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Selinexor in Combination With MTX+Ritu to Treat R/R CNSL

Primary Purpose

Central Nervous System Lymphoma

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Selinexor
Rituximab
Methotrexate
Sponsored by
Tong Chen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Central Nervous System Lymphoma focused on measuring Relapse refractory, Selinexor, ATG-010, Primary Central Nervous System Lymphoma(PCNSL), Secondary Central Nervous System Lymphoma(SCNSL)

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients must meet all of the following inclusion criteria to be eligible to enroll in this study: Participants must be able to understand and be willing to sign a written informed consent document. Men and woman who are 18-75 years old on the day of consenting to the study. Histologically documented PCNSL and SCNSL secondary to histologically documented systemic diffuse large B-cell lymphoma (DLBCL). Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL. Patients must have response or remain stable disease for 2 months to prior methotrexate-based regimen. Patients who had prior autologous hematopoietic stem cell transplantation are eligible. Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 28 days prior to cycle1 day 1(C1D1). For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells. Participants must have an Eastern Cooperative Oncology Group performance status of 0-3. Participants must have adequate bone marrow and organ function shown by: Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 14 days prior to study registration c Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study registration International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal. Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome. Calculated creatinine clearance(CrCl)≥50ml/min using the Cockcroft-Gault equation or 24-hour urine collection. Life expectancy of > 3 months. Exclusion Criteria: Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded. Lymphoma patients with only intraocular involvement. Pathological diagnosis of PCNSL is T-cell lymphoma. Patients with disease progression within 6 months of prior methotrexate-containing regimen. patients only had received stereotactic radiation therapy as prior treatment. Patients have received chemotherapy, monoclonal antibodies or targeted anticancer therapy within 21 days or 5 half-lives, whichever is shorter, prior to C1D1. Patients with active, unstable cardiovascular diseases, fits any of the following: myocardial infarction within 6 months prior to the study enrollment unstable angina within 3 months prior to the study enrollment Uncontrolled clinically-significant conduction abnormalities (e.g., ventricular tachycardia, ventricular fibrillation, etc.) Congestive heart failure (CHF) of New York Heart Association (NYHA) ≥ Grade 3 Echocardiography showing left ventricular ejection fraction less than 50% Uncontrolled active infection within 1 week prior to the first dose of study drug. Known active hepatitis B, or C infection or HIV infection; Note: Hepatitis B virus (HBV) surface antigen (HBsAg) and or hepatitis B core antibody-positive but undetectable HBV DNA or Hepatitis C virus (HCV) antibody positive but hepatitis C virus RNA undetectable are allowed. Active GI dysfunction interfering with the ability to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment. Prior exposure to a selective inhibitor of nuclear export(SINE) compound, including selinexor. Serious, active psychiatric, or medical conditions which, in the opinion of the Investigator, could interfere with study treatment.

Sites / Locations

  • The First Affiliated Hospital Of Anhui Medical University
  • Beijing Tiantan Hospital, Capital Medical University
  • The First Affiliated Hospital Of Fujian Medical University
  • Oncology Department of The First Affiliated Hospital of Zhengzhou University
  • Department of Hematology, Huashan Hospital, Fudan UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

X-MTX-Ritu

Arm Description

Escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle.and the phase 2 expansion at the recommended dose level based on phase 1b trial. And, Methotrexate 3.5 g/m2, d1 and Rituximab 375 mg/m2, d0, 28-days cycle.The total 6 cycles, 28 days per cycle.

Outcomes

Primary Outcome Measures

Dose Escalation: Maximum Tolerated Dose (MTD) of Selinexor
The MTD will be determined by study definition as the highest dose level without significant safety and tolerability concern.
Dose Escalation: Recommended Phase 2 Does (RP2D) of Selinexor
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability, efficacy data collected during the dose escalation portion of the study
Objective Response Rate (ORR)
ORR is defined as the proportion of patients with a best response of Complete remission (CR) or Unconfirmed(CRu), or PR during induction therapy

Secondary Outcome Measures

Duration of Response (DOR)
Duration from the first observation of at least PR to time of progressive disease(PD), or deaths due to disease progression,whichever occurs first
Overall Survival (OS)
Occurrence of death regardless of cause
Progression-Free Survival (PFS)
Duration from start of study treatment to PD or death (regardless of cause), whichever comes first
Number of Participants with Adverse Events
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Full Information

