A Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) With or Without Selinexor in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma

Relapsed/Refractory Diffuse Large B-cell Lymphoma Clinical Trial

Official title:

A Phase 2/3, Multicenter Randomized Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) With or Without Selinexor in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (RR DLBCL)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04442022
• Other study ID #: XPORT-DLBCL-030
• Secondary ID: 2020-000605-84
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: September 3, 2020
• Est. completion date: December 2025

Study information

• Verified date: June 2024
• Source: Karyopharm Therapeutics Inc
• Contact: Karyopharm Medical Information
• Phone: (888) 209-9326
• Email: clinicaltrials[@]karyopharm.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this Phase 2/3 study is to evaluate efficacy and safety of the combination of selinexor and R-GDP (SR-GDP) in patients with RR DLBCL who are not intended to receive hematopoetic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR-T) therapy. This study consists of 3 arms each in Phase 2 and 3. Phase 2 portion of the study will assess the two doses of selinexor (40 milligram [mg] or 60 mg) in combination with R-GDP, for up to 6 cycles (21-day per cycle), followed by 60 mg selinexor single agent continuous therapy for those who have reached a partial or complete response. Phase 3 portion of the study will evaluate the selected dose of SR-GDP (identified in Phase 2) versus standard R-GDP + matching placebo, for up to 6 cycles (21-day per cycle), followed by placebo or 60 mg selinexor single agent continuous therapy for those who have reached partial or complete response.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 501
• Est. completion date: December 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Have pathologically confirmed de novo DLBCL or DLBCL transformed from previously diagnosed indolent lymphoma (e.g., follicular lymphoma). Patient with high-grade lymphoma with c-MYC, Bcl2 and/or Bcl6 rearrangements are eligible (only for Phase 2). (Documentation to be provided).

• Have received at least 1 but no more than 3 prior lines of systemic therapy for the treatment of DLBCL with relapsed or refractory disease following their most recent regimen.

• Salvage chemoimmunotherapy followed by stem cell transplantation will be considered as 1 line of systemic therapy.

• Maintenance therapy will not be counted as a separate line of systemic therapy.

• Radiation with curative intent for localized DLBCL will not be counted as 1 line of systemic therapy.

• Positron emission tomography (PET) positive measurable disease with at least 1 node having the longest diameter (LDi) greater than (>) 1.5 centimeter (cm) or 1 extranodal lesion with LDi >1 cm (per the Lugano Criteria 2014). The Deauville 5-point scale (D5PS) score assessed on the FDG PET/CT should be between 3 to 5.

• Not intended for HSCT or CAR-T cell therapy based on objective clinical criteria determined by the treating physician. Patients who cannot receive HSCT due to active disease are allowed on study (up to approximately 15 percent [%] of patients enrolled in each Phase). Documentation on lack of intention to proceed to receive HSCT or CAR-T therapy must be provided by the treating physician.

• Adequate bone marrow function at screening, defined as:

• Absolute neutrophil count (ANC) =1*10^9 per liter (/L).

• Platelet count =100*10^9/L (without platelet transfusion less than [<] 14 days prior to Cycle 1 Day 1 [C1D1]).

• Hemoglobin =8.5 gram per deciliter (g/dL) (without red blood cell transfusion <14 days prior to C1D1).

• Circulating lymphocytes less than or equal to (=) 50*10^9/L.

• Adequate liver and kidney function, defined as:

• Aspartate transaminase (AST) or alanine transaminase (ALT) =2.5*upper limit of normal (ULN), or =5*ULN in cases with known lymphoma involvement in the liver.

• Serum total bilirubin =2*ULN, or =5*ULN if due to Gilbert syndrome or in cases with known lymphoma involvement in the liver.

• Calculated creatinine clearance (CrCl) =30 milliliter per minute (mL/min) based on Cockcroft-Gault formula.

• Eastern Cooperative Oncology Group (ECOG) performance status of =2.

• An estimated life expectancy of >3 months at Screening.

• Patients with primary refractory DLBCL defined as no response or relapse within 6 months after ending first-line treatment, will be allowed in the study.

• Agree to highly effective contraception during the duration of the study with contraception use continuing for 12 months after the last dose of study treatment

• Female patients of childbearing potential must have a negative serum pregnancy test at Screening and agree to use highly effective methods of contraception throughout the study and for 12 months following the last dose of study treatment (except patients with Non-Childbearing potential: Age >50 years and naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy).

• Male patients who are sexually active must use highly effective methods of contraception throughout the study and for 12 months following the last dose of study treatment. Male patients must agree not to donate sperm during the study treatment period and for 12 months following the last dose of study treatment.

Exclusion Criteria:

• DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma, composite lymphoma (Hodgkin's lymphoma + non-Hodgkin's lymphoma [NHL]), DLBCL transformed from diseases other than indolent NHL; primary mediastinal (thymic) large B-cell lymphoma (PMBL); T-cell rich large B-cell lymphoma.

• Previous treatment with selinexor or other XPO1 inhibitors.

• Contraindication to any drug contained in the combination therapy regimen (SR-GDP).

• Known active central nervous system or meningeal involvement by DLBCL at time of Screening.

• Use of any standard or experimental anti-DLBCL therapy (including nonpalliative radiation, chemotherapy, immunotherapy, radio-immunotherapy, or any other anticancer therapy) <21 days prior to C1D1 (prednisone <30 mg or equivalent is permitted; palliative radiation is permitted only if on non-target lesions).

• Any AE, by C1D1, which has not recovered to Grade =1 (Common Terminology Criteria for Adverse Events [CTCAE], v.5.0), or returned to baseline, related to the previous DLBCL therapy, except hematological abnormalities (as specified in the inclusion criteria) and alopecia.

• Major surgery <14 days of Cycle 1 Day 1.

• Hematopoietic stem cell transplantation/CAR-T therapy as follows:

• Autologous stem cell transplant (SCT) <100 days or allogeneic-SCT <180 days prior to C1D1

• Active graft-versus-host disease (GVHD) after allogeneic SCT (or cannot discontinue GVHD treatment or prophylaxis)

• CAR-T cell infusion <90 days prior to Cycle 1

• Neuropathy Grade =2 (CTCAE, v.5.0).

• Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety, or being compliant with the study procedures.

• 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).

• Patient with active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infections:

• Patient with active HBV are allowed if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 International units (IU)/mL prior to first dose of study treatment.

• Patients with known history of HCV or found to be HCV antibody positive on screening, are allowed if there is documentation of negative viral load per institutional standard.

• Patients with HIV are allowed if they have a negative viral load per institutional standard, and no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections in the last year.

• Inability to swallow tablets, malabsorption syndrome, or any other gastrointestinal (GI) disease or dysfunction that could interfere with absorption of study treatment.

• Breastfeeding or pregnant women.

• Inability or unwillingness to sign an informed consent form (ICF).

• In the opinion of the Investigator, patient who are significantly below their ideal body weight.

• Patients who received a live attenuated vaccine within prior 28 days of the first dose of study treatment.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Relapsed/Refractory Diffuse Large B-cell Lymphoma

Intervention

Drug:
• Selinexor (combination therapy)
Dose: 40 mg on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Selinexor (combination therapy)
Dose: 60 mg on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Selinexor (combination therapy)
Dose: Selected dose of selinexor (from Phase 2) on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Placebo matching for Selinexor (combination therapy)
Dose: Placebo matching for selected dose of selinexor (from Phase 2) on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Rituximab (combination therapy)
Dose: 375 milligram per meter square (mg/m^2) on Day 1; Route of administration: intravenous (IV)
• Rituximab (combination therapy)
Dose: 375 mg/m^2 on Day 1; Route of administration: IV
• Gemcitabine (combination therapy)
Dose: 1000 mg/m^2 on Days 1 and 8; Route of administration: IV
• Dexamethasone (combination therapy)
Dose: 40 mg (20 mg if patient is more than 70 years old) on Days 1, 2, 3, and 4; Route of administration: oral or IV
• Cisplatin (combination therapy)
Dose: 75 mg/m^2 on Day 1; Route of administration: IV
• Selinexor (continuous therapy)
Dose: 60 mg QW for each 28-day cycle until PD; Route of administration: oral
• Placebo matching for Selinexor (continuous therapy)
Dose: Placebo matching for 60 mg selinexor QW for each 28-day cycle until PD; Route of administration: oral

