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Selinexor in Combination With R-CHOP Followed by Selinexor Maintenance for Untreated EBV-positive DLBCL Patients

Primary Purpose

EBV-Positive Diffuse Large B-Cell Lymphoma, Nos

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Selinexor
R-CHOP Protocol
Sponsored by
Sun Yat-sen University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for EBV-Positive Diffuse Large B-Cell Lymphoma, Nos focused on measuring untreated, EBV-positive diffuse large B-cell lymphoma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Subjects fully understand and voluntarily participate in this study and sign informed consent
  2. Age ≥18, ≤70 years, no gender limitation.
  3. Histologically confirmed diagnosis of EBV-positive diffuse large B-cell lymphoma (DLBCL) (more than 50% of tumor cells are positive with EBV encoded small RNAs (EBERs) in situ hybridization were considered EBERs positive).
  4. Untreated patients, except for the short-time use of prednisone for controlling tumor-induced symptoms (no more than 30mg/d (or other equivalent amounts of other glucocorticoids), no more than 7 days).
  5. There must be at least one measurable or evaluable lesion that meets the evaluation criteria for Lugano 2014 lymphoma: measurable lesion: Positron emission tomography/computed tomography (PET/CT) or CT and/or MRI, intranodal lesions with long diameter >1.5cm, and short diameter >1.0cm, or extranodal lesions with long diameter > 1.0 cm.
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2.
  7. Expected survival ≥ 3 months.
  8. Adequate function of bone marrow:

    White blood cell ≥3.0×10E9/L, absolute neutrophil count ≥1.5×10E9/L Platelet ≥100×10E9/L (Bone marrow invasive patient≥75×109/L) Hemoglobin≥ 90g/L No granulocyte growth factor, platelet, or red blood cell transfusions were received within 14 days prior to examination.

  9. Adequate function of the liver and renal:

    Total bilirubin≤2×upper limit of normal (ULN) (patients with liver invasion or Gilbert syndrome ≤5×ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (patients with liver invasion ≤5×ULN) Serum creatinine ≤1.5×ULN or creatinine clearance rate ≥60 mL/min

  10. The patients agree to take effective contraceptive measures during the study period and till 12 months after the last administration of the study treatment.

Exclusion Criteria:

  1. EBV-positive DLBCL combined with other types of lymphoma. Transformed DLBCL.
  2. EBV-positive DLBCL with central nervous system invasion.
  3. The patients had previously received XPO1 inhibitors, such as selinexor and so on.
  4. The patients have contraindications to any drug in the combined treatment.
  5. The major surgery is performed within 4 weeks before enrollment, except for diagnosis.
  6. There are any life-threatening diseases, medical conditions or organ system dysfunction that the investigator believes may affect the safety or compliance of patients.
  7. Heart function and disease meet one of the following conditions:

    1. Heart failure with the classification of New York Heart Association heart function of grade II;
    2. A history of unstable angina pectoris;
    3. A history of myocardial infarction within the past 1 years;
    4. Patients with clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention;
  8. A history of other malignant tumors within the past 5 years (except the cured cervical cancer and basal cell carcinoma of the skin).
  9. Patients with active bleeding.
  10. Uncontrolled infection exists within 7 days before treatment and parenteral antibiotics, antiviral drugs or antifungal drugs are needed; However, preventive use of these drugs (including parenteral anti-infective drugs) is allowed.
  11. Patients with chronic active hepatitis B or active hepatitis C. If the background hepatitis B Surface Antigen (HBsAg) and/or hepatitis B core Antibody (HBcAb) or hepatitis C Virus (HCV) antibody are positive, the further determination for Hepatitis B Virus (HBV) DNA (no more than 2500 copies /mL or 500 IU/mL) and HCV RNA (no more than the lower limit of the assay) can be included. The patients with HBsAg and/or HBcAb positive need to receive anti-HBV drugs.
  12. Patients with the infection of human immunodeficiency virus (HIV) and/or acquired Immunodeficiency syndrome.
  13. Inability to swallow tablets, presence of malabsorption syndrome, or any other gastrointestinal disease or dysfunction that may affect the absorption of the study drug.
  14. Pregnant and lactating women, and subjects of childbearing age who do not want to use contraception.
  15. Mentally ill persons or persons unable to obtain informed consent.
  16. The investigators think that the patient is not suitable for the study.

Sites / Locations

  • Sun Yat-sen Universitiy Cancer CenterRecruiting
  • Fudan University Shanghai Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Selinexor in Combination With R-CHOP

Arm Description

Patients with untreated EBV-positive diffuse large B-cell lymphoma will receive sequentially higher doses of selinexor in combination with R-CHOP regimen from the second cycle of R-CHOP (3 weeks per cycle).The initial dose of selinexor is 40mg qw po. After 8 cycles of induction therapy, if the response is assessed as complete remission (CR), maintenance therapy with selinexor will be conducted.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD)
To identify the MDT
Recommended Phase II Dose (RP2D)
To identify the RP2D
Complete response rate (CRR)
To investigate the preliminary antitumor efficacy

Secondary Outcome Measures

Disease-free survival (DFS)
To investigate the preliminary antitumor efficacy
Objective response rate (ORR)
To investigate the preliminary antitumor efficacy
Progression-free survival (PFS)
To investigate the preliminary antitumor efficacy
Overall survival (OS)
To investigate the preliminary antitumor efficacy
Number of participants with adverse events (AE) and severe adverse events (SAE) as assessed by CTCAE v5.0
To identify the incidence of AE and SAE

Full Information

First Posted
October 6, 2022
Last Updated
November 10, 2022
Sponsor
Sun Yat-sen University
Collaborators
Fudan University, Antengene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT05577364
Brief Title
Selinexor in Combination With R-CHOP Followed by Selinexor Maintenance for Untreated EBV-positive DLBCL Patients
Official Title
A Single-arm, Multi-center, Phase Ib/II Study of Selinexor in Combination With R-CHOP Followed by Selinexor Maintenance for Untreated EBV-positive DLBCL Patients (Xplore Trial)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2022 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
February 28, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Sun Yat-sen University
Collaborators
Fudan University, Antengene Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
This is a prospective, single-arm, multi-center, phase Ib/II clinical trial to evaluate the safety, tolerability, and efficacy of selinexor in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) followed by selinexor maintenance for untreated EBV-positive diffuse large B-cell lymphoma (DLBCL) patients.
Detailed Description
This is a prospective, single-arm, multi-center, phase Ib/II clinical trial to explore the maximum tolerated dose (MTD) of selinexor when combined with R-CHOP regimen for untreated EBV-positive DLBCL patients. Phase Ib study: Selinexor will be given orally at two different doses (40mg qw, and 60mg qw ) and combined with the R-CHOP regimen from the second cycle based on the "3+3" principle. In the induction therapy period, 6 cycles of R-CHOP regimen and 2 cycles of rituximab in combination with selinexor are planned. The dose limited toxicity (DLT) will be evaluated after the first cycle of selinexor in combination with R-CHOP. Phase II study: The phase II study of selinexor at recommended phase II dose (RP2D) dose level combined with R-CHOP regimen was conducted to explore the efficacy and safety of the combined regimen. After 8 cycles of induction therapy, if the response is assessed as complete remission (CR), maintenance therapy with selinexor will be conducted.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
EBV-Positive Diffuse Large B-Cell Lymphoma, Nos
Keywords
untreated, EBV-positive diffuse large B-cell lymphoma

