Phase I Trial of Selinexor (KPT-330) and Ifosfamide, Carboplatin, Etoposide (ICE) in Peripheral T-cell Lymphoma
Condition: Peripheral T-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a single center, open-label, phase I trial with a standard 3+3 dose escalation schema
      to identify the maximum tolerated dose (MTD) of selinexor when combined with ICE. Once MTD is
      determined, there will be an expansion phase and tumor biopsies and peripheral blood will be
      taken pre and post selinexor to examine the study's biologic objectives.
    

Detailed description: 
      STUDY OBJECTIVES:

      Primary:

      • To determine the maximum tolerated dose (MTD) of selinexor when given in combination with a
      standard dose regimen of ifosfamide, carboplatin and etoposide (ICE) in patients with
      relapsed or refractory PTCL

      Secondary:

        -  To assess the response rates (complete and partial), progression-free survival (PFS) and
           overall survival (OS) in patients with relapsed or refractory PTCL

        -  To estimate the feasibility of stem cell collection after selinexor and ICE

      Laboratory objectives:

      • Paired tumor specimens pre and post selinexor will be examined ex vivo for

        -  Response to chemotherapy agents such as doxorubicin and etoposide

        -  Nuclear localization of tumor suppressor proteins (p53, p73, FOXO), drug targets
           (topoisomerase II) and mRNA targets

      STUDY DESIGN:

      This is a single center, open-label, phase I trial with a standard 3+3 dose escalation schema
      to identify the maximum tolerated dose (MTD) of selinexor when combined with ICE. Once MTD is
      determined, there will be an expansion phase and tumor biopsies and peripheral blood will be
      taken pre and post selinexor to examine the study's biologic objectives.

      Dose escalation:

        -  If 0/3 dose-limiting toxicity (DLT) is observed, dose escalation will continue to the
           next higher dose level.

        -  If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose
           level; if no DLT is observed from the additional 3 patients, then dose escalation will
           continue to the next higher dose level. If any DLT is observed from the additional 3
           patients, then the previous lower dose will be chosen as the MTD.

        -  If ≥ 2/3 DLTs are observed, then the previous lower dose level will be chosen as the MTD
           and the dose finding procedure will be terminated.

      PATIENTS:

      Subjects will be enrolled at the National Cancer Centre Singapore (NCCS).

      Key eligibility criteria include the following:

        -  Pathologically confirmed aggressive T-cell lymphomas including the following
           histologies: PTCL-NOS, AITL, ALCL (independent of ALK status), NK/T-cell lymphoma

        -  Treatment with at least two cycles of one prior regimen administered with curative
           intent

        -  Adequate end-organ and bone marrow function

        -  Absence of known or suspected CNS involvement

        -  Absence of active viral hepatitis or uncontrolled HIV

      STUDY DURATION:

      Based on prior and existing patient volumes and accrual to clinical trials, we expect to
      enroll 1-2 patients per month. We expect to complete study accrual within 2 years.

      TOTAL SAMPLE SIZE:

      The MTD will be identified using a standard 3+3. A maximum of 18 patients will be required
      for this phase I study. An additional 5 patients will be treated at the recommended phase II
      dose to assess safety and to examine the study's biologic objectives.

      DOSING REGIMEN:

      Dose escalation schedule for selinexor:

      Dose level -1: 20mg

      Dose level 1: 40mg

      Dose level 2: 60mg

      Dose level 3: 80mg

      Selinexor will be administered on days 3, 5 and 7 of each chemotherapy cycle and ICE will be
      administered from day 1. In the expansion phase of the study, selinexor is administered on
      days -5 and -3 prior to cycle 1 of chemotherapy.

      All subjects will receive

      (I) Standard dose ICE on a 21-day cycle.

        -  IV Etoposide 100mg/m^2 on D1-3

        -  IV Carboplatin AUC 5 on D2 (inpatient) or D1 (outpatient)

        -  IV Ifosfamide 5g/m^2 on D2 (inpatient) or D1-3 (outpatient)

      (II) Dexamethasone

        -  20mg QD D3-7

        -  20mg QD D-5 and D-3 (for patients in the expansion phase)

      Patients will receive 2-6 cycles of selinexor and ICE. If determined eligible by their
      treating physician, patients who demonstrate response will undergo autologous stem cell
      transplantation anytime following the second cycle of selinexor and ICE. Transplant
      ineligible patients will complete up to 6 cycles of selinexor and ICE, and those with
      responses or stable disease are eligible for maintenance selinexor at the discretion of the
      treating physician. Maintenance selinexor will be administered weekly at the dose of 60mg.
      Dexamethasone 4-12mg should also be given on the selinexor dosing days.

      ASSESSMENT:

      CT Neck to pelvis or FDG-PET/CT skull base to mid-thigh to be performed repeated after every
      2 cycles on days 17 +/- 3 days except after cycle 2 where FDG-PET/CT will be performed
    

Intervention name(s): Selinexor; ICE Chemotherapy
Intervention type(s): Drug; Drug
Intervention description(s): Oral KPT-330 is administered on Day 3, 5, and 7 of each 21-day cycle. Starting dose is 40mg will be adjusted according to toxicity; IV Ifosfamide 5g/m^2 on Day 2 (inpatient) or D1 (outpatient) of each 21-day cycle
IV Carboplatin AUC 5 on Day 2 (inpatient) or D1-3 (outpatient) of each 21-day cycle
IV Etoposide 100 mg/m^2 on Days 1-3 of each 21-day cycle
Other intervention name(s): Ifosfamide, Carboplatin, Etoposide
Intervention MeSH terms: Carboplatin; Etoposide; Ifosfamide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment