Clinical Trials /

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

NCT03955783

Description:

This phase Ib trial studies the toxicity and dosing of venetoclax in combination with selinexor, and how well the combination works in treatment of patients with high risk hematologic malignancies such as diffuse large B-cell lymphoma and acute myeloid leukemia that has come back (recurrent) or does not respond to initial treatment (refractory). Venetoclax functions by inhibiting 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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Selinexor in Treating Patients With Relapsed or Refractory High Risk Hematologic Malignancies
  • Official Title: An Investigator-Sponsored Phase Ib Trial of Venetoclax and SINE: Selective Inhibition of Nuclear Export in Patients With High Risk Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: VICC HEM 1755
  • SECONDARY ID: NCI-2019-02953
  • NCT ID: NCT03955783

Conditions

  • Diffuse Large B-cell Lymphoma
  • Acute Myeloid Leukemia
  • Non-Hodgkin's Lymphoma

Interventions

DrugSynonymsArms
VenetoclaxTreatment (venetoclax, selinexor)
SelinexorTreatment (venetoclax, selinexor)

Purpose

This phase Ib trial studies the toxicity and dosing of venetoclax in combination with selinexor, and how well the combination works in treatment of patients with high risk hematologic malignancies such as diffuse large B-cell lymphoma and acute myeloid leukemia that has come back (recurrent) or does not respond to initial treatment (refractory). Venetoclax functions by inhibiting 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.

Detailed Description

      Primary:

        -  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.

      Exploratory Objectives:

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

        -  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 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
      toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, selinexor)ExperimentalPatients receive venetoclax PO QD on days 1-28. Patients with DLBCL receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Venetoclax naïve AML patients receive 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 receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Venetoclax
  • Selinexor

Eligibility Criteria

        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.

          -  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
             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 NOS).
                  Patients with Burkitt's, lymphoblastic lymphoma, follicular lymphoma, and mantle
                  cell lymphoma are not included. OR

               -  Acute Myeloid Leukemia (AML)

               -  Expansion:

               -  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
                  Refractory cohort.

          -  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
             benefit.

          -  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
                  x ULN

               -  Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula).

        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
             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
             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 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
             (HSCT).

          -  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
             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 (e.g. 8 mg ondansetron or equivalent), loss of appetite, and fatigue.

          -  Patients unwilling to comply with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (escalation)
Time Frame:Up to 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method with 95% confidence intervals. Descriptive statistics will be used to summarize survival outcomes among subgroups. Will be compared with historical controls of patients that received venetoclax monotherapy
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method with 95% confidence intervals. Descriptive statistics will be used to summarize survival outcomes among subgroups. Will be compared with historical controls of patients that received venetoclax monotherapy.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Michael Byrne

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