XPOVIO- selinexor_tablet, film coated

In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leads to accumulation of TSPs in the nucleus and reductions in several oncoproteins, such as c-myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells. Selinexor demonstrated pro-apoptotic activity in vitro in multiple myeloma cells and showed anti-tumor activity in murine xenograft models of multiple myeloma and diffuse large B cell lymphoma. The combination of selinexor and dexamethasone or bortezomib demonstrated synergistic cytotoxic effects in multiple myeloma in vitro and increased anti-tumor activity in murine xenograft multiple myeloma models in vivo, including those resistant to proteasome inhibitors. An increase in selinexor exposure was associated with an increase in the probability of dose modification and some adverse reactions. Cardiac Electrophysiology The effect of multiple doses of XPOVIO, up to 175 mg per dose (1. 75 times the maximum approved recommended dose), on the QTc interval was evaluated in patients with heavily pretreated hematologic malignancies. XPOVIO had no large effect (i. no greater than 20 ms) on QTc interval at the therapeutic dose level. Selinexor C max 2 2 2 max 0-INF Table 10 Table 10: Selinexor C max Mean (XD) XPOVIO Dose 60 mg 80 mg 100 mg C max 442 (188) 680 (124) 693 (201) AUC 0-INF 4,096 (1,185) 5,386 (1,116) 6,998 (818) Absorption The C max Effect of Food Concomitant administration of a high-fat meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) did not affect the pharmacokinetics of selinexor to a clinically significant extent. Distribution The apparent volume of distribution of selinexor is 133 L in patients with cancer. The protein binding of selinexor is 95%. Elimination Following a single dose of XPOVIO, the mean half-life is 6 to 8 hours. The apparent total clearance of selinexor is 18. 6 L/h in patients with cancer. Metabolism Selinexor is metabolized by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione Stransferases (GSTs). Specific Populations No clinically significant differences in the pharmacokinetics of selinexor were observed based on age (18 to 94 years old), sex, body weight (36 to 168 kg), ethnicity, mild to severe renal impairment (CL CR CR Drug Interaction Studies Clinical Studies Acetaminophen: Clarithromycin (a strong CYP3A4 inhibitor): In vitro Studies CYP Enzymes: Non-CYP Enzyme Systems Transporter Systems: Selinexor is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.

XPOVIO is a nuclear export inhibitor indicated: In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy ( 1. 1 In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody ( 1. 1 For the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s) ( 1. 2 XPOVIO in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. XPOVIO in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. XPOVIO is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. This indication is approved under accelerated approval based on response rate [see Clinical Studies ( 14.

DOSAGE AND ADMINISTRATION
Multiple Myeloma in Combination with Bortezomib and Dexamethasone (XVd): 2. 1 Multiple Myeloma in Combination with Dexamethasone (Xd): 2. 2 In Combination with Bortezomib and Dexamethasone (XVd) The recommended dosage of XPOVIO is 100 mg taken orally once weekly on Day 1 of each week until disease progression or unacceptable toxicity in combination with: Bortezomib 1. 3 mg/m 2 Dexamethasone 20 mg taken orally twice weekly on Days 1 and 2 of each week. Refer to Clinical Studies ( 14. 1 In Combination with Dexamethasone (Xd) The recommended dosage of XPOVIO is 80 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity in combination with dexamethasone 20 mg taken orally with each dose of XPOVIO on Days 1 and 3 of each week. For additional information regarding the administration of dexamethasone, refer to its prescribing information. The recommended dosage of XPOVIO is 60 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity. Monitor complete blood count (CBC) with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated. Monitor more frequently during the first three months of treatment [see Warning and Precautions ( 5. 4 [see Dosage and Administration ( 2. 5 Advise patients to maintain adequate fluid and caloric intake throughout treatment. Consider intravenous hydration for patients at risk of dehydration [see Warnings and Precautions ( 5. 4 Provide prophylactic antiemetics. Administer a 5-HT3 receptor antagonist and other anti-nausea agents prior to and during treatment with XPOVIO [see Warnings and Precautions ( 5. 