Selinexor in Combination With R-CHOP Followed by Selinexor Maintenance for Untreated EBV-positive DLBCL Patients
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Selinexor in Combination With R-CHOP 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. |
Drug: Selinexor
Selinexor: 40mg qw po, and 60mg qw po (phase Ib); RP2D (II study);
Selinexor is added from the second cycle of R-CHOP regimen.
Other Names:
Drug: R-CHOP Protocol
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;
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose (MTD) [The first cycle of selinexor in combination with R-CHOP regimen (21 days)]
To identify the MDT
- Recommended Phase II Dose (RP2D) [The first cycle of selinexor in combination with R-CHOP regimen (21 days)]
To identify the RP2D
- Complete response rate (CRR) [Up to 24 weeks.]
To investigate the preliminary antitumor efficacy
Secondary Outcome Measures
- Disease-free survival (DFS) [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]
To investigate the preliminary antitumor efficacy
- Objective response rate (ORR) [Up to 24 weeks.]
To investigate the preliminary antitumor efficacy
- Progression-free survival (PFS) [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]
To investigate the preliminary antitumor efficacy
- Overall survival (OS) [From date of the first injection until the date of death from ant cause, assessed up to 24 months]
To investigate the preliminary antitumor efficacy
- Number of participants with adverse events (AE) and severe adverse events (SAE) as assessed by CTCAE v5.0 [Through study completion, an average of 2 years.]
To identify the incidence of AE and SAE
Other Outcome Measures
- The correlation between EBV-DNA level and efficacy indicators, such as CRR, DFS, ORR, PFS, and OS [Through study completion, an average of 2 years.]
To explore the correlation between EBV-DNA level and response
- The gene mutations such as DDX3X、TET2、PTPN2 and so on are sequenced by whole genome sequencing. [Through study completion, an average of 2 years.]
To explore the correlations between gene mutations and response and prognosis.
- The mRNA and lncRNA alterations are sequenced by transcriptome sequencing. [Through study completion, an average of 2 years.]
To explore the correlations between RNA alterations and response and prognosis.
- Immune-related indicators such as LAG-3, PD-1, PD-L1, TIGIF, CTLA-4, and so on are assessed by immunohistochemical (IHC) staining. [Through study completion, an average of 2 years.]
To explore the correlations between immune-related indicators and response and prognosis.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Subjects fully understand and voluntarily participate in this study and sign informed consent
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Age ≥18, ≤70 years, no gender limitation.
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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).
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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).
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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.
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Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2.
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Expected survival ≥ 3 months.
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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:
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EBV-positive DLBCL combined with other types of lymphoma. Transformed DLBCL.
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EBV-positive DLBCL with central nervous system invasion.
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The patients had previously received XPO1 inhibitors, such as selinexor and so on.
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The patients have contraindications to any drug in the combined treatment.
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The major surgery is performed within 4 weeks before enrollment, except for diagnosis.
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There are any life-threatening diseases, medical conditions or organ system dysfunction that the investigator believes may affect the safety or compliance of patients.
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Heart function and disease meet one of the following conditions:
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Heart failure with the classification of New York Heart Association heart function of grade II;
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A history of unstable angina pectoris;
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A history of myocardial infarction within the past 1 years;
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Patients with clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention;
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A history of other malignant tumors within the past 5 years (except the cured cervical cancer and basal cell carcinoma of the skin).
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Patients with active bleeding.
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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.
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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.
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Patients with the infection of human immunodeficiency virus (HIV) and/or acquired Immunodeficiency syndrome.
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Inability to swallow tablets, presence of malabsorption syndrome, or any other gastrointestinal disease or dysfunction that may affect the absorption of the study drug.
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Pregnant and lactating women, and subjects of childbearing age who do not want to use contraception.
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Mentally ill persons or persons unable to obtain informed consent.
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The investigators think that the patient is not suitable for the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sun Yat-sen Universitiy Cancer Center | Guangzhou | Guangdong | China | 51000 |
| 2 | Fudan University Shanghai Cancer Center | Shanghai | China | 200032 |
Sponsors and Collaborators
- Sun Yat-sen University
- Fudan University
- Antengene Corporation
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- B2022-534-01