoietic stem cell transplant
- Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics,
antivirals, or antifungals within one week prior to first dose; however, prophylactic
use of these agents is acceptable even if parenteral.
- Major surgery within 2 weeks of first dose of study drug.
- Any life-threatening illness, medical condition or organ system dysfunction which, in
the investigator's opinion, could compromise the patient's safety.
- Unstable cardiovascular function:
- Symptomatic ischemia, or
- Uncontrolled clinically significant conduction abnormalities (i.e., ventricular
tachycardia on anti-arrhythmia therapy are excluded; 1st degree AV block or
asymptomatic LAFB/RBBB will not be excluded), or
- Congestive heart failure (CHF) of NYHA Class ≥3, or
- Myocardial infarction (MI) within 3 months.
- Known active Hepatitis B or Hepatitis C infection (Hepatitis testing is not required
as part of this study).
- Known human immunodeficiency virus (HIV) infection (HIV testing is not required as
part of this study).
- Subject has received the following ≤ 7 days prior to Cycle 1, Day 1: Strong and
moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's
- Subject has received the following ≤ 5 days prior to Cycle 1, Day 1: Strong and
moderate CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin.
- Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Starfruit ≤ 3 days prior to Cycle 1, Day 1.
- Inability to swallow oral medication; or the presence of a poorly controlled
gastrointestinal disease, disorder, syndrome, or dysfunction that could significantly
affect the absorption of oral study drug - e.g. Crohn's disease, ulcerative colitis,
chronic diarrhea (defined as > 4 loose stools per day), malabsorption syndrome, or
- Inability or unwillingness to take required and recommended medications intended to
prevent and treat potential adverse events of tumor lysis syndrome (TLS), nausea and
vomiting (e.g. 8 mg ondansetron or equivalent), loss of appetite, and fatigue.
- Patients unwilling to comply with the protocol