Locations

Country	Name	City	State
Austria	Kepler Universitaetskrankenhaus Med Campu III - Onkologie	Linz
Austria	Hospital Hietzing	Vienna
Austria	University of Vienna, Medical Clinic I, Hematology	Vienna
China	Huaxi Hospital Sichuan University	Chengdu	Sichuan
China	The first affiliated Hospital, Zhejiang University	Hangzhou	Zhejiang
China	Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School	Huangpu	Shanghai
China	Jiangsu Province Hospital	Nanjing	Jiangsu
China	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu
China	Zhongshan Hospital Fudan University	Xuhui District	Shanghai
Israel	Assuta Ashdod Medical Center	Ashdod
Israel	Soroka Medical Center	Beer Sheva
Israel	Rambam health care campus (Department of Hematology & Bone Marrow Transplantation)	Haifa
Israel	Wolfson Medical Center	Holon
Israel	Hadassah Medical Center	Jerusalem
Israel	Rabin Medical Center	Petach Tikva
Israel	Assuta medical centers - Ramat Hachayal	Tel aviv
Israel	Sourasky Medical Center	Tel Aviv
Italy	AOU Ospedali Riuniti-Università Politecnica delle Marche Clinica di Ematologia	Ancona
Italy	AOU Policlinico S.Orsola Malpighi di Bologna, University of Bologna	Bologna
Italy	UOC Ematologia ad Indirizzo Oncologico, AORN "Sant'Anna e San Sebastiano"	Caserta
Italy	National Cancer Institute	Naples	Napoli
Italy	AOU Maggiore della Carità SCDU Ematologia	Novara
Italy	Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello	Palermo	Sicilia
Italy	DIP. Oncologia- Ematologia, UOSD Centro Diagnosie TerapiaDei Linfomi	Pescara
Italy	Fondatione Policlinico Universitario A. Gemelli	Rome
Italy	AOU City of Health and Science of Turin	Turin	Torino
Poland	Szpitale pomorskie gdynia dept of haematology	Gdynia	Pomerania
Poland	Pratia Onkologia Katowice	Katowice	Slaskie
Poland	Pratia MCM Krakow	Krakow	Lesser
Poland	CM Pratia Poznan	Skorzewo	Wielkopolska
Poland	Institute of Hematology and Transfusion Medicine	Warsaw
Poland	Department of Lymphoid Malignancies, Maria Sklodowska-Curie National Research Institute of Oncology	Warszawa
Poland	Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku Uniwersytecki Szpital Kliniczny im. Jana Mikulicza - Radeckiego we Wroclawiu	Wroclaw	Radeckiego
Spain	Institut català d'oncologia-hospital germans trias i pujol	Badalona	Barcelona
Spain	Hospital Vall Hebron	Barcelona
Spain	Institut Catala D'oncolocia	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Virgen del Rocío	Seville
United States	New Mexico Cancer Care Alliance	Albuquerque	New Mexico
United States	University of Maryland Greenebaum Comprehensive Cancer Center	Baltimore	Maryland
United States	Gabrail Cancer Center Research LLC	Canton	Ohio
United States	The Oncology Institute (TOI) Clinical Research	Cerritos	California
United States	Ironwood Physicians P.C. dba Ironwood Cancer and Research Centers	Chandler	Arizona
United States	Texas Oncology - Medical City Dallas	Dallas	Texas
United States	Texas Oncology - Presbyterian Dallas Cancer Center	Dallas	Texas
United States	Texas Oncology - Sammons	Dallas	Texas
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Texas Oncology - Fort Worth	Fort Worth	Texas
United States	Investigative Clinical Research of Indiana, LLC	Indianapolis	Indiana
United States	Comprehensive Cancer Centers of Nevada - Town Center	Las Vegas	Nevada
United States	Norton Cancer Institute, St. Matthews	Louisville	Kentucky
United States	Tulane Cancer Center	New Orleans	Louisiana
United States	Texas Oncology - Plano East	Plano	Texas
United States	Stony Brook	Stony Brook	New York
United States	Arizona Oncology Associates	Tucson	Arizona
United States	Texas Oncology - Tyler	Tyler	Texas
United States	The University of Texas Health Science Center at Tyler DBA UT Health East Texas HOPE Cancer Center	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Austria,  China,  Israel,  Italy,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 2: Overall Response Rate (ORR): Based on Lugano Criteria 2014		From date of initial randomization to the date of disease progression or initiating a new DLBCL treatment (maximum of 5 years from randomization)
Primary	Phase 3: Progression-free Survival (PFS): Based on Lugano Criteria 2014		From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Secondary	Phase 2: Progression-free Survival: Based on Lugano Criteria 2014		From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Secondary	Phase 2: Overall Survival (OS)		From date of initial randomization until death (maximum of 5 years from randomization)
Secondary	Phase 3: Overall Response Rate: Based on Lugano Criteria 2014		From date of initial randomization to the date of disease progression or initiating a new DLBCL treatment (maximum of 5 years from randomization)
Secondary	Phase 3: Overall Survival		From date of initial randomization until death (maximum of 5 years from randomization)
Secondary	Phase 2: Overall Response Rate at the End of Combination Therapy (ORR-EoC): Based on Lugano Criteria 2014		From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Secondary	Phase 2: Overall Response Rate at the End of Combination Therapy: Based on Modified Lugano Criteria		From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Secondary	Phase 2: Duration of Response (DOR): Based on Lugano Criteria 2014		From time of first response until disease progression or death (maximum of 5 years from randomization)
Secondary	Phase 2: Number of Patients with Adverse Events (AEs)		Up to 30 days after last dose of study drug (maximum of 5 years from randomization)
Secondary	Phase 3: Overall Response Rate at the End of Combination Therapy: Based on Lugano Criteria 2014		From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Secondary	Phase 3: Overall Response Rate at the End of Combination Therapy: Based on Modified Lugano Criteria		From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Secondary	Phase 3: Duration of Response: Based on Lugano Criteria 2014		From time of first response until disease progression or death (maximum of 5 years from randomization)
Secondary	Phase 3: Progression-free Survival: Based on Modified Lugano Criteria		From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Secondary	Phase 3: Number of Patients with Adverse Events		Up to 30 days after last dose of study drug (maximum of 5 years from randomization)