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
54 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Selinexor in Combination With R-CHOP
Arm Type
Experimental
Arm Description
Patients with untreated EBV-positive diffuse large B-cell lymphoma will receive sequentially higher doses of selinexor in combination with R-CHOP regimen from the second cycle of R-CHOP (3 weeks per cycle).The initial dose of selinexor is 40mg qw po. After 8 cycles of induction therapy, if the response is assessed as complete remission (CR), maintenance therapy with selinexor will be conducted.
Intervention Type
Drug
Intervention Name(s)
Selinexor
Other Intervention Name(s)
exportin 1 (XPO1) inhibitor
Intervention Description
Selinexor: 40mg qw po, and 60mg qw po (phase Ib); RP2D (II study); Selinexor is added from the second cycle of R-CHOP regimen.
Intervention Type
Drug
Intervention Name(s)
R-CHOP Protocol
Other Intervention Name(s)
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone
Intervention Description
Rituximab: 375mg/m2 iv.drip D1; Cyclophosphamide: 750mg/m2 iv.drip D1; Doxorubicin: 50mg/m2 iv.drip D1; Vincristine: 1.4g/m2 iv D1; Prednisone: 100mg po D1-5;
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD)
Description
To identify the MDT
Time Frame
The first cycle of selinexor in combination with R-CHOP regimen (21 days)
Title
Recommended Phase II Dose (RP2D)
Description
To identify the RP2D
Time Frame
The first cycle of selinexor in combination with R-CHOP regimen (21 days)
Title
Complete response rate (CRR)
Description
To investigate the preliminary antitumor efficacy
Time Frame
Up to 24 weeks.
Secondary Outcome Measure Information:
Title
Disease-free survival (DFS)
Description
To investigate the preliminary antitumor efficacy
Time Frame
From date of the first complete response until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Title
Objective response rate (ORR)
Description
To investigate the preliminary antitumor efficacy
Time Frame
Up to 24 weeks.
Title
Progression-free survival (PFS)
Description
To investigate the preliminary antitumor efficacy
Time Frame
From date of the first injection until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Title
Overall survival (OS)
Description
To investigate the preliminary antitumor efficacy
Time Frame
From date of the first injection until the date of death from ant cause, assessed up to 24 months
Title
Number of participants with adverse events (AE) and severe adverse events (SAE) as assessed by CTCAE v5.0
Description
To identify the incidence of AE and SAE
Time Frame
Through study completion, an average of 2 years.
Other Pre-specified Outcome Measures:
Title
The correlation between EBV-DNA level and efficacy indicators, such as CRR, DFS, ORR, PFS, and OS
Description
To explore the correlation between EBV-DNA level and response
Time Frame
Through study completion, an average of 2 years.
Title
The gene mutations such as DDX3X、TET2、PTPN2 and so on are sequenced by whole genome sequencing.
Description
To explore the correlations between gene mutations and response and prognosis.
Time Frame
Through study completion, an average of 2 years.
Title
The mRNA and lncRNA alterations are sequenced by transcriptome sequencing.
Description
To explore the correlations between RNA alterations and response and prognosis.
Time Frame
Through study completion, an average of 2 years.
Title
Immune-related indicators such as LAG-3, PD-1, PD-L1, TIGIF, CTLA-4, and so on are assessed by immunohistochemical (IHC) staining.
Description
To explore the correlations between immune-related indicators and response and prognosis.
Time Frame
Through study completion, an average of 2 years.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects fully understand and voluntarily participate in this study and sign informed consent Age ≥18, ≤70 years, no gender limitation. Histologically confirmed diagnosis of EBV-positive diffuse large B-cell lymphoma (DLBCL) (more than 50% of tumor cells are positive with EBV encoded small RNAs (EBERs) in situ hybridization were considered EBERs positive). Untreated patients, except for the short-time use of prednisone for controlling tumor-induced symptoms (no more than 30mg/d (or other equivalent amounts of other glucocorticoids), no more than 7 days). There must be at least one measurable or evaluable lesion that meets the evaluation criteria for Lugano 2014 lymphoma: measurable lesion: Positron emission tomography/computed tomography (PET/CT) or CT and/or MRI, intranodal lesions with long diameter >1.5cm, and short diameter >1.0cm, or extranodal lesions with long diameter > 1.0 cm. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2. Expected survival ≥ 3 months. Adequate function of bone marrow: White blood cell ≥3.0×10E9/L, absolute neutrophil count ≥1.5×10E9/L Platelet ≥100×10E9/L (Bone marrow invasive patient≥75×109/L) Hemoglobin≥ 90g/L No granulocyte growth factor, platelet, or red blood cell transfusions were received within 14 days prior to examination. Adequate function of the liver and renal: Total bilirubin≤2×upper limit of normal (ULN) (patients with liver invasion or Gilbert syndrome ≤5×ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (patients with liver invasion ≤5×ULN) Serum creatinine ≤1.5×ULN or creatinine clearance rate ≥60 mL/min The patients agree to take effective contraceptive measures during the study period and till 12 months after the last administration of the study treatment. Exclusion Criteria: EBV-positive DLBCL combined with other types of lymphoma. Transformed DLBCL. EBV-positive DLBCL with central nervous system invasion. The patients had previously received XPO1 inhibitors, such as selinexor and so on. The patients have contraindications to any drug in the combined treatment. The major surgery is performed within 4 weeks before enrollment, except for diagnosis. There are any life-threatening diseases, medical conditions or organ system dysfunction that the investigator believes may affect the safety or compliance of patients. Heart function and disease meet one of the following conditions: Heart failure with the classification of New York Heart Association heart function of grade II; A history of unstable angina pectoris; A history of myocardial infarction within the past 1 years; Patients with clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention; A history of other malignant tumors within the past 5 years (except the cured cervical cancer and basal cell carcinoma of the skin). Patients with active bleeding. Uncontrolled infection exists within 7 days before treatment and parenteral antibiotics, antiviral drugs or antifungal drugs are needed; However, preventive use of these drugs (including parenteral anti-infective drugs) is allowed. Patients with chronic active hepatitis B or active hepatitis C. If the background hepatitis B Surface Antigen (HBsAg) and/or hepatitis B core Antibody (HBcAb) or hepatitis C Virus (HCV) antibody are positive, the further determination for Hepatitis B Virus (HBV) DNA (no more than 2500 copies /mL or 500 IU/mL) and HCV RNA (no more than the lower limit of the assay) can be included. The patients with HBsAg and/or HBcAb positive need to receive anti-HBV drugs. Patients with the infection of human immunodeficiency virus (HIV) and/or acquired Immunodeficiency syndrome. Inability to swallow tablets, presence of malabsorption syndrome, or any other gastrointestinal disease or dysfunction that may affect the absorption of the study drug. Pregnant and lactating women, and subjects of childbearing age who do not want to use contraception. Mentally ill persons or persons unable to obtain informed consent. The investigators think that the patient is not suitable for the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Qingqing Cai, MD. PhD.
Phone
0086-20-87342823
Email
caiqq@sysucc.org.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Huiqiang Huang, MD. PhD.
Phone
0086-20-87342823
Email
huanghq@sysucc.org.cn
Facility Information:
Facility Name
Sun Yat-sen Universitiy Cancer Center
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
51000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qing qing Cai, MD
Phone
0086-20-87342823
Email
caiqq@sysucc.org.cn
Facility Name
Fudan University Shanghai Cancer Center
City
Shanghai
ZIP/Postal Code
200032
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rong Tao, MD. PhD.
Phone
86-13651603660
Email
taorong@xinhuamed.com.cn

12. IPD Sharing Statement

Learn more about this trial

Selinexor in Combination With R-CHOP Followed by Selinexor Maintenance for Untreated EBV-positive DLBCL Patients

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