3 Recommended XPOVIO dosage reduction steps are presented in Table 1 Table 1: XPOVIO Dosage Reduction Steps for Adverse Reactions Recommended Starting Dosage Multiple Myeloma In Combination with Bortezomib and Dexamethasone (XVd) Multiple Myeloma In Combination with Dexamethasone (Xd) Diffuse Large B-Cell Lymphoma 100 mg once weekly 80 mg Days 1 and 3 of each week 60 mg Days 1 and 3 of each week First Reduction 80 mg once weekly 100 mg once weekly 40 mg Days 1 and 3 of each week Second Reduction 60 mg once weekly 80 mg once weekly 60 mg once weekly Third Reduction 40 mg once weekly 60 mg once weekly 40 mg once weekly Fourth Reduction Permanently discontinue Permanently discontinue Permanently discontinue Recommended dosage modifications for hematologic adverse reactions in patients with multiple myeloma and DLBCL are presented in Table 2 Table 3 Table 4 Table 2: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Multiple Myeloma Adverse Reaction Occurrence Action Thrombocytopenia [see Warning and Precautions ( 5. 1 Platelet count 25,000 to less than 75,000/mcL Any Reduce XPOVIO by 1 dose level (see Table 1 Platelet count 25,000 to less than 75,000/mcL with Any Interrupt XPOVIO. Restart XPOVIO at 1 dose level lower (see Table 1 Administer platelet transfusions per clinical guidelines. Platelet count less than 25,000/mcL Any Interrupt XPOVIO. Monitor until platelet count returns to at least 50,000/mcL. Restart XPOVIO at 1 dose level lower (see Table 1 Adverse Reaction Occurrence Action Neutropenia [see Warning and Precautions ( 5. 2 Absolute neutrophil count of 0. 5 to 1 x 10 9 Any Reduce XPOVIO by 1 dose level (see Table 1 Absolute neutrophil count less than 0. 5 x 10 9 OR Any Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 10 9 Restart XPOVIO at 1 dose level lower (see Table 1 Anemia Hemoglobin less than 8 g/dL Any Reduce XPOVIO by 1 dose level (see Table 1 Administer blood transfusions per clinical guidelines. Life-threatening consequences Any Interrupt XPOVIO. Monitor hemoglobin until levels return to 8 g/dL or higher. Restart XPOVIO at 1 dose level lower (see Table 1 Administer blood transfusions per clinical guidelines. Table 3: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Diffuse Large B-Cell Lymphoma Adverse Reaction Occurrence Action Thrombocytopenia [see Warning and Precautions ( 5. 1 Platelet count 50,000 to less than 75,000/mcL Any Interrupt one dose of XPOVIO. Restart XPOVIO at the same dose level. Platelet count 25,000 to less than 50,000/mcL without 1st Interrupt XPOVIO. Reduce XPOVIO by 1 dose level (see Table 1 Platelet count 25,000 to less than 50,000/mcL with Any Interrupt XPOVIO. Neutropenia [see Warning and Precautions ( 5. 5 to less than 1 x 10 9 1st occurrence Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 10 9 Restart XPOVIO at the same dose level. Recurrence Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 10 9 Administer growth factors per clinical guidelines. Restart XPOVIO at 1 dose level lower (see Table 1 Absolute neutrophil count less than 0. Restart XPOVIO at 1 dose level lower (see Table 1 Anemia Hemoglobin less than 8 g/dL Any Reduce XPOVIO by 1 dose level (see Table 1 Administer blood transfusions per clinical guidelines. Table 4: XPOVIO Dosage Modification Guidelines for Non-Hematologic Adverse Reactions Adverse Reaction Occurrence Action Nausea and Vomiting [see Warning and Precautions ( 5. 3 Grade 1 or 2 nausea (oral intake decreased without significant weight loss, OR Any Maintain XPOVIO and initiate additional anti-nausea medications. Grade 3 nausea (inadequate oral caloric or fluid intake) OR Any Interrupt XPOVIO. Monitor until nausea or vomiting has resolved to Grade 2 or lower or baseline. Initiate additional anti-nausea medications. Restart XPOVIO at 1 dose level lower (see Table 1 Diarrhea [see Warning and Precautions ( 5. 3 Grade 2 (increase of 4 to 6 stools per day over baseline) 1 st Maintain XPOVIO and institute supportive care. 2 nd Reduce XPOVIO by 1 dose level (see Table 1 Institute supportive care. Grade 3 or higher (increase of 7 stools or more per day over baseline; hospitalization indicated) Any Interrupt XPOVIO and institute supportive care. Monitor until diarrhea resolves to Grade 2 or lower. Restart XPOVIO at 1 dose level lower (see Table 1 Weight Loss and Anorexia [see Warning and Precautions ( 5. 3 Weight loss of 10% to less than 20% OR Any Interrupt XPOVIO and institute supportive care. Monitor until weight returns to more than 90% of baseline weight. Restart XPOVIO at 1 dose level lower (see Table 1 Hyponatremia [see Warning and Precautions ( 5. 