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

DLBCL Germinal Center B-Cell Type Clinical Trial

Official title:

Frontline Selinexor(ATG-010) Plus R-CHOP Therapy for High-risk GCB-subtype Diffuse Large B-Cell Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05422066
• Other study ID #: ATG-010-MA-CL-DLBCL-002
• Status: Recruiting
• Phase: Phase 2
• Start date: July 26, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: June 2024
• Source: Sun Yat-sen University
• Contact: Zhiming Li, Ph.D
• Phone: +86-020-87343765
• Email: lizhm[@]sysucc.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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since the initiation of the study drug, or the last patient has expired, has been lost to follow-up, or has withdrawn consent, whichever occurs first.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 31, 2025
• Est. primary completion date: July 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• DLBCL Germinal Center B-Cell Type
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Selinexor
Selinexor (ATG-010# is a first-in-class, oral selective exportin 1 (XPO1) inhibitor (1,2). Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus along with inhibition of translation of oncoprotein mRNAs. Selinexor 60mg on day 1,8,15 for 21 days cycles
• Rituximab
Induction Chemotherapy: 375mg/sqm, Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease, up to 6 cycles.
• Cyclophosphamide
Induction Chemotherapy: 750mg/m2, Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease, up to 6 cycles.
• Doxorubicin
Induction Chemotherapy: 70mg/m2, Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease, up to 6 cycles.
• Vincristine
Induction Chemotherapy: 1.4mg/m2 (Max: 2mg), Intravenous administration on day 1 of each 3-week cycle until disease progression/stable disease, up to 6 cycles.
• Prednisone
Induction Chemotherapy: 100mg, oral administration on day 1 to 5 of each 3-week cycle until disease progression/stable disease, up to 6 cycles.

Locations

Country	Name	City	State
China	Hunan Cancer Hospital	Changsha	Hunan
China	Department of Medical Oncology, Sun Yat-Sen University Cancer Center	Guangzhou	Guangdong
China	The Affiliated People's Hospital of Ningbo University	Ningbo	Zhejiang
China	Hubei Cancer Hospital	Wuhan	Hubei
China	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	Henan Cancer Hospital	Zhengzhou	Henan

Sponsors (2)

Lead Sponsor	Collaborator
Li Zhiming	Antengene Corporation

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Response Rate (CR)	Complete Remission (CR) rate at any time up of cycle 6 defined by Lugano 2014 defined response. Number of patients who achieved complete response after treatment by XR-CHOP	up to 18 months
Secondary	Overall Response Rate (ORR)	Overall Response Rate (ORR) per the Lugano Classification 2014 [ Time Frame: Cycle 1 Day 1 (each cycle consists of maximum 21 days) until a complete response (CR) or partial response (PR)	up to 18 months
Secondary	Progression Free Survival(PFS)	Duration from start of study treatment to Progressive disease(PD) or death (regardless of cause), whichever comes first.	up to 18 months
Secondary	Disease free survival(DFS)	To assess only the population with the best response to CR, Duration from patients who achieve CR or better time to first occurrence of PD or death(regardless of cause),whichever comes first.	up to 18 months
Secondary	Overall survival(OS)	Duration from start of study treatment to death (regardless of cause).	up to 18 months
Secondary	Safety/toxicity profile	Adverse events as per CTCAE. V5.0. Number of Participants With Adverse Events (AEs) by Occurrence, Nature, and Severity [ Time	From start of study drug administration up to 30 days after last dose of study treatment