Skip to main content

Venetoclax and Selinexor in Treating Patients with Relapsed or Refractory High Risk Hematologic Malignancies

Trial Status: Active

This phase Ib trial studies the side effects and best dose of venetoclax and selinexor and how well they work in treating patients with high risk hematologic malignancies such as diffuse large B-cell lymphoma, multiple myeloma, or acute myeloid leukemia that have come back (recurrent) or do not respond to treatment (refractory). Venetoclax functions by inhibiting or slowing down a protein in the body called bcl-2, which is involved in slowing down the normal process by which old cells in the body are cleared (called apoptosis). Selinexor functions by trapping “tumor suppressing proteins” within the cell and causing the cancer cells to die or stop growing. This study examines the effects, if any, of selinexor and venetoclax on high risk hematologic malignancies and on the body, including any side-effects.

Inclusion Criteria

  • Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure
  • 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 World Health Organization (WHO) diagnostic criteria: * Escalation: ** 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 not otherwise specified [NOS]). Patients with Burkitt’s, lymphoblastic lymphoma, follicular lymphoma, and mantle cell lymphoma are not included OR ** Acute myeloid leukemia (AML) * Expansion: ** DLBCL and AML as above. ** Venetoclax (VEN) refractory expansion cohort (DLBCL or AML only): 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.)
  • Relapsed or refractory following >= 1 line(s) of prior therapy
  • 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 2-3 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
  • DLBCL: Hemoglobin (Hgb) >= 10 g/dL
  • DLBCL: Platelets >= 75,000 cells/mm^3
  • DLBCL: Absolute neutrophil count (ANC) >= 1,000 cells/mm^3
  • 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)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to < 2 x ULN
  • Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula)
  • Patients with laboratory evidence of liver or kidney dysfunction secondary to underlying disease, that is expected to reverse with treatment, may be enrolled after discussion with the sponsor/investigator

Exclusion Criteria

  • 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 cycle 1 day 1 (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 (National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0) residual toxicity prior to first dose of protocol-indicated treatment
  • 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 tumor lysis syndrome (TLS) during prior VEN exposure
  • In dose expansion cohorts, except venetoclax relapsed cohort, no prior treatment with selective inhibitor of nuclear export (SINE) compounds, another XPO1 inhibitor, or BCL-2 inhibitors
  • Active graft versus host disease (GVHD) requiring calcineurin inhibitors or steroid dosing >= 10 mg/day prednisone (or equivalent) or < 3 months from allogenic hematopoietic cell transplant (HCT)
  • 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 atrioventricular [AV] block or asymptomatic left anterior fascicular block (LAFB)/right bundle branch block (RBBB) will not be excluded), or * Congestive heart failure (CHF) of New York Heart Association (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 wort
  • 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 bowel obstruction
  • 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, loss of appetite, and fatigue
  • Patients unwilling to comply with the protocol

New York

Buffalo
Roswell Park Cancer Institute
Status: ACTIVE

Ohio

Cleveland
University Hospitals Cleveland Medical Center
Status: ACTIVE
Contact: Benjamin Kent Tomlinson

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: ACTIVE
Contact: Michael T. Byrne
Phone: 877-936-8422

U.S. Minor Outlying Islands

UNKNOWN
University of Texas, Southwestern Medical Center at Dallas
Status: ACTIVE
Contact: Farrukh Tauseef Awan

PRIMARY OBJECTIVES:

I. Identify the maximum tolerated dose(s) (MTD) and recommended phase 2 dose(s) (RP2D) of selinexor (SEL)-venetoclax (VEN) combination therapy in patients diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). (Escalation)

II. Determine the overall response rate of SEL-VEN combination therapy in patients with relapsed/refractory hematologic malignancies. (Expansion)

EXPLORATORY OBJECTIVES:

I. To explore biomarkers of response to SEL-VEN therapy.

II. To determine the progression free survival (PFS) and overall survival (OS) of SEL-VEN combination therapy.

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 receive selinexor PO on days 8, 15, and 22 of cycle 1, followed by days 1, 8, 15, and 22 of subsequent cycles. Patients with venetoclax refractory AML receive selinexor PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and every 3 months for 2 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Vanderbilt University / Ingram Cancer Center

Principal Investigator
Michael T. Byrne

  • Primary ID VICCHEM1755
  • Secondary IDs NCI-2019-02953
  • Clinicaltrials.gov ID NCT03955783