First Posted
January 4, 2023
Last Updated
September 20, 2023
Sponsor
Tong Chen
Collaborators
Antengene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT05698147
Brief Title
Selinexor in Combination With MTX+Ritu to Treat R/R CNSL
Official Title
Selinexor in Combination With Methotrexate and Rituximab for Relapsed /Refractory Central Nervous System (CNS) Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 3, 2023 (Actual)
Primary Completion Date
June 30, 2026 (Anticipated)
Study Completion Date
December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Tong Chen
Collaborators
Antengene Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a single-arm and open-label study to explore X+MTX+Ritu (ATG-010, Methotrexate, Rituximab) regimen in Relapse refractory PCNSL patients. Approximately 30 patients will be enrolled in the study. In dose escalation phase, patients with Relapse refractory PCNSL will be treated with X+MTX+Ritu regimen and escalating doses of oral ATG-010 weekly in a 3+3 design. Then a phase 2 expansion at the recommended dose level based on phase 1b trial will be conducted to evaluate the efficacy, safety and tolerability.
Detailed Description
In dose escalation phase, patients with Relapse refractory PCNSL will be treated with X+MTX+Ritu regimen (Methotrexate 3.5 g/m2, d1; Rituximab 375 mg/m2, d0)and escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle. The phase 2 expansion at the recommended dose level based on phase 1b trial. The total 6 cycles, 28 days per cycle . And, Subjects participating in the study will undergo a screening period(up to 21days), a treatment period, and a follow-up period. The screening period is a maximum of 21 days before treatment period, And will be followed by 6 cycles of combination treatment(28 days per cycle). partial remission(PR) patients after induction treatment will continue ATG-010 maintenance up to 1 year or until disease progression, intolerable toxicity, death.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Central Nervous System Lymphoma
Keywords
Relapse refractory, Selinexor, ATG-010, Primary Central Nervous System Lymphoma(PCNSL), Secondary Central Nervous System Lymphoma(SCNSL)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
X-MTX-Ritu
Arm Type
Experimental
Arm Description
Escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle.and the phase 2 expansion at the recommended dose level based on phase 1b trial. And, Methotrexate 3.5 g/m2, d1 and Rituximab 375 mg/m2, d0, 28-days cycle.The total 6 cycles, 28 days per cycle.
Intervention Type
Drug
Intervention Name(s)
Selinexor
Other Intervention Name(s)
ATG-010
Intervention Description
Selinexor dose escalation: 60,80,100mg respectively on day 1,8,15,22 for 28 days cycles, and dose expansion at the RP2D of Selinexor. PR patients after induction treatment will continue ATG-010 maintenance up to 1 year or until disease progression, intolerable toxicity, death.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
RiTUXimab Injection
Intervention Description
Rituximab 375 mg/m2 intravenous infusion d1, every 28 days for 6 cycles during combination induction treatment.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
MTX
Intervention Description
high-dose Methotrexate 3.5 g/m2 intravenous infusion d1, every 28 days for 6 cycles during combination induction treatment.
Primary Outcome Measure Information:
Title
Dose Escalation: Maximum Tolerated Dose (MTD) of Selinexor
Description
The MTD will be determined by study definition as the highest dose level without significant safety and tolerability concern.
Time Frame
Assessed from the date of first dose of study treatment to the first cycle ends (maximum 21days)
Title
Dose Escalation: Recommended Phase 2 Does (RP2D) of Selinexor
Description
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability, efficacy data collected during the dose escalation portion of the study
Time Frame
Assessed from the date of first dose of study treatment to the first cycle ends (maximum 21days)
Title
Objective Response Rate (ORR)
Description
ORR is defined as the proportion of patients with a best response of Complete remission (CR) or Unconfirmed(CRu), or PR during induction therapy
Time Frame
Cycle 1 Day 1 (each cycle consists of maximum 21 days) until a CR, CRu or PR (up to 18 cycles(each cycle is 21 days)).
Secondary Outcome Measure Information:
Title
Duration of Response (DOR)
Description
Duration from the first observation of at least PR to time of progressive disease(PD), or deaths due to disease progression,whichever occurs first
Time Frame
From first dose of study drug administration to end of treatment, up to 18 cycles(each cycle is 21 days)
Title
Overall Survival (OS)
Description
Occurrence of death regardless of cause
Time Frame
up to 12 months
Title
Progression-Free Survival (PFS)
Description
Duration from start of study treatment to PD or death (regardless of cause), whichever comes first
Time Frame
up to 12 months
Title
Number of Participants with Adverse Events
Description
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Time Frame
From first dose of study drug administration to end of treatment (up to 18 cycles(each cycle is 21 days))
Other Pre-specified Outcome Measures:
Title
Gene mutations and frequency of 475 gene and whole exon
Description
The types of gene mutations and frequency of tumor are measured by whole exon sequencing via NGS(next-generation sequencing).
Time Frame
At baseline
Title
The concentration of interleukin-10(IL-10),interleukin-6(IL-6),CXCL-13 cytokine in cerebrospinal fluid(CSF)
Description
The levels of cytokines will be analyzed by flow cytometry
Time Frame
At the baseline, day 1 at cycle 3, 5 (21 days/cycle), and every 3 months in the maintenance stage (up to 1 year))
Title
Circulating tumor DNA (ctDNA) in the CSF
Description
The levels of ctDNA will be analyzed by next-generation sequencing.
Time Frame
At the baseline, day 1 at cycle 3, 5 (21days/cycle), and every 3 months in the maintenance stage (up to 1 year))

