| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse Large B-Cell Lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012856 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012857 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 2: To compare efficacy (ORR - overall response rate) in patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR DLBCL) treated with Rituximab-Gemcitabine-Dexamethasone-Platinum plus either selinexor 40 mg or selinexor 60 mg to R-GDP alone based on the Lugano 2014 Criteria.
Phase 3: To compare Progression-free survival (PFS) in patients with RR DLBCL treated with SR-GDP (selinexor + rituximab, gemcitabine, dexamethasone, platinum) followed by selinexor to PR-GDP (placebo plus rituximab, gemcitabine, dexamethasone, platinum) followed by placebo based on the Lugano 2014 Criteria. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 2:
To compare PFS in patients with RR DLBC treated with R-GDP plus either selinexor 40 mg or selinexor 60 mg to R-GDP alone based on the Lugano 2014 Criteria.
To assess overall survival (OS) in each treatment arm.
Phase 3:
To evaluate overall response rate (ORR) in patients with RR DLBCL treated with SR-GDP (selinexor + rituximab, gemcitabine, dexamethasone, platinum) followed by selinexor and with SR-GDP (selinexor + rituximab, gemcitabine, dexamethasone, platinum) followed by placebo compared to PR-GDP (placebo plus rituximab, gemcitabine, dexamethasone, platinum) followed by placebo based on the Lugano 2014 Criteria.
To assess OS in each treatment arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria are similar in the Phase 2 and Phase 3 portions of the study except where noted.
I1 Patients ≥18 years of age.
I2 Have pathologically confirmed de novo DLBCL or DLBCL transformed from previously diagnosed indolent lymphoma (eg, follicular lymphoma). Patients with high grade lymphoma with myc, bcl2 and/or bcl6 rearrangements are eligible (for Phase 2 only). (Documentation to be provided).
I3 Have received at least 1 but no more than 2 prior lines of systemic theraphy for the treatment of DLBCL (Documentation to be provided).
• Salvage chemoimmunotherapy followed by stem cell transplantation will be considered as 1 line of 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 therapy.
I4 PET positive measurable disease per the revised criteria for response assessment of lymphoma (with at least 1 node having longest diameter (LDi) >1.5 centimeter (cm) or 1 extranodal lesion with LDi >1 cm (per the Lugano Classification 2014) (Documentation to be provided).
I5 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 10% 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.
I6 Adequate bone marrow function at screening, defined as (Documentation to be provided):
• ANC ≥1 x 109/L
• Platelet count ≥100 x 109/L (without platelet transfusion <14 days prior to C1D1)
• Hemoglobin ≥ 8.5g/dL (without red blood cell transfusion <14 days prior to C1D1)
I 7 Circulating lymphocytes ≤50 x 109/L.
I 8 Adequate liver and kidney function, defined as (Documentation to be provided):
• Aspartate transaminase (AST) or alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or ≤5 x ULN in cases with known lymphoma involvement in the liver;
• Serum total bilirubin ≤2 x ULN, or ≤5 ULN if due to Gilbert syndrome or in cases with known lymphoma involvement in the liver;
• Calculated creatinine clearance (CrCl) ≥30 mL/min based on Cockcroft-Gault formula.
I9 Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
I10 An estimated life expectancy of >3 months at Screening.
I11 Patients with primary refractory DLBCL defined as no response or relapse within 6 months after ending first-line treatment will be allowed on study (up to 20% of enrolled patients in each phase).
I12 Agree to effective contraception during the duration of the study with contraception use for 14 months for female patients and 11 months for male patients 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 14 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 11 months following the last dose of study treatment. Male patients must agree not to donate sperm during the study treatment period and for 11 months following the last dose of study treatment. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria are similar in the Phase 2 and Phase 3 portions of the study except where noted.
E1 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; or primary mediastinal (thymic) large B-cell lymphoma (PMBL); T-cell rich large B-cell lymphoma.
E2 Previous treatment with selinexor or other XPO1 inhibitors.
E3 Contraindication to any drug contained in the combination therapy regimen (SR-GDP).
E4 Known active central nervous system or meningeal involvement by DLBCL at time of Screening.
E5 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 Cycle 1 Day 1 (Prednisone <30mg or equivalent are permitted; palliative radiation is permitted only if on non-target lesions).
E6 Any AE, by Cycle 1 Day 1, 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 alopecia.
E7 Major surgery <14 days of Cycle 1 Day 1.
E8 Autologous stem cell transplant (SCT) <100 days or allogeneic-SCT <180 days prior to Cycle 1 Day 1 or active graft-versus-host disease after allogeneic (or cannot discontinue GVHD treatment or prophylaxis) or CAR-T cell infusion <90 days prior to Cycle 1.
E9 Neuropathy Grade ≥2 (CTCAE, v. 5.0).
E10 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.
E11 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).
E12 Patients with active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infections. Patients with active HBV are allowed if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 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 who have CD4+ T-cell counts ≥350 cells/μL, negative viral load per institutional standard, and no history of AIDS-defining opportunistic infections in the last year are allowed.
E13 Inability to swallow tablets, malabsorption syndrome, or any other gastrointestinal (GI) disease or dysfunction that could interfere with absorption of study treatment.
E14 Breastfeeding women.
E15 Inability or unwillingness to sign an informed consent form (ICF)
E16 In the opinion of the Investigator, patients who are significantly below their ideal body weight. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2: overall response rate (ORR) based on the Lugano Classification 2014.
Phase 3: Progression-free survival (PFS) based on the Lugano Classification 2014 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the study |
|
| E.5.2 | Secondary end point(s) |
Phase 2: Progression-free survival (PFS) based on the Lugano Classification 2014. Overall survival
Phase 3: overall response rate (ORR) based on the Lugano Classification 2014. Overall survival. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
- Genetic analysis including but not limited to DNA and ribonucleic acid (RNA) sequencing of tumor tissue and blood samples
- Quality of life (QoL)
- Prognostic markers: Cytogenetic and fluorescence in situ hybridization (FISH) and immunochemistry (IHC) |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Poland |
| Serbia |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The End of Study (EoS) will be upon completion of the follow-up period for the last patient.
This will occur when the last patient in the study has expired, has been followed for 12 months after enrollment, has been lost to follow-up, has withdrawn consent, or the study is closed, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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