4 Sodium level 130 mmol/L or less Any Interrupt XPOVIO, evaluate, and provide supportive care. Monitor until sodium levels return to greater than 130 mmol/L. Restart XPOVIO at 1 dose level lower (see Table 1 Fatigue Grade 2 lasting greater than 7 days OR Any Interrupt XPOVIO. Monitor until fatigue resolves to Grade 1 or baseline. Restart XPOVIO at 1 dose level lower (see Table 1 Ocular Toxicity [see Warning and Precautions ( 5. 8 Grade 2, excluding cataract Any Perform ophthalmologic evaluation. Interrupt XPOVIO and provide supportive care. Monitor until ocular symptoms resolve to Grade 1 or baseline. Restart XPOVIO at 1 dose level lower (see Table 1 Grade >=3, excluding cataract Any Permanently discontinue XPOVIO. Perform ophthalmologic evaluation. Other Non-Hematologic Adverse Reactions [see Warning and Precautions ( 5. 6 Grade 3 or 4 Any Interrupt XPOVIO. Monitor until resolved to Grade 2 or lower; restart XPOVIO at 1 dose level lower (see Table 1 Each XPOVIO dose should be taken at approximately the same time of day and each tablet should be swallowed whole with water. Do not break, chew, crush, or divide the tablets. If a dose of XPOVIO is missed or delayed, instruct patients to take their next dose at the next regularly scheduled time. If a patient vomits a dose of XPOVIO, the patient should not repeat the dose and the patient should take the next dose on the next regularly scheduled day.
Principal Display Panel – 60 mg (Twice Weekly) Blister Pack Label
XPO registered 60 mg Push tablets Swallow IMPORTANT: Take each dose as prescribed by your physician. Take only one 60 mg dose in a single day. Take one 60 mg dose on Day 1 and one 60 mg dose on Day 3 of the week. Refer to Prescribing Information for dosing instructions. Principal Display Panel en dash 60 mg (Twice Weekly) Blister Pack Label.
Principal Display Panel – 40 mg (Twice Weekly) Blister Pack Label
XPO registered 40 40 mg IMPORTANT Take only one 40 mg dose in a single day. Take one 40 mg dose on Day 1 and one 40 mg dose on Day 3 of the week. Refer to Prescribing Information for dosing instructions. Push tablet through foil. Swallow whole with water. Principal Display Panel en dash 40 mg (Twice Weekly) Blister Pack Label.

The following clinically significant adverse reactions are described in detail in other labeling sections: Thrombocytopenia [see Warnings and Precautions ( 5. 1 Neutropenia [see Warnings and Precautions ( 5. 2 Gastrointestinal Toxicity [see Warnings and Precautions ( 5. 3 Hyponatremia [see Warnings and Precautions ( 5. 4 Serious Infection [see Warnings and Precautions ( 5. 5 Neurological Toxicity [see Warnings and Precautions ( 5. 6 Cataract [see Warnings and Precautions ( 5. 8 The most common adverse reactions (>=20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight decreased, cataract, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia ( 6. 1 The most common adverse reactions (>=20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, weight decreased, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection ( 6. 1 The most common adverse reactions (incidence >=20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, decreased appetite, weight decreased, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities (>=15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Multiple Myeloma XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) The safety of XPOVIO in combination with bortezomib and dexamethasone was evaluated in BOSTON [see Clinical Studies ( 14. 1 Serious adverse reactions occurred in 52% of patients who received XPOVIO in combination with bortezomib and dexamethasone. Serious adverse reactions in >3% of patients included pneumonia (14%), sepsis, diarrhea and vomiting (4% each). Fatal adverse reactions occurred in 6% of patients within 30 days of last treatment, including pneumonia (n=3) and sepsis (n=3). Grade >=2 peripheral neuropathy, a pre-specified key secondary endpoint, was lower in the XVd arm (21%) compared to the Vd arm (34%); odds ratio 0. 50 [95% CI: 0. The median treatment duration was 30 weeks (range: 1-120 weeks) in patients who received once weekly XVd as compared to 32 weeks (range: 1-122 weeks) in patients who received twice weekly Vd. Permanent discontinuation of XPOVIO due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation of XPOVIO in >2% of patients included fatigue (3. 6%), nausea (3. 1%), thrombocytopenia, decreased appetite, peripheral neuropathy, and vomiting (2. Dosage interruptions of XPOVIO due to an adverse reaction occurred in 83% of patients. Adverse reactions which required dosage interruption in >5% of patients included thrombocytopenia (