Selinexor Plus R-CHOP in High-risk GCB-subtype Diffuse Large B-Cell Lymphoma

This is a phase II, multicenter, single-arm and open-label study to explore Selinexor in combination with standard of care R-CHOP in New Diagnosed high-risk GCB-subtype DLBCL (IPI 3-5). Approximately 35 patients plan to be enrolled in about 6-8 study sites of the study. And the objective is to Evaluate the safety and efficacy of XR-CHOP in High-Risk (IPI 3-5) GCB-subtype DLBCL.The enrollment period for this study is expected to be approximately 18 months. The study will end when all patients have completed 6 cycles treatment/follow-up since the initiation of the study drug, or the last patient has expired, has been lost to follow-up, or has withdrawn consent, whichever occurs first.

This is a phase II, multicenter, single-arm and open-label study to explore Selinexor in combination with standard of care R-CHOP in New Diagnosed high-risk GCB-subtype DLBCL (IPI 3-5). Approximately 35 patients plan to be enrolled in about 6-8 study sites of the study.

Enrolled patients will be treated with 6 cycles of R-CHOP (Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2 , doxorubicin 50 mg/m2 IV, vincristine 0.5 mg/kg on day 1, prednisone 100 mg po on days 1-5 in a 21 day cycle) and a fixed dose, 60 mg of selinexor, orally, weekly, each 3 week a cycle. Disease assessment will be made by positron emission tomography computed tomography (PET-CT) or PET- magnetic resonance imaging (MRI) scans (if CT is contraindicated) at screening (within 14 days of Cycle 1 Day 1). The PET-CT or PET-MRI scans (if CT is contraindicated) will be performed on Cycle 3 Day 1 (±1 week) and then every 8 weeks ± 1 week (i.e., Day 1 of odd numbered cycles) until disease progression is confirmed. The CT (or MRI) is allowed at alternating assessment time points (i.e., every 16 weeks, or every other scan) to replace PET if PET cannot be performed for every assessment.

Enrolled patients will be treated with 6 cycles of R-CHOP (Rituximab 375 mg/m2, Cyclophosphamide 750 mg/m2, Doxorubicin 50 mg/m2 IV, Vincristine 0.5 mg/kg on day 1, Prednisone 100 mg po on days 1-5 in a 21 day cycle) and a fixed dose, 60 mg of selinexor, orally, weekly, each 3 week a cycle. Treatment will continue for six cycles, or until intolerability, inadequate response, disease progression, consent withdrawal, or death, whichever occur first.

Two additional Rituximab doses (1 dose/21-day cycle) are permitted at cycles 7 and 8 if prespecified and considered standard of care per local practice. Investigators could prospectively give prespecified local radiotherapy consolidation after chemotherapy to treat a particular bulky disease site (at least 7 cm) or large mass. Additional prophylaxis or supportive care are recommended for better patient management.

The enrollment period for this study is expected to be approximately 18 months. The study will end when all patients have completed 6 cycles treatment/follow-up since the initiation of the study drug, or the last patient has expired, has been lost to follow-up, or has withdrawn consent, whichever occurs first.

Eligibility Criteria:
Inclusion Criteria:

* Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:

  1. Willing and able to written informed consent (ICF) .
  2. Age ≥ 18 years and ≤ 75 years.
  3. Histologically confirmed Diffuse Large B-Cell Lymphoma of the germinal center B-cell(DLBCL) subtype by Hans.
  4. Patients no prior chemotherapy or radiotherapy for DLBCL, with the exception of no more than 5 days of treatment with glucocorticoids for symptom control.
  5. International Prognostic Index score of 3-5.
  6. Computed Tomography(CT)/Positron emission tomography (PET) positive measurable disease per the Lugano Classification 2014, having at least 1 node with longest diameter (LDi) greater than \> 1.5cm or 1 extranodal lesion with LDi \>1 cm.
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  8. Adequate bone marrow function at Screening(Except for underlying diseases, such as secondary hypersplenism due to bone marrow invasion or splenic invasion identified by the investigator).

     1. Absolute neutrophil count (ANC)≥1.5×109/L;
     2. Platelet count (PLT) ≥100×109/L(no platelet transfusion within 14 days prior to C1D1), or PLT≥ 75×109/L if due to lymphoma with bone marrow involvement.
     3. Hemoglobin (HB)≥85g/L(no red blood cell transfusion within 14 days prior to C1D1).
  9. Adequate hepatic and renal function:

     1. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤2.0 x upper limit of normal (ULN), or AST and ALT≤5.0 x ULN(if due to lymphoma involvement),
     2. Serum total bilirubin ≤2×ULN, or Serum total bilirubin ≤5×ULN if due to Gilbert syndrome or lymphoma involvement.
     3. Estimated creatinine clearance ≥ 30 mL/min (calculated using the formula of Cockroft-Gault).
  10. Participants of childearing potential must agree to use highly effective methods of contraception during the duration of the study and following the last dose of study treatment, female and male participants should continue contraception for 14 and 11 months, respectively.

      1. Female participants of childbearing potential must have a negative serum pregnancy test at screening(Non-Childbearing potential: Age \>50 years and naturally amenorrhoeic for \>1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy).
      2. Male participants must agree to avoid sperm donation during the duration of the study and 14 months following the last dose of study treatment.

Exclusion Criteria:

* Inclusion/Exclusion Criteria:

Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:

1. Willing and able to written informed consent (ICF) .
2. Age ≥ 18 years and ≤ 75 years.
3. Histologically confirmed Diffuse Large B-Cell Lymphoma of the germinal center B-cell(DLBCL) subtype by Hans.
4. Patients no prior chemotherapy or radiotherapy for DLBCL, with the exception of no more than 5 days of treatment with glucocorticoids for symptom control.
5. International Prognostic Index score of 3-5.
6. Computed Tomography(CT)/Positron emission tomography (PET) positive measurable disease per the Lugano Classification 2014, having at least 1 node with longest diameter (LDi) greater than \> 1.5cm or 1 extranodal lesion with LDi \>1 cm.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
8. Adequate bone marrow function at Screening(Except for underlying diseases, such as secondary hypersplenism due to bone marrow invasion or splenic invasion identified by the investigator).

   1. Absolute neutrophil count (ANC)≥1.5×109/L;
   2. Platelet count (PLT) ≥100×109/L(no platelet transfusion within 14 days prior to C1D1), or PLT≥ 75×109/L if due to lymphoma with bone marrow involvement.
   3. Hemoglobin (HB)≥85g/L(no red blood cell transfusion within 14 days prior to C1D1).
9. Adequate hepatic and renal function:

   1. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤2.0 x upper limit of normal (ULN), or AST and ALT≤5.0 x ULN(if due to lymphoma involvement),
   2. Serum total bilirubin ≤2×ULN, or Serum total bilirubin ≤5×ULN if due to Gilbert syndrome or lymphoma involvement.
   3. Estimated creatinine clearance ≥ 30 mL/min (calculated using the formula of Cockroft-Gault).
10. Participants of childearing potential must agree to use highly effective methods of contraception during the duration of the study and following the last dose of study treatment, female and male participants should continue contraception for 14 and 11 months, respectively.

    1. Female participants of childbearing potential must have a negative serum pregnancy test at screening(Non-Childbearing potential: Age \>50 years and naturally amenorrhoeic for \>1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy).
    2. Male participants must agree to avoid sperm donation during the duration of the study and 14 months following the last dose of study treatment.

Exclusion Criteria:

Patients who meet any of the following criteria will not be enrolled:

1. DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma; composite lymphoma (Hodgkin lymphoma + NHL); Gray zone lymphoma; DLBCL transformed from Chronic Lymphocytic Leukemia (Richter Syndrome); Primary mediastinal large B-cell lymphoma (PMBCL); T-cell rich large B-cell lymphoma.
2. Known active central nervous system lymphoma or meningeal involvement at screening. Participants with a history of CNS disease treated into remission may be enrolled. The DLBCL of Testis involvement or more than two extranodal involvement.
3. Previous treatment with selinexor or other XPO1 inhibitors.
4. Contraindication to any drug contained in these regimen.
5. Major surgery \<14 days of C1D1, Except for disease diagnosis.
6. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety, or able to comply with the study procedures.
7. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral).
8. Subjects with known active Hepatitis B (HB) infection, active Hepatitis C (HCV) infection or Human Immunodeficiency Virus (HIV) positivity. Participants with active hepatitis B Virus (HBV) are eligible if antiviral therapy for hepatitis B has been given for \>8 weeks and viral load is \<100 international units per milliliter (IU/mL); participants with untreated hepatitis C Virus (HCV) are eligible if viral load is negative per institutional standard; participants with human immunodeficiency virus (HIV) are eligible if cluster of differentiation 4 (CD4+) T-cell counts ≥350 cells per microliter (cells/μL), viral load is negative and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year.
9. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral).
10. Breastfeeding women or pregnant women.
11. In the opinion of the Investigator, participants who are below their ideal body weight and would be unduly impacted by changes in their weight.
12. Life expectancy of less than 6 months.