Clinical trial NCT04442022: A Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) with or Without Selinexor in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Relapsed/refractory Diffuse Large B-cell Lymphoma
Keywords: Relapsed/Refractory DLBCL
Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP)
Selinexor
Karyopharm
KCP-330
XPOVIO
DLBCL
XPORT-DLBCL-030
R-GDP
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2020-06-22
Enrollment: 501
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase 2: Overall Response Rate (ORR): Based on Lugano Criteria 2014
timeFrame: From date of initial randomization to the date of disease progression or initiating a new DLBCL treatment (maximum of 5 years from randomization)
measure: Phase 3: Progression-free Survival (PFS): Based on Lugano Criteria 2014
timeFrame: From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Secondary outcomes:
measure: Phase 2: Progression-free Survival: Based on Lugano Criteria 2014
timeFrame: From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
measure: Phase 2: Overall Survival (OS)
timeFrame: From date of initial randomization until death (maximum of 5 years from randomization)
measure: Phase 3: Overall Response Rate: Based on Lugano Criteria 2014
timeFrame: From date of initial randomization to the date of disease progression or initiating a new DLBCL treatment (maximum of 5 years from randomization)
measure: Phase 3: Overall Survival
timeFrame: From date of initial randomization until death (maximum of 5 years from randomization)
measure: Phase 2: Overall Response Rate at the End of Combination Therapy (ORR-EoC): Based on Lugano Criteria 2014
timeFrame: From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
measure: Phase 2: Overall Response Rate at the End of Combination Therapy: Based on Modified Lugano Criteria
timeFrame: From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
measure: Phase 2: Duration of Response (DOR): Based on Lugano Criteria 2014
timeFrame: From time of first response until disease progression or death (maximum of 5 years from randomization)
measure: Phase 2: Number of Patients with Adverse Events (AEs)
timeFrame: Up to 30 days after last dose of study drug (maximum of 5 years from randomization)
measure: Phase 3: Overall Response Rate at the End of Combination Therapy: Based on Lugano Criteria 2014
timeFrame: From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
measure: Phase 3: Overall Response Rate at the End of Combination Therapy: Based on Modified Lugano Criteria
timeFrame: From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
measure: Phase 3: Duration of Response: Based on Lugano Criteria 2014
timeFrame: From time of first response until disease progression or death (maximum of 5 years from randomization)
measure: Phase 3: Progression-free Survival: Based on Modified Lugano Criteria
timeFrame: From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
measure: Phase 3: Number of Patients with Adverse Events
timeFrame: Up to 30 days after last dose of study drug (maximum of 5 years from randomization)
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Ironwood Physicians P.C. dba Ironwood Cancer and Research Centers
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Cerritos
country: United States
facility: The Oncology Institute (TOI) Clinical Research
state: California
city: Indianapolis
country: United States
facility: Investigative Clinical Research of Indiana, LLC
state: Indiana
city: Louisville
country: United States
facility: Norton Cancer Institute, St. Matthews
state: Kentucky
city: New Orleans
country: United States
facility: Tulane Cancer Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Comprehensive Cancer Center
state: Maryland
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada - Town Center
state: Nevada
city: Albuquerque
country: United States
facility: New Mexico Cancer Care Alliance
state: New Mexico
city: Stony Brook
country: United States
facility: Stony Brook
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research LLC
state: Ohio
city: Dallas
country: United States
facility: Texas Oncology - Medical City Dallas
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Presbyterian Dallas Cancer Center
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Sammons
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology - Fort Worth
state: Texas
city: Plano
country: United States
facility: Texas Oncology - Plano East
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler
state: Texas
city: Tyler
country: United States
facility: The University of Texas Health Science Center at Tyler DBA UT Health East Texas HOPE Cancer Center
state: Texas
city: Everett
country: United States
facility: Providence Regional Cancer Partnership
state: Washington
city: Linz
country: Austria
facility: Kepler Universitaetskrankenhaus Med Campu III - Onkologie
city: Vienna
country: Austria
facility: University of Vienna, Medical Clinic I, Hematology
city: Vienna
country: Austria
facility: Hospital Hietzing
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Huangpu
country: China
facility: Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School
state: Shanghai
city: Xuhui District
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Chengdu
country: China
facility: Huaxi Hospital Sichuan University
state: Sichuan
city: Hangzhou
country: China
facility: The first affiliated Hospital, Zhejiang University
state: Zhejiang
city: Ashdod
country: Israel
facility: Assuta Ashdod Medical Center
city: Beer Sheva
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Rambam health care campus (Department of Hematology & Bone Marrow Transplantation)
city: Holon
country: Israel
facility: Wolfson Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
city: Tel aviv
country: Israel
facility: Assuta medical centers - Ramat Hachayal
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Naples
country: Italy
facility: National Cancer Institute
state: Napoli
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
state: Sicilia
city: Turin
country: Italy
facility: AOU City of Health and Science of Turin
state: Torino
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti-Università Politecnica delle Marche Clinica di Ematologia
city: Bologna
country: Italy
facility: AOU Policlinico S.Orsola Malpighi di Bologna, University of Bologna
city: Caserta
country: Italy
facility: UOC Ematologia ad Indirizzo Oncologico, AORN "Sant'Anna e San Sebastiano"
city: Novara
country: Italy
facility: AOU Maggiore della Carità SCDU Ematologia
city: Pescara
country: Italy
facility: DIP. Oncologia- Ematologia, UOSD Centro Diagnosie TerapiaDei Linfomi
city: Rome
country: Italy
facility: Fondatione Policlinico Universitario A. Gemelli
city: Krakow
country: Poland
facility: Pratia MCM Krakow
state: Lesser
city: Gdynia
country: Poland
facility: Szpitale pomorskie gdynia dept of haematology
state: Pomerania
city: Wroclaw
country: Poland
facility: Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku Uniwersytecki Szpital Kliniczny im. Jana Mikulicza - Radeckiego we Wrocławiu
state: Radeckiego
city: Skorzewo
country: Poland
facility: CM Pratia Poznań
state: Wielkopolska
city: Warsaw
country: Poland
facility: Institute of Hematology and Transfusion Medicine
city: Warszawa
country: Poland
facility: Department of Lymphoid Malignancies, Maria Sklodowska-Curie National Research Institute of Oncology
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
state: Śląskie
city: Badalona
country: Spain
facility: Institut català d'oncologia-hospital germans trias i pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Vall Hebron
city: Barcelona
country: Spain
facility: Institut Catala D'oncolocia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Seville
country: Spain
facility: Hospital Virgen del Rocío
Study officials:
References: