Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Selinexor · 32 trials · 48 indications
Compare progression free survival of the two treatment arms as assessed by the investigator, per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
PFS was defined as time from date of randomization until the first date of IRC-confirmed PD, per International Myeloma Working Group (IMWG) response criteria, or death due to any cause, whichever occurs first. PD included increase of 25% from lowest confirmed response value in 1 or more of the following criteria: a) serum M-protein with absolute increase of \>= 0.5 gram per deciliter (g/dL); b) serum M-protein increase \>= 1 g/dL if the lowest M-component was \>=5 g/dL; c) urine M-protein (absolute increase must be \>= 200 mg per 24 hours); d) in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be greater than \[\>\] 10 mg/dL); e) in participants without measurable serum and urine M-protein levels and without measurable involved FLC levels: bone marrow plasma cell percentage irrespective of baseline status (absolute increase must be \>=10%).
Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of complete response (CR) or morphologic complete response with incomplete blood count recovery (CRi), as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet: CR: Absolute Neutrophil count (ANC) \>1.0x10\^9/L, Platelet count \>100x10\^9/L, Bone marrow blasts \<5%, no Auer rods, no evidence of extramedullary disease. CRi: Same as CR, but ANC may be \<1.0x10\^9/L and/or Platelet count \<100x10\^9/L. Patients with morphologic leukemia free-state (MLFS) were included in the group of responders. MLFS: Bone marrow blasts \<5%, no Auer rods, no evidence of extramedullary disease. The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s).
Measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) Scan by Investigator assessment.
To determine the safety of two agents in combination to reverse platinum resistance in ovarian cancer: the hypomethylating agent, decitabine, and the nuclear export receptor XPO1 inhibitor, selinexor, combined with carboplatin and paclitaxel in patients with relapsed/refractory epithelial ovarian carcinoma
The study will assess how long participants will not have the cancer get worse while treated with selinexor
Overall response rate (ORR) will be reported as the fraction of participants achieving either complete response (CR) or partial response (ORR = CR + PR) to study treatment. Response to therapy will be assessed by treating physician using International Myeloma Working Group 2016 response criteria.
To evaluate the overall response rate achieved with physician's choice selinexor-based combination therapy as measured by International Myeloma Working Group criteria (based on Kumar et al 2016).
percentage of patients who had complete response. Complete response is when patients achieve a negative immunofixation on the serum and urine and who also have an appearance of a soft tissue plasmacytomas and achieve less than or equal to 5 percent (%) plasma cells in the bone marrow.
percentage of patients who had stringent complete response. Patients with a stringent complete response in addition to the criteria that is required to have a complete response are required to have a normal free light chain ratio in the serum and absence of clonal cells in the bone marrow determined by either immunofluorescence or immunohistochemistry.
frequency (incidence rate) of adverse effects
ORR at end of induction, with response defined according to IMWG response criteria
Ordinal Scale 2-Point improvement was defined as percentage of participants with at least a 2-points improvement (increase from baseline) by Day 14. Baseline score was defined as the last score measured before first dosing. The 8-point ordinal scale ranges from 1 to 8: where 1= death, 2= hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3= hospitalized, on non-invasive ventilation or high flow oxygen devices; 4= hospitalized, requiring supplemental oxygen; 5= hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (coronavirus disease 2019 \[COVID-19\] related or otherwise); 6= hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7= not hospitalized, limitation on activities and/or requiring home oxygen; 8= not hospitalized, no limitations on activities.
PFS was defined as the time from the date of randomization until the first date of Independent Review Committee (IRC)-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest sum of the longest diameter (SLD) recorded from baseline or the appearance of 1 or more new lesions.
PFS was defined as the time from the date of randomization in the Phase 3 open-label period until the first date of IRC-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
PFS was defined as the time from date of randomization until the first date of IRC-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
PFS was defined as the time from date of randomization in the Phase 2 open-label period until the first date of IRC-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
IRC assessed ORR per 2016 IMWG criteria: Percentage of participants who experienced Partial response (PR): greater than or equal to (\>=) 50 percent (%) reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>= 90% or to lesser than (\<) 200 mg per 24 hours; Very good partial response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours; Complete response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and lesser than or equal to (\<=) 5% plasma cells in bone marrow; or stringent complete response (sCR): CR as defined+Normal free light chain (FLC) ratio+Absence of clonal cells in bone marrow biopsy by immunohistochemistry).
Assessed according to the revised response criteria based on the Guidelines of the International Working Group (IWG).
Assessed according to the response assessment of lymphoma based on Lugano classification.
Disease Control Rate (DCR) was defined as the point estimate of the percentage of participants who had complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks, assessed according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants without documented disease progression were censored on the date of last radiologic assessment.
Overall survival was defined as the time (in days) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact.
-All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0
* Morphologic complete remission (CR): neutrophil count \> 1.0 x 109 /L, platelet count ≥ 100 x 109/L, \< 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). * Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be \<1000/mcl or platelet count \<100,000/mcl * Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint.
To determine the maximum tolerated dose for the combination of selinexor and ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia(SLL)/B-cell prolymphocytic leukemia (PLL) or aggressive non-Hodgkin lymphoma (NHL).
To determine the maximum tolerated dose for the combination of selinexor and ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia(SLL)/B-cell prolymphocytic leukemia (PLL) or aggressive non-Hodgkin lymphoma (NHL).
The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 will be used to characterize toxicities.
Types of toxicities, incidences and severity will be summarized by descriptive statistics such as frequencies/proportions.
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Adverse events will be assessed by evaluating Grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
MTD for once weekly and twice weekly selinexor dose cohorts in the 11 Arms will be evaluated.
RP2D for each Arm will be determined.
Cmax of selinexor over a dosing interval when given with and without clarithromycin.
Total exposure of selinexor in the blood (AUC0-last) from the time of dosing to the last measurable concentration collected when given with and without clarithromycin.
ORR for each Arm independently. ORR to include stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), according to the International Myeloma Working Group (IMWG) criteria.
Duration of response for each Arm. DOR is defined as the number of days from the date of the first evidence of objective response until progression.
CBR is defined the point estimate of the percentage of patients in that arm who have a response of sCR, CR, VGPR, PR or Minimal response (MR), as assessed by IMWG criteria.
An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) was defined as an AE that meets one or more of the mentioned criteria; is fatal, life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect, or important medical events. Number of participants with TEAEs and TESAEs were reported.
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A treatment-related AE was any untoward medical occurrence in a clinical investigation participant administered a medicinal product; the event had a causal relationship with the treatment or usage.
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. A treatment related AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage.
Evaluation of DLTs was only conducted in participants who participated in the Dose-escalation Phase. A DLT was defined as any of the following, considered possibly related to drug administration, occurring in the first 28 days (or 21 days for participants on Schedule 8) at the target dose (ie, for Schedule 2 this meant the first 4 weeks after the 12 mg/m2 run-in week): Missed selinexor doses due to drug-related toxicities, discontinuation of a participant due to a toxicity that was at least possibly related to study drug before completing Cycle 1.
The RP2D was the maximum tolerated dose (MTD) or less. MTD was defined as the next lower dose level below the one in which \>1 of 3 participants or ≥2 of 6 participants experienced DLT, provided that dose level was ≤25 percent (%) lower than the highest (intolerable) dose tested. If the projected MTD was \>25% lower than the highest dose tested, then an additional cohort of ≥3 participants was added at a dose that was intermediate between the intolerable dose and the next lower dose.
| Arm | Type | Description |
|---|---|---|
| Selinexor | EXPERIMENTAL | Participants will receive a fixed dose of selinexor 60 milligrams (mg) oral tablets once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle. |
| Placebo | PLACEBO_COMPARATOR | Participants will receive matching placebo for selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle. |
| Phase 1a: Cohort 1: Selinexor 40 mg + Ruxolitinib BID | EXPERIMENTAL | Participants with MF will receive a dose of 40 milligrams (mg) selinexor oral tablets once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib twice a day (BID) based on the participants baseline platelet count. |
| Phase 1a: Cohort 2: Selinexor 60 mg + Ruxolitinib BID | EXPERIMENTAL | Participants with MF will receive a dose of 60 mg selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. |
| Phase 1b: Selinexor and Ruxolitinib BID | EXPERIMENTAL | Participants with MF will receive a dose of 40 or 60 mg selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. |
| Phase 3: Selinexor 60 mg + Ruxolitinib BID | EXPERIMENTAL | Participants with MF will receive a fixed starting dose of 60 mg selinexor (RD) oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with a starting dose of 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. |
| Phase 3: Placebo + Ruxolitinib BID | ACTIVE_COMPARATOR | Participants with MF will receive a matching placebo of selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle in combination with a starting dose of 15 or 20 mg ruxolitinib BID based on the participants baseline platelet count. |
| Matching placebo for selinexor | PLACEBO_COMPARATOR | Participants will receive matching placebo for selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle. |
| SVd Arm: Selinexor + Bortezomib + Dexamethasone | EXPERIMENTAL | Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m\^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study. |
| Vd Arm: Bortezomib + Dexamethasone | EXPERIMENTAL | Participants received SC injection of 1.3 mg/m\^2 bortezomib on Days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles, followed by greater than or equal to (\>=) 9 cycles on Days 1, 8, 15, and 22 of each 35-day cycle, and received oral dose of 20 mg dexamethasone BIW on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for the first 8 cycles and for cycles \>= 9 on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study. |
| SVdX Arm: Selinexor + Bortezomib + Dexamethasone | EXPERIMENTAL | Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m\^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study. |
| SdX Arm: Selinexor + Dexamethasone | EXPERIMENTAL | Participants in the VD arm who had IRC-confirmed PD and were unable to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study. |
| Cohort 1 / Selinexor 40 mg/m^2 in combination with cytarabine and idarubicin | EXPERIMENTAL | All enrolled patients are treated with cytarabine at a dose of 100 mg/m² continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m\^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3. Selinexor is administered at a dose of 40 mg/m\^2 twice weekly orally starting on day 2 (total of 8 doses per induction cycle). |
| Cohort 2 / Selinexor 60 mg flat dose in combination with cytarabine and idarubicin | EXPERIMENTAL | All enrolled patients are treated with cytarabine at a dose of 100 mg/m\^2 continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m\^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3. Selinexor is administered at a flat dose of 60 mg twice weekly orally in weeks 1-3 of a 4-week cycle starting on day 2 (total of 6 doses per induction cycle). |
| Selinexor 60 mg (Arm 1) | EXPERIMENTAL | Participants will receive selinexor 60 milligrams (mg) oral tablets once weekly (QW) (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment. Optional add-on medication dosing may be initiated based on Spleen Volume Reduction (SVR) values at Week 12 or Week 24 of treatment. |
| Selinexor 40 mg (Arm 2) | EXPERIMENTAL | Participants will receive selinexor 40 mg oral tablets QW (Days 1, 8, 15, and 22 of each 28-day cycle) until PD, intolerable toxicity, or until they meet the criteria for discontinuation of study treatment. Optional add-on medication dosing may be initiated based on Spleen Volume Reduction (SVR) values at Week 12 or Week 24 of treatment. |
| Decitabine / Selinexor/ Carboplatin / Paclitaxel | EXPERIMENTAL | C1: Days 1-5: Decitabine 10 mg/m2 IV daily Day 6: carboplatin AUC 5 and paclitaxel 80 mg/ m2 Days 13, 20, and 27: paclitaxel 80 mg/m2 For a single 28 day cycle Assess Response toxicities and immune effector cell changes C2-C6: Days 1-5: Decitabine 10 mg/m2 IV daily Day 6: carboplatin AUC 5 and paclitaxel 80 mg/ m2 Day 7 and weekly thereafter (day 14, 21, 28, 35…) Selinexor 60 mg PO Days 13, 20, and 27: paclitaxel 80 mg/m2 each given x five 28 day cycles Assess responses by exam, CT scan and blood tests, assess toxicities, and immune effector cell changes as well as progression and overall survival |
| Experimental: Treatment | EXPERIMENTAL | Selinexor 40mg weekly for up to 12 cycles. Each cycle will be 28 days in length. |
| XVenD Group | EXPERIMENTAL | Participants will receive XVenD combination therapy of Selinexor (X), Venetoclax (Ven) and Dexamethasone (D) orally during each 28-day cycle. Doses will be administered as follows: * Cycle 1 Days 1 to 7: * Venetoclax 400 mg orally (PO), Days 1-7 * Dexamethasone 40 mg PO, Day 1 * Cycle 1 Days 8 to 28: * Venetoclax 800 mg PO, Days 8-28 * Dexamethasone 40 mg PO, Days 8, 15, and 22 * Cycles 2 to 4: * Selinexor 80 mg PO, Days 1, 8, 15, and 22 * Venetoclax 800 mg PO, Days 1-28 * Dexamethasone 40 mg PO, Days 1, 8, 15, and 22 * Cycle 5 and beyond: * Selinexor 80 mg PO, Days 1, 8, 15, and 22 * Venetoclax 800 mg PO, Days 1-28 * Dexamethasone 20 mg PO, Days 1, 8, 15, and 22 Selinexor dose will be reduced to 60 mg for remaining participants if after the first 6 participants complete the first cycle and 2 or more out of these first 6 participants experience dose-limiting toxicities (DLTs). |
| Arm 1 | EXPERIMENTAL | Treatment Options: Selinexor 60 mg PO days 1, 8, 15 Pomalidomide 4 mg PO on days 1-21 Dexamethasone 40 mg PO or IV on days 1, 8, 15, 22 28 day treatment cycles Selinexor 80 mg PO days 1, 8, 15 Daratumumab 1,800mg/30,000 units subcutaneous injection on days 1, 8, 15, 22 of cycles 1 and 2, days 1, 15 of cycles 3-6, day 1 of cycles \>6 Dexamethasone 40 mg PO or IV days 1, 8, 15, 22 28 day treatment cycle Selinexor 80 mg PO days 1, 8, 15 Carfilzomib IV infusion 20 mg/m2 cycle 1, day 1, 56 mg/m2 cycle 1 day 8, 15. Cycle 2+ days 1, 8, 15. Dexamethasone 40 mg IV or PO days 1, 8, 15, 22 28 day treatment cycle |
| Selinexor plus DRd | EXPERIMENTAL | 1. Lenalidomide 15 mg orally on Days 1-21 of each 28-day cycle 2. Dexamethasone 40 mg on Days 1, 8, 15, 22 of each cycle. However, those \>75 years old may be administered a weekly dose of 20 mg dexamethasone. 3. Daratumumab 1800 mg subcutaneous injection once weekly in Cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter. 4. Selinexor 60 mg on Days 1, 8, 15, of cycles 1-3, with a planned dose-reduction to 40 mg on Days 1, 8, 15 for cycles beyond 3. If patient was previously dose reduced prior to cycle 4, then at cycle 4 planned dose reduction, you will again decrease dose by 1 level. |
| B -selinexor-lenalidomide/bortezomib-dexamethasone | EXPERIMENTAL | Alternating cycles of: Selinexor oral 40mg once weekly Lenalidomide oral 25mg d 1-21 Dexamethasone 20mg d 1+2, 8+9 and 15+16 i 28 days cycles and Selinexor oral 80mg once weekly Bortezomib sc 1.3mg/sqm once weekly Dexamethasone 20mg d 1+2, 8+9 and 15+16 in 28 days cycles for up to 16 cycles (8 of each, alternating) followed by continuos selinexor 40mg(once weekly)-lenalidomide-dexamethasone for up to 16 cycles followed by continuos lenalidomide-dexamethasone |
| Arm S: Selinexor | EXPERIMENTAL | Participants with MF who had previously received at least 6 months of treatment with JAK 1/2 inhibitor will receive a dose of selinexor 80 mg for first 2 cycles followed by selinexor 60 mg once weekly (QW) in subsequent cycles orally on Days 1, 8, 15, and 22 of each 28-day cycle to participants on Arm S. |
| Arm PC: Physician's Choice Treatment | ACTIVE_COMPARATOR | Participants with MF who had previously received at least 6 months of treatment with JAK 1/2 inhibitor will receive Physician's choice treatment which will be administered as per clinical practice. |
| Phase 2: Selinexor 40 mg + R-GDP | EXPERIMENTAL | Patients with RR DLBCL will receive combination therapy of selinexor 40 mg orally at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by single-agent continuous therapy with selinexor 60 mg orally once weekly (QW) for each 28-day cycle until progressive disease (PD) or unacceptable toxicity. |
| Phase 2: Selinexor 60 mg + R-GDP | EXPERIMENTAL | Patients with RR DLBCL will receive combination therapy of selinexor 60 mg orally at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by single-agent continuous therapy with selinexor 60 mg orally QW for each 28-day cycle until PD or unacceptable toxicity. |
| Phase 2: R-GDP | ACTIVE_COMPARATOR | Patients with RR DLBCL will receive R-GDP on specified days (Days 1, 2, 3, 4, and 8) for each 21-day cycle for up to 6 cycles. |
| Phase 3: Selinexor (Selected Dose) + R-GDP followed by Selinexor 60 mg | EXPERIMENTAL | Patients with RR DLBCL will receive combination therapy of selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by selinexor 60 mg orally QW for each 28-day cycle until PD or unacceptable toxicity. |
| Phase 3: Selinexor (Selected Dose) + R-GDP followed by Placebo | EXPERIMENTAL | Patients with RR DLBCL will receive combination therapy of selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by matching placebo for selinexor orally QW for each 28-day cycle until PD or unacceptable toxicity. |
| Phase 3: Placebo + R-GDP followed by Placebo | PLACEBO_COMPARATOR | Patients with RR DLBCL will receive combination therapy of placebo matching for selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by matching placebo for selinexor orally QW for each 28-day cycle until PD or unacceptable toxicity. |
| Selinexor + Low-dose Dexamethasone (Sd-40 BIW) | EXPERIMENTAL | Participants will receive fixed dose of 40 milligram (mg) of Selinexor oral tablet followed by 20 mg of low-dose Dexamethasone oral tablet twice weekly (BIW) on Days 1, 3, 8, 10, 15, 17, 22, and 24 of each 28-day cycle. |
| Selinexor + Low-dose Dexamethasone (Sd-100 QW) | EXPERIMENTAL | Participants will receive fixed dose of 100 mg of Selinexor oral tablet followed by 40 mg of low-dose Dexamethasone oral tablet once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle. (Dexamethasone may be given as 20 mg on days 1 and 2 of each week at the discretion of the treating physician). |
| Selinexor + Low-dose Dexamethasone (Sd-80 BIW) | EXPERIMENTAL | Participants will receive fixed dose of 80 mg of Selinexor oral tablet followed by 20 mg of low-dose Dexamethasone oral tablet BIW on Days 1, 3, 8, 10,15, 17, 22, and 24 of each 28-day cycle. Closed for recruitment. |
| Selinexor + Bortezomib + Dexamethasone (SVd) | EXPERIMENTAL | Participants will receive fixed dose of 100 mg of Selinexor oral tablet on Days 1, 8, 15, 22, and 29 followed by 1.3 milligram per square-meter (mg/m\^2) of Bortezomib subcutaneous (SC) injection on Days 1, 8, 15, and 22 and followed by 40 mg of low-dose Dexamethasone oral tablet on Days 1, 8, 15, 22, and 29 of each 35-day cycle (Dexamethasone dose may be split to 20 mg on days 1 and 2 of each week at the discretion of the treating physician). Closed for recruitment. |
| Selinexor 20 mg | EXPERIMENTAL | Participants will receive 20 milligram (mg) of selinexor oral tablet on Days 1, 3, and 5 of each week for up to 2 weeks (14 days). If the participant is tolerating therapy and clinically benefitting, dosing can continue for an additional 2 weeks (28 days). |
| Phase 2 Double-blinded: Selinexor | EXPERIMENTAL | Participants received a fixed blinding dose of 60 milligrams (mg) selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until progressive disease (PD). |
| Phase 3 Double-blinded: Selinexor | EXPERIMENTAL | Participants received a fixed blinding dose of 60 mg selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until PD. |
| Phase 2 Double-blinded: Placebo Followed by Open Label- Selinexor | PLACEBO_COMPARATOR | Participants received a fixed blinding dose of placebo matched to selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until PD in double-blinded treatment period. Participants in the placebo group who had PD during the Phase 2 double-blinded treatment, will be elected to cross over to open-label selinexor. |
| Phase 3 Double-blinded: Placebo Followed by Open Label- Selinexor | PLACEBO_COMPARATOR | Participants received a fixed blinding dose of placebo matched to selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until PD or development of unacceptable toxicity. Participants in the placebo group who had PD during the Phase 3 double-blinded treatment, will be elected to cross over to open-label selinexor. |
| Part 1 | EXPERIMENTAL | Participants with quad-exposed, double-class-refractory (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, but not an anti-CD38 mab) and penta-exposed, triple-class-refractory multiple myeloma (MM) (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, and refractory to prior treatment with glucocorticoids, an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and the anti-CD38 mAb daratumumab) received, two dosing schedules (1) Selinexor 80 milligrams (mg) plus low-dose dexamethasone 20 mg (Sd) twice-weekly on Days 1 and 3 for 3 weeks of each 4-week cycle (2) Selinexor 80 mg plus low-dose dexamethasone 20 mg (Sd) twice-weekly continuously in 4-week cycles; until disease progression, death, or unacceptable toxicity (maximum duration of approximately 13 months). |
| Part 2 | EXPERIMENTAL | Participants who previously had received more than 3 anti-MM regimens and had penta-exposed, triple class-refractory MM (i.e. previously treated with lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, and refractory to prior treatment with glucocorticoids, an IMiD, a PI, and the anti-CD38 mAb daratumumab) received, Selinexor 80 mg post oral (PO) plus low-dose dexamethasone 20 mg Sd twice-weekly on Days 1 and 3 until disease progression, death, or unacceptable toxicity (maximum duration of approximately 17 months). |
| Part 1: Selinexor 60 mg | EXPERIMENTAL | Participants received fixed dose of 60 mg selinexor orally, twice weekly (BIW) on Days 1 and 3 (e.g., Monday and Wednesday or Tuesday and Thursday, etc.) of Weeks 1-4 of each four week (each cycle of 28 days) cycle (total of 8 doses per cycle). |
| Part 2: Arm A-Selinexor 40 mg | EXPERIMENTAL | Participants received selinexor 40 mg orally BIW on Days 1 and 3 of each week of 4-week treatment cycles (28 days) until disease progression (total of 8 doses per cycle). |
| Part 2: Arm B-Selinexor 60 mg | EXPERIMENTAL | Participants received selinexor 60 mg orally BIW on Days 1 and 3 of each week of 4-week treatment cycles) for 2 cycles (each cycle of 28 days) followed by 60 mg once weekly (QW) in the subsequent cycles until disease progression (total of 8 doses per cycle). |
| Part 1: Cohort A-Ovarian carcinoma: Selinexor up to 60 mg/m^2 BIW | EXPERIMENTAL | Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 50 milligram per meter square (mg/m\^2) of selinexor oral tablets twice weekly (BIW) (doses at least 36 hours apart) with light meal and 120 milliliters (mL) of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 once weekly (QW). This treatment continued until progression of disease (PD) or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. |
| Part 1: Cohort B-Endometrial carcinoma: Selinexor up to 60 mg/m^2 BIW | EXPERIMENTAL | Participants with endometrial carcinoma who had received at least one line of chemotherapy for relapsed or advanced (Stage IVb, IIIc) disease received a dose of 50 mg/m\^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. |
| Part 1: Cohort C-Cervical carcinoma: Selinexor up to 60 mg/m^2 BIW | EXPERIMENTAL | Participants with cervical carcinoma who had received at least one line of chemotherapy for relapsed or advanced (Stage IV) disease received a dose of 50 mg/m\^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. |
| Part 2: Cohort A-Ovarian carcinoma Schedule 1: Selinexor up to 50 mg/m^2 BIW | EXPERIMENTAL | Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 35 mg/m\^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 6 weeks of treatment, a dose of 50 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. |
| Part 2: Cohort A-Ovarian carcinoma Schedule 2: Selinexor up to 60 mg/m^2 QW | EXPERIMENTAL | Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 50 mg/m\^2 of selinexor oral tablets QW (doses at least 5 days apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 6 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets QW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. |
| Selinexor approximately 55 mg/m^2 (60 to 120 mg based on BSA) | EXPERIMENTAL | Participants under protocol versions (PV) less than (\<) 5.0 (those who had one prior line of acute myeloid leukemia (AML) therapy), receive oral selinexor tablets at a dose of approximately 55 mg/m\^2 (milligrams per square meter) (60 to 120 mg based on body surface area \[BSA\]) twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). |
| Selinexor 60 mg (PV <5) (Equivalent to 35 mg/m^2) | EXPERIMENTAL | Participants under PV \< 5.0 (those who had one prior line of AML therapy), receive oral selinexor tablets at a fixed dose of 60 mg (equivalent to 35 mg/m\^2), based on BSA, twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). |
| Selinexor 60 mg (PV >=5) (Equivalent to 35 mg/m^2) | EXPERIMENTAL | Participants under PV \>= 5 (PV 5: those who had at least one prior line of AML therapy, PV 5.1: who had at least two prior line of AML therapy), receive oral selinexor tablets at a dose of 60 mg (equivalent to 35 mg/m\^2) twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). |
| Physician's Choice 1 (PV <5) | ACTIVE_COMPARATOR | Participants under PV \< 5.0 (those who had one prior line of AML therapy) received Best Supportive Care (BSC) which included blood product transfusions, antimicrobials, growth factors as needed, and hydroxyurea. |
| Physician's Choice 2 (PV >=5) | ACTIVE_COMPARATOR | Participants under PV \>= 5 (PV 5: those who had at least one prior line of AML therapy, PV 5.1: who had at least two prior line of AML therapy), received BSC along with subcutaneous injection of arabinoside cytosine (Ara-C), 20 mg, twice daily, for 10 days, repeated at 28 to 42 day intervals. |
| Selinexor + immunochemotherapy | EXPERIMENTAL | Selinexor will be administered orally on Day1, 3, 8 and 10 of each 3-week cycle with an immunochemotherapy, R-DHAOx (Group A: rituximab + dexamethasone + oxaliplatin + cytarabine) or R-GDP (Group B: rituximab + dexamethasone + gemcitabine + cisplatin) for 3 cycles (choice of the immunochemotherapy left at the investigator's decision before patient's inclusion). Different dose levels of selinexor will be examined sequentially in each group: 20 mg flat (DL-1), 40 mg flat (DL1), 60 mg flat (DL2), 80 mg flat (DL3). |
| Phase I Schedule A (selinexor) | EXPERIMENTAL | * Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. * Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). * Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8. * G-CSF will be given 300 mcg SC once daily on Days 3-8. * Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8. * Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. |
| Phase I Schedule B (selinexor) | EXPERIMENTAL | * Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO. * Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). * Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8. * G-CSF will be given 300 mcg SC once daily on Days 3-8. * Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8. * Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. |
| Phase II (selinexor) | EXPERIMENTAL | * Selinexor will be given at the schedule as determined in Phase 1. * Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). * Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8. * G-CSF will be given 300 mcg SC once daily on Days 3-8. * Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8. * Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. |
| Treatment (selinexor, ibrutinib) | EXPERIMENTAL | Patients receive ibrutinib PO on days 8-28 of course 1 and on days 1-28 on subsequent courses and selinexor PO BID weekly on day 1 or bi-weekly on days 1 and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Cohort A (mitoxantrone, etoposide, cytarabine, selinexor) | EXPERIMENTAL | Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity. |
| Cohort B (etoposide, selinexor) | EXPERIMENTAL | Patients receive etoposide PO QD on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving response after 4 courses discontinue treatment; patients achieving response may receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue selinexor as monotherapy at the discretion of the principal investigator. |
| Treatment (selinexor) | EXPERIMENTAL | Patients receive selinexor PO BIW. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Blood will be collected for correlative studies to perform pK (pharmacokinetics) and pDn (pharmacodynamics) analysis pretreatment on day 1 and 8 hours after treatment, on day 1 of cycles 1 and 2. |
| Treatment (decitabine and selinexor) | EXPERIMENTAL | INDUCTION: Patients receive decitabine IV over 1 hour on days 1-10 and selinexor PO on days 11, 13, 18, 20, 25 and 27. Treatment repeats every 31 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive decitabine IV over 1 hour on days 1-5 and selinexor PO on days 6, 8, 13, 15, 20 and 22. Courses repeat every 31 days in the absence of disease progression or unacceptable toxicity. |
| Phase 1: Selinexor, Carfilzomib, Isatuximab, and Dexamethasone | EXPERIMENTAL | Participants will receive selinexor at their assigned dose taken orally on a 28-day cycle combined with carfilzomib, isatuximab, and dexamethasone IV administered on a 28-day cycle until disease progression or for an unacceptable toxicity. |
| Phase 2: Selinexor, Carfilzomib, Isatuximab, and Dexamethasone | EXPERIMENTAL | Participants will receive selinexor at their assigned dose taken orally on a 28-day cycle combined with carfilzomib, isatuximab, and dexamethasone IV administered on a 28-day cycle until disease progression or for an unacceptable toxicity. |
| Monotherapy: Normal Hepatic Function (Selinexor) | EXPERIMENTAL | (Closed for Enrollment) Cohort 1: * Week 1: selinexor 5 x 20-mg tablet daily; * Week 2: selinexor 1 x 100-mg tablet daily Cohort 2: * Week 1: selinexor 1 x 100-mg tablet daily; * Week 2: selinexor 5 x 20-mg tablet daily. |
| Monotherapy: Impaired Hepatic Function (Selinexor) | EXPERIMENTAL | Cohort 3: Patients with Moderate Hepatic Impairment with any Solid Tumors; \- Selinexor 2 x 20-mg tablet once weekly (QW). Cohort 4: Patients with Severe Hepatic Impairment with any Solid Tumors; \- Selinexor 2 x 20-mg tablet QW. |
| Combination Therapy: NSCLC Arm A: (Selinexor + Docetaxel) | EXPERIMENTAL | (Closed for Enrollment) Selinexor 60 mg oral dose QW and docetaxel 75 mg/m\^2 intravenously (IV) once every 3 weeks (Non-small cell lung cancer \[NSCLC\] patients). |
| Combination Therapy: CRC Arm B: (Selinexor + Pembrolizumab) | EXPERIMENTAL | (Closed for Enrollment) Selinexor 80 mg oral does QW and pembrolizumab 200 mg IV every 3 weeks (Colorectal cancer \[CRC\] Patients). |
| Combination Therapy: CRC Arm C: (Selinexor + FOLFIRI) | EXPERIMENTAL | (Closed for Enrollment) Cohort 1: Selinexor 40 mg oral dose Days 1, 3, 15 and 18 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m\^2; leucovorin 400 mg/m\^2; 5- fluorouracil (5-FU) 400 mg/m\^2 bolus then 5-FU 2400 mg/m\^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients). Cohort 2: Selinexor 80 mg oral dose Days 1 and 15 in a 28-day cycle and FOLFIRI (irinotecan 180 mg/m\^2; leucovorin 400 mg/m\^2; 5-FU 400 mg/m\^2 bolus then 5-FU 2400 mg/m\^2 continuous over 46-48 hours; IV on Day 1 and 15 in a 28-day cycle) (CRC Patients). |
| 1: Selinexor, Low-dose Dexamethasone and Pomalidomide (SPd) | EXPERIMENTAL | Each cycle is of 28 days Cohort 1.1: Selinexor (SEL) 60/80/100 mg orally (PO) once weekly (QW); Dexamethasone (DEX) 40 mg PO once weekly; Pomalidomide (POM) 2/3/4 mg PO Days 1-21. Cohort 1.2: SEL 40/60/80 mg PO twice weekly (BIW); DEX 20 mg PO twice weekly; POM 3/4 mg PO Days 1-21. Cohort 1.3: Selinexor, Dexamethasone and Pomalidomide will be dosed at RP2D-1. Cohort 1.4: SEL 40 mg PO QW; DEX 40 mg PO QW; POM 4mg PO once daily (QD) Days 1-21. |
| 2: Selinexor, Low-dose Dexamethasone and Bortezomib (SVd) | EXPERIMENTAL | Each cycle is of 35 days Cohort 2.1: SEL 60/80/100 mg PO once weekly; DEX 40 mg PO once weekly; Bortezomib (BOR) 1.3 milligram per meter square (mg/m\^2) subcutaneous (SC) once weekly. Cohort 2.2: SEL 40/60/80 mg PO twice weekly; DEX 20 mg PO twice weekly; BOR 1.3 mg/m\^2 subcutaneous (SC) once weekly. Cohort 2.3: Selinexor, Dexamethasone and Bortezomib will be dosed at RP2D-2. |
| 3: Selinexor, Low-dose DEX, and Lenalidomide (SRd) in RRMM | EXPERIMENTAL | Each cycle is of 28 days Cohort 3.1: SEL 40/60/80/100 mg PO once weekly; DEX 40 mg PO once weekly; Lenalidomide (LEN) 15/25 mg PO Days 1-21. Cohort 3.2: SEL 40/60/80 mg PO twice weekly; DEX 20 mg PO twice weekly; LEN 15/25 mg PO Days 1-21. Cohort 3.3: Selinexor, Dexamethasone and Lenalidomide will be dosed at RP2D-3. |
| 4:Selinexor, Low-dose dexamethasone, Pomalidomide, Velcade (SPVd) | EXPERIMENTAL | PK Run-in Period: Selinexor and Clarithromycin: * For the first 9 patients enrolled into this dose escalation arm * 14 day run-in period after which patients will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-escalation Phase: * All patients enrolled into this Arm * Each cycle is of 28 days. Cohort 4.1: SEL 40/60 mg PO once weekly; DEX 40 mg PO once weekly; POM 4 mg PO Days 1-21; BOR 1.3 mg/m\^2 subcutaneous (SC) once weekly. Cohort 4.3: Selinexor, Dexamethasone, Pomalidomide, Velcade (Bortezomib) will be dosed at RP2D-4. |
| 5: Selinexor, Low-dose dexamethasone, and Daratumumab (SDd) | EXPERIMENTAL | Each cycle is of 28 days Cohort 5.1: SEL 80/100 mg PO once weekly; DEX 40 mg once weekly (IV or PO); DARA: 16 mg/kg IV infusion Cycle 1-2: Once weekly, Cycle 3-6: Every other week, Cycle 6 and greater: Once a month. Cohort 5.2: SEL: 60 mg PO twice weekly; DEX: 40 mg weekly (IV or PO); DARA: 16 milligram per kilogram (mg/kg) IV infusion Cycle 1-2: Once. weekly, Cycle 3-6: Every other week, Cycle 6 and greater: Once a month. Cohort 5.3: Selinexor, Dexamethasone and Daratumumab will be dosed at RP2D-5. |
| 6: Selinexor, Low-dose dexamethasone, and Carfilzomib (SKd) | EXPERIMENTAL | PK Run-in Period: Selinexor and Clarithromycin: * For the first 9 patients enrolled into this dose escalation arm * 14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-Escalation Phase: * All patients enrolled into this Arm * Each cycle is of 28 days Cohort 6.1: SEL 40/60/80/100 mg PO once weekly on days 1, 8, 15, and 22; DEX 40 mg IV or PO once weekly; Carfilzomib (CAR) 56 or 70 mg/m\^2 IV infusion once weekly on days 1, 8, and 15. Cohort 6.2: SEL 60/80/100 mg PO once weekly on days 1, 8, and 15; DEX 40 mg IV or PO once weekly; CAR 56 or 70 mg/m\^2 IV infusion once weekly on days 1, 8, and 15. Cohort 6.3: Selinexor, Dexamethasone and Carfilzomib will be dosed at RP2D-6. |
| 7: Selinexor, Low-dose DEX and Lenalidomide (SRd) in NDMM | EXPERIMENTAL | Each cycle is of 28 days Cohort 7.1: SEL 40/60/80 mg PO once weekly; DEX 40 mg PO once weekly; LEN 25 mg PO Days 1-21. Cohort 7.3: Selinexor, Dexamethasone and Lenalidomide will be dosed at RP2D-7. |
| 8: Selinexor, Low-dose dexamethasone, and Ixazomib (SNd) | EXPERIMENTAL | PK Run-in Period: Selinexor \& Clarithromycin: * For the first 9 patients enrolled into this dose escalation arm * 14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-Escalation Phase: * All patients enrolled into this Arm * Each cycle is of 28 days Cohort 8.1: SEL 40/60/80/100 mg PO once weekly; DEX 20 mg PO twice weekly; IXA 3/4 mg PO once weekly. Cohort 8.3: Selinexor, Dexamethasone and Ixazomib will be dosed at RP2D-8. |
| 9: Selinexor, Low-dose DEX, Pomalidomide and Elotuzumab (SPEd) | EXPERIMENTAL | PK Run-in Period: Selinexor and Clarithromycin: * For the first 9 patients enrolled into this dose escalation arm * 14 day run-in period after which patient will proceed to Dose-Escalation Phase C1D1 Selinexor 40 mg will be dosed on Days 1 and 8. Clarithromycin 500 mg will be dosed twice daily on Days 2-8. PK samples will be collected on Days 1 and 8 at 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours post dose. Dose-Escalation Phase: * All patients enrolled into this Arm * Each cycle is of 28 days Cohort 9.1: SEL 20/40/60 mg PO once weekly; DEX 28/20 mg PO twice weekly; POM 4 mg PO QD Days 1-21; Elotuzumab (ELO) 10/20 mg/kg IV will be given once weekly on Days 1,8, 15 and 22 of Cycles 1-2. Starting on Cycle 3 and continuing for future cycles, elotuzumab will be dosed at 20 mg/kg on Day 1 of each cycle only. Cohort 9.3: Selinexor, Dexamethasone, Pomalidomide and Elotuzumab will be dosed at RP2D-9. |
| 10. Selinexor, Dexamethasone, and Belantamab Mafodotin (SBd) | EXPERIMENTAL | Each cycle is of 21 days Cohort 10.1: SEL 40/60/80 mg PO once weekly on Days 1, 8, and 15; DEX 40 mg PO QW on Days 1, 8, and 15; Belantamab Mafodotin (BEL) 2.5 mg/kg IV infusion every 3 weeks (Q3W) Day 1 of each cycle. Cohort 10.3: Selinexor, Dexamethasone, and Belantamab Mafodotin will be dosed at RP2D-10. |
| 11. Selinexor, Dexamethasone, Pomalidomide, and Daratumumab (SDPd) | EXPERIMENTAL | Each Cycle is of 28 days Cohort 11.1 SEL 40/60 mg PO once weekly on Days 1, 8, and 15; DEX total 40 mg weekly (IV or PO) single or divided doses on Days 1, 8, 15, and 22; POM 4 mg PO QW Days 1-21; DARA 16 mg/kg IV or SC QW on Days 1, 8, 15 and 22 of Cycles 1-2 and on Days 1 and 15 of Cycles 3-6, Day 1 of every Cycle greater than (\>6). Cohort 11.3 Selinexor, Dexamethasone, Pomalidomide, and Daratumumab will be dosed at RP2D-11. |
| 12. Selinexor + dexamethasone + mezigdomide (SMd) | EXPERIMENTAL | The dose of selinexor will be formally escalated from 40 mg QW to 60 mg QW in combination with mezigdomide 0.6 mg daily. Mezigdomide dosing may be de-escalated as per 3+3 criteria to 0.3 mg or escalated to 1.0 mg. The dose level that passes DLT evaluation will be considered the MTD for the cohort. |
| Arm A (Colorectal Cancer) | EXPERIMENTAL | Participants with colorectal cancer and liver metastasis received oral selinexor as single agent in 8 schedules, Schedule1: ≤12milligrams per meter square(mg/m\^2) 3 times weekly(TIW) during Weeks 1 and 3, twice weekly(BIW) during Weeks 2 and 4 up to 10 doses/cycle(28 days/cycle); Schedule2: \>12mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle(28 days/cycle); Schedule3: ≥30mg/m\^2 BIW(Days 1 and 3) up to 8 doses/cycle(28 days/cycle); Schedule4: ≥20mg/m\^2 BIW(Days 1 and 2) up to 8 doses/cycle(28 days/cycle); Schedule5: ≥35mg/m\^2 BIW(Days 1 and 4) up to 8 doses(28 days/cycle); Schedule6: ≥20mg/m\^2 BIW(Days 1 and 4) after 500 mg(Week 1) to 1000 mg(Week 2 onwards) acetaminophen(given 1 hour prior to each selinexor dose) up to 8 doses/cycle (28 days/cycle); Schedule7: ≥50mg/m\^2 once weekly(QW) up to 4 doses/cycle(28 days per cycle); Schedule8: ≥45mg/m\^2 BIW(Days 1 and 3) up to 4 doses/cycle(21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Arm B (Gynecological Cancer) | EXPERIMENTAL | Participants with gynecological cancer received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Arm C (Squamous Cell Cancer) | EXPERIMENTAL | Participants with squamous cell cancer received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Arm D (Castrate-resistant Prostate Cancer) | EXPERIMENTAL | Participants with castrate-resistant prostate cancer (CRPC) received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Arm E (Glioblastoma Multiforme) | EXPERIMENTAL | Participants with glioblastoma multiforme (GBM) received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Arm F (Melanoma) | EXPERIMENTAL | Participants with Melanoma received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Arm G (Other Solid Tumors) | EXPERIMENTAL | Participants with other solid tumors received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. |
| Name | Type | Description |
|---|---|---|
| Selinexor | DRUG | Dose: 60 mg (3 tablets); Dosage form: film-coated, immediate-release tablet of 20 mg each; Route of administration: oral |
| Matching Placebo for selinexor | DRUG | Dose:60 mg (3 tablets); Dosage form: film-coated, immediate-release tablet of 20 mg each; Route of administration: oral |
| Placebo | OTHER | Participants will receive a matching placebo of selinexor oral tablets QW |
| Ruxolitinib | DRUG | Participants will receive a dose of 15 or 20 mg ruxolitinib oral tablets BID. |
| Bortezomib | DRUG | subcutaneous dose of 1.3 mg/m2 |
| Dexamethasone | DRUG | oral dose of 20mg |
| Idarubicin | DRUG | Infusion, iv, 10 mg/m\^2, on days 1,3,5 in cycle 1, on days 1,3 in cycle 2 |
| Cytarabine | DRUG | Continuous infusion day 1 to 7, 100 mg/m\^2, iv, |
| Selinexor 60 mg | DRUG | Participants will receive selinexor 60 mg oral tablets QW. |
| Selinexor 40 mg | DRUG | Participants will receive selinexor 40 mg oral tablets QW. |
| Pacritinib | DRUG | Participants will receive pacritinib per local package insert. For countries where not approved, 200 mg twice daily is the starting dose. |
| Momelotinib | DRUG | Participants will receive momelotinib per local package insert. |
| Decitabine | DRUG | Decitabine is classified as hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. |
| Carboplatin | DRUG | Carboplatin is classified as an alkylating agent that is used to treat ovarian cancer. |
| Paclitaxel | DRUG | Paclitaxel is classified as a "plant alkaloid," a "taxane" and an "antimicrotubule agent." |
| Venetoclax | DRUG | Venetoclax tablets will be administered orally (PO) once per day at assigned dosage and frequency per protocol. |
| Pomalidomide | DRUG | Oral Table |
| Daratumumab | DRUG | Injection |
| Carfilzomib | DRUG | Injection |
| Dexamethasone Oral | DRUG | Dexamethasone 40 mg on Days 1, 8, 15, 22 of each cycle. However, those \>75 years old may be administered a weekly dose of 20 mg dexamethasone. |
| Lenalidomide | DRUG | Patients will receive a 21-day supply of lenalidomide (15 mg) as oral capsules, as appropriate, for each 28-day treatment cycle |
| Selinexor 20 MG Oral Tablet | DRUG | Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone |
| Bortezomib Injection | DRUG | Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone |
| Lenalidomide capsule | DRUG | Comparing an alternating regimen of selinexor-lenalidomide/bortezomib-dexamethasone to standard bortezomib-lenalidomide-dexamethasone |
| Physician's Choice Treatment | OTHER | Physician's choice treatment may include ruxolitinib retreatment, fedratinib, chemotherapy (e.g., hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, immunomodulatory agent, androgen, interferon (all as per clinical practice) and may include supportive care only with no MF treatment; no investigational therapies are allowed. |
| Selinexor (combination therapy) | DRUG | Dose: 40 mg 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) | DRUG | 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) | DRUG | Dose: 375 milligram per meter square (mg/m\^2) on Day 1; Route of administration: intravenous (IV) |
| Gemcitabine (combination therapy) | DRUG | Dose: 1000 mg/m\^2 on Days 1 and 8; Route of administration: IV |
| Dexamethasone (combination therapy) | DRUG | 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) | DRUG | Dose: 75 mg/m\^2 on Day 1; Route of administration: IV |
| Selinexor (continuous therapy) | DRUG | Dose: 60 mg QW for each 28-day cycle until PD; Route of administration: oral |
| Placebo matching for Selinexor (continuous therapy) | DRUG | Dose: Placebo matching for 60 mg selinexor QW for each 28-day cycle until PD; Route of administration: oral |
| Hydroxyurea | DRUG | - |
| Ara-C | DRUG | Ara-C Subcutaneous Injection. |
| Rituximab | DRUG | - |
| Oxaliplatin | DRUG | - |
| Cisplatin | DRUG | - |
| Gemcitabine | DRUG | - |
| Cladribine | DRUG | - |
| G-CSF | DRUG | - |
| Bone marrow biopsy | PROCEDURE | - |
| Ibrutinib | DRUG | Given PO |
| Pharmacological Study | OTHER | Correlative studies |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| mitoxantrone hydrochloride | DRUG | Given IV |
| etoposide | DRUG | Given IV and PO |
| Correlative studies | OTHER | Blood will be collected for pK and pDn analysis pretreatment on day 1 and 8 hours after treatment, on day 1 of cycles 1 and 2. |
| Isatuximab | DRUG | Phase I and Phase II: Isatuximab 1400mg will be administered by injection from the wearable device. For the first 28 days isatuximab will be administered on days 1, 8, 15, and 22. For every cycle after isatuximab will be administered on days 1 and 15. |
| Isatuximab SC Wearable Injection System | DEVICE | Phase I and Phase II: Isatuximab 1400mg will be administered by injection from the wearable device. For the first 28 days isatuximab will be administered on days 1, 8, 15, and 22. For every cycle after isatuximab will be administered on days 1 and 15. |
| Selinexor 100 mg | DRUG | 100-mg 2 formulations: * 5 × 20-mg tablets (Tablet A) * 1 × 100-mg tablet (Tablet B) |
| Docetaxel | DRUG | 75 mg/m\^2 IV |
| Pembrolizumab | DRUG | 200 mg IV |
| FOLFIRI | DRUG | FOLFIRI: * Irinotecan 180 mg/m\^2 * Leucovorin 400 mg/m\^2 * 5-FU 400 mg/m\^2 bolus * 5-FU 2400 mg/m\^2 IV |
| Selinexor 80 mg | DRUG | \- 4 × 20-mg tablets (Tablet A) |
| Ixazomib | DRUG | Oral capsule |
| Elotuzumab | DRUG | Intravenous infusion |
| Clarithromycin | DRUG | Tablets |
| Belantamab Mafodotin | DRUG | Intravenous infusion |
| Mezigdomide | DRUG | Oral Capsules |
| Acetaminophen | DRUG | Oral 500 mg (in Cycle 1, Week 1) to 1000 mg (in Cycle 1, Week 2 and onwards) of acetaminophen will be administered 1 hour prior to each selinexor dose up to 8 doses per cycle (28 days per cycle) |
Inclusion Criteria: Patients must meet all of the following inclusion criteria in order to be eligible to participate in this study: * Adults (Aged ≥ 18 years) * Histologically confirmed endometrial cancer (endometrioid, serous, undifferentiated, or carcinosarcoma sub-types) that is TP53 wild type ...