Trial Title:
Selinexor With ICE Chemotherapy in Secondary Central Nervous System Involving B-cell Non-Hodgkin Lymphoma
NCT ID:
NCT06552559
Condition:
B-cell Lymphoma Recurrent
B-cell Lymphoma Refractory
CNS Metastases
Conditions: Official terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Dexamethasone
Carboplatin
Etoposide
Ifosfamide
Conditions: Keywords:
Non-Hodgkin B-cell lymphoma
Secondary CNS involvement
Selinexor
ICE
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Phase 1/2 study of selinexor in combination with dexamethasone, ifosfamide, carboplatin,
etoposide chemotherapy in patients with secondary central nervous system involving
relapsed or refractory B-cell non-Hodgkin lymphoma: a single arm, open label, multicentre
study
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Selinexor
Description:
Combination chemotherapy
Arm group label:
Selinexor plus ICED
Other name:
Ifosfamide, carboplatin, etoposide, dexamethasone
Summary:
Secondary involvement of the central nervous system (CNS), such as CNS relapse after
treatment or progression during treatment, is a rare but deadly occurrence in patients
with B-cell non-Hodgkin lymphoma (NHL), particularly in cases of diffuse large B-cell
lymphoma (DLBCL) and transformed follicular lymphoma (FL). Despite the grim prognosis
associated with secondary CNS involvement, no definitive treatment strategy exists.
Selinexor®, an oral, first-in-class, potent selective inhibitor of nuclear export that
binds to XPO1, leads to the nuclear retention of tumor suppressor and growth regulator
proteins, as well as topoisomerase II enzymes, thereby restoring their functions.
Preclinical studies have also shown that selinexor can sensitize cancer cells to
topoisomerase inhibitors, alkylating agents, and steroids. Selinexor has been approved by
the Food and Drug Administration for relapsed or refractory DLBCL. We hypothesize that
selinexor could work synergistically with ifosfamide (an alkylating agent) and etoposide
(a topoisomerase II inhibitor) in the ifosfamide, carboplatin, and etoposide (ICE)
regimen. High-dose dexamethasone was added to this regimen to enhance the efficacy of ICE
as a salvage regimen for secondary CNS involvement, due to its ability to cross the
blood-brain barrier.
This phase I/II study aims to evaluate the efficacy and safety of selinexor in
combination with ifosfamide, carboplatin, etoposide (ICE), and dexamethasone in patients
with relapsed or refractory B-cell non-Hodgkin lymphoma with secondary CNS involvement.
Detailed description:
1. Background Secondary central nervous system (CNS) involvement, such as CNS relapse
after treatment or progression involving the CNS during treatment, is a rare but
deadly occurrence in patients with B-cell non-Hodgkin lymphoma (NHL), particularly
in cases of diffuse large B-cell lymphoma (DLBCL) and transformed follicular
lymphoma (FL). Despite the grim prognosis associated with secondary CNS involvement,
no definitive treatment strategy has been established. Various salvage treatment
regimens followed by autologous stem cell transplantation (ASCT) have been
attempted, but their effectiveness remains uncertain due to most data coming from
retrospective analyses of small case series, with a lack of prospective studies.
Since secondary CNS involvement often coincides with systemic disease progression,
high-dose methotrexate (MTX)-based regimens may be inadequate for treating systemic
disease progression, although they could be effective against CNS tumor cells.
Consequently, ICE/D (ifosfamide 1,500 mg/m2/day on days 1-5, carboplatin AUC 5.5 on
day 1, etoposide 100 mg/m2 on days 1-5, and dexamethasone 40 mg/day on days 1-4
every 3 weeks) has emerged as another salvage treatment option due to its proven
efficacy for both CNS and systemic disease. However, the outcomes of these regimens,
including high-dose MTX and/or ICE/D, are still unsatisfactory, with response rates
generally below 30-40%. Moreover, most patients who respond to these treatments
eventually experience relapse, even after undergoing consolidative ASCT,
highlighting the need for improved complete response rates in salvage regimens.
Exportin 1 (XPO1/CRM1) serves as a nuclear export protein, facilitating the movement
of tumor suppressor and growth regulator proteins, such as TP53, p21, p27, FOXO3,
and nucleophosmin 1 (NPM1), from the nucleus to the cytoplasm, leading to their
deactivation. XPO1 overexpression is common in various malignancies and correlates
with poor prognosis. Additionally, XPO1 is responsible for the cytoplasmic transport
of topoisomerase II enzymes, and their cytoplasmic presence is linked to drug
resistance, as the separation from DNA prevents topoisomerase II inhibitors from
triggering cell death.
Selinexor® is an orally administered, pioneering selective inhibitor of nuclear
export, targeting XPO1 to retain tumor suppressor and growth regulator proteins,
along with topoisomerase II enzymes, in the nucleus, thus reinstating their
activity. Preclinical studies have shown that selinexor can enhance the sensitivity
of cancer cells to topoisomerase inhibitors, alkylating agents, and steroids.
Selinexor has been approved by the Food and Drug Administration for the treatment of
relapsed or refractory DLBCL. We propose that selinexor could enhance the
effectiveness of the ifosfamide, carboplatin, and etoposide (ICE) regimen when
combined with ifosfamide (an alkylating agent) and etoposide (a topoisomerase II
inhibitor), and have included high-dose dexamethasone to potentially increase ICE's
efficacy as a salvage therapy for secondary CNS involvement, due to its ability to
cross the blood-brain barrier.
2. Study design Phase: I/II Therapeutic Area: Salvage treatment and maintenance for
secondary CNS involvement of B-cell NHL Primary Compound: Selinexor Additional
compounds (if applicable): Ifosfamide, carboplatin, etoposide, dexamethasone
3. Phase I In the phase 1 study, patients must complete one therapy cycle (3 weeks) at
a given dose level before considering escalation to the next level. Escalation is
allowed if the initial three patients at a dose level show no dose-limiting
toxicities (DLTs) during the first cycle. If one patient experiences DLTs at a dose
level of selinexor, three more patients will be added to that level. Escalation to
the next selinexor dose level occurs if only one out of six patients experiences
DLTs. However, if two out of six patients experience DLTs, the previous dose level
is established as the maximum tolerated dose (MTD). If two of the first three
patients experience DLTs, the previous dose is deemed the MTD after treating up to
six patients at that dose with no more than two experiencing DLTs. If none or only
one of the initial three patients, or one out of six patients at a dose level of
selinexor, experience DLTs, the dose will be escalated. If the dose level at
60mg/dose of selinexor is to be increased further, 60mg/dose (DL 2) will be
considered the MTD, and this dose will be used in the subsequent phase 2 study.
Phase 1 part of the study:
Treatment will be repeated every three weeks. - Selinexor: DL1 (40mg)/DL2 (60mg)/DL3
(80mg) PO, day 3, 5, 7 - Ifosfamide 1500 mg/m(2) infused over 2 h on days 1-3 -
Carboplatin (5 AUC) on day 1
- Etoposide 100 mg/m(2) on days 1-3
- Dexamethasome 40 mg PO or IV on days 1-4
4. Phase 2 Patients with relapsed or refractory DLBCL or FL involving the CNS may be
considered for enrollment. Those eligible for transplantation may undergo ASCT
following a minimum of two cycles of the study treatment. Patients ineligible for
ASCT may be administered up to six cycles of the study treatment. Additionally,
maintenance selinexor may be provided irrespective of ASCT eligibility, provided
there is no disease progression after completing selinexor-ICED.
Phase 2 part of the study:
Treatment will be repeated every three weeks. - Selinexor: MTD (determined by phase
1 part of the study) PO, day 3, 5, 7
- Ifosfamide 1500 mg/m(2) infused over 2 h on days 1-3
- Carboplatin (5 AUC) on day 1
- Etoposide 100 mg/m(2) on days 1-3
- Dexamethasome 40 mg PO or IV on days 1-4
6) Study endpoints
Primary Endpoint:
Phase 1 part of the study: To determine the maximum tolerated dose (MTD) and recommended
phase 2 dose level (RDL) of Selinexor combined with ifosfamide, carboplatin, etoposide
and dexamethasone Phase 2 part of the study: Objective response rate - complete and
partial response
Secondary Endpoints:
Phase 1 part of the study: Number of participants with dose limiting toxicities Phase 2
part of the study: Duration of response, Progression-free survival, Overall survival, and
safety
7) Statistical analysis Phase 1 part of the study: For phase 1, up to 12 patients for 3
levels of Selinexor (3 patients at each level, one cycle) will be recruited on the
basis of 3+3 dose escalation design. The aim of this phase 1 study is to evaluate
the safety and adverse events, and to reveal minimal efficacy for the next phase 2
clinical trial; thus, the sample size was not determined based on the statistical
power.
Phase 2 part of the study: As the primary endpoint of the phase 2 study is objective
response rate (ORR) consisting of complete and partial response at the end-of treatment.
Although there is limited data about the ORR for relapsed or refractory secondary CNS
involving B-cell NHL, the estimated ORR rates were around 20% for those patients. Thus,
the sample size calculation for this study is as follows. P1 as 40% (40% being the
response proportion that would imply the treatments warrants further investigation) and
P0 as 20% (20% being the usual probability of response while using conventional therapy).
According to the Simon's Minimax design, we obtained a sample size of 33 (a = 0.05, b =
0.80). If the ORR is ≤ 4/18, the trial would be stopped. If the ORR is > 4/18, the
recruitment of subjects would be continued until the number of 33. Considering 10%
drop-out rate, a total of 37 patients will be recruited.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically confirmed B-cell NHL with CNS involvement DLBCL
including ABC, GCB or PMBCL subtypes Indolent lymphomas transformed to aggressive
lymphomas Follicular lymphomas
- Patients must have received at least one cycles of anthracycline based chemotherapy
administered with curative intent
- Patients must be age ≥18 years.
- Patients must have at least one site of measurable disease, 1.5 cm in diameter or
greater.
- Patients must have ECOG performance status of 0-2.
- Patients must have laboratory test results within these ranges: Absolute neutrophil
count ≥ 1500/mm³, Platelet count ≥ 100,000/mm³, Serum creatinine clearance ≥40
mL/min, Total bilirubin ≤ 1.5x ULN (Higher levels are acceptable if these can be
attributed to active hemolysis or ineffective erythropoiesis.), AST (SGOT) and ALT
(SGPT) ≤ 2x ULN
- Women of childbearing potential must agree to use dual methods of contraception and
have a negative serum pregnancy test prior to selinexor treatment. Male patients
must use an effective barrier method of contraception if sexually active with a
female of child-bearing potential.
- Patients must be able to understand and willing to sign a written informed consent
document.
- Patients must be able to adhere to the study visit schedule and other protocol
requirements.
- Patients must not have any serious medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from signing the informed consent
form.
- Patients must not have any condition, including the presence of laboratory
abnormalities, which places the subject at unacceptable risk if he/she were to
participate in the study or confounds the ability to interpret data from the study.
- Patients with hepatitis B virus including HBsAg-positive carrier or IgG anti-
HBc-positive can be enrolled if they can receive anti-viral prophylaxis
Exclusion Criteria:
- Patients cannot fulfill the above-mentioned inclusion criteria
- Patients with primary CNS lymphoma
- Patients with a prior history with selinexor
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Samsung Cancer Research Institute
Address:
City:
Seoul
Zip:
135-710
Country:
Korea, Republic of
Status:
Recruiting
Contact:
Last name:
Insuk Sohn, PhD
Email:
insuk.sohn@samsung.com
Facility:
Name:
Samsung Medical Center
Address:
City:
Seoul
Zip:
135-710
Country:
Korea, Republic of
Status:
Recruiting
Contact:
Last name:
Seok Jin Kim, MD, PhD
Phone:
82-2-3410-1766
Email:
kstwoh@skku.edu
Investigator:
Last name:
Seok Jin Kim, MD, PhD
Email:
Principal Investigator
Investigator:
Last name:
Won Seog Kim, MD, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Sivia Park, MD, PhD
Email:
Sub-Investigator
Start date:
May 1, 2024
Completion date:
December 30, 2027
Lead sponsor:
Agency:
Samsung Medical Center
Agency class:
Other
Collaborator:
Agency:
Korean Society of Hematology
Agency class:
Other
Source:
Samsung Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06552559
