Phase I Trial of Selinexor (KPT-330) and Ifosfamide, Carboplatin, Etoposide (ICE) in Peripheral T-cell Lymphoma

Peripheral T-cell Lymphoma Clinical Trial

Official title: A Phase I Investigator Sponsored Trial of Selinexor (KPT-330), a Selective Inhibitor of Nuclear Export / SINE™ Compound and Ifosfamide, Carboplatin, Etoposide (ICE) in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma

Status Completed

Clinical Trial 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.

Clinical Trial 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 ;

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• Peripheral T-cell Lymphoma

• NCT number: NCT03212937
• Study type: Interventional
• Source: National Cancer Centre, Singapore
• Status: Completed
• Phase: Phase 1
• Start date: July 1, 2016
• Completion date: November 2020