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must meet all of the following inclusion criteria to be eligible to enroll in this study: Participants must be able to understand and be willing to sign a written informed consent document. Men and woman who are 18-75 years old on the day of consenting to the study. Histologically documented PCNSL and SCNSL secondary to histologically documented systemic diffuse large B-cell lymphoma (DLBCL). Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL. Patients must have response or remain stable disease for 2 months to prior methotrexate-based regimen. Patients who had prior autologous hematopoietic stem cell transplantation are eligible. Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 28 days prior to cycle1 day 1(C1D1). For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells. Participants must have an Eastern Cooperative Oncology Group performance status of 0-3. Participants must have adequate bone marrow and organ function shown by: Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 14 days prior to study registration c Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study registration International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal. Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome. Calculated creatinine clearance(CrCl)≥50ml/min using the Cockcroft-Gault equation or 24-hour urine collection. Life expectancy of > 3 months. Exclusion Criteria: Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded. Lymphoma patients with only intraocular involvement. Pathological diagnosis of PCNSL is T-cell lymphoma. Patients with disease progression within 6 months of prior methotrexate-containing regimen. patients only had received stereotactic radiation therapy as prior treatment. Patients have received chemotherapy, monoclonal antibodies or targeted anticancer therapy within 21 days or 5 half-lives, whichever is shorter, prior to C1D1. Patients with active, unstable cardiovascular diseases, fits any of the following: myocardial infarction within 6 months prior to the study enrollment unstable angina within 3 months prior to the study enrollment Uncontrolled clinically-significant conduction abnormalities (e.g., ventricular tachycardia, ventricular fibrillation, etc.) Congestive heart failure (CHF) of New York Heart Association (NYHA) ≥ Grade 3 Echocardiography showing left ventricular ejection fraction less than 50% Uncontrolled active infection within 1 week prior to the first dose of study drug. Known active hepatitis B, or C infection or HIV infection; Note: Hepatitis B virus (HBV) surface antigen (HBsAg) and or hepatitis B core antibody-positive but undetectable HBV DNA or Hepatitis C virus (HCV) antibody positive but hepatitis C virus RNA undetectable are allowed. Active GI dysfunction interfering with the ability to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment. Prior exposure to a selective inhibitor of nuclear export(SINE) compound, including selinexor. Serious, active psychiatric, or medical conditions which, in the opinion of the Investigator, could interfere with study treatment.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tong Chen, Ph.D
Phone
+862152887102
Email
chentong@fudan.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Yuan Yan, Ph.D
Phone
+862152888283
Email
yuanyan@fudan.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tong Chen, Ph.D
Organizational Affiliation
Huashan Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
The First Affiliated Hospital Of Anhui Medical University
City
Hefei
State/Province
Anhui
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jian Ge, Ph.D
Facility Name
Beijing Tiantan Hospital, Capital Medical University
City
Beijing
State/Province
Beijing
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wenbin Li, Ph.D
Phone
+8615301377998
Email
neure55@126.com
Facility Name
The First Affiliated Hospital Of Fujian Medical University
City
Fuzhou
State/Province
Fujian
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhiyong Zeng, Ph.D
Facility Name
Oncology Department of The First Affiliated Hospital of Zhengzhou University
City
Zhengzhou
State/Province
Henan
ZIP/Postal Code
450052
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mingzhi Zhang, PhD
Phone
13838565629
Email
mingzhi_zhang@126.com
First Name & Middle Initial & Last Name & Degree
Mingzhi Zhang, PhD
Facility Name
Department of Hematology, Huashan Hospital, Fudan University
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200040
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tong Chen
Phone
+862152887102
Email
chentong@fudan.edu.cn
First Name & Middle Initial & Last Name & Degree
Yan Yuan
Phone
+862152888283
Email
yuanyan@fudan.edu.cn

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Selinexor in Combination With MTX+Ritu to Treat R/R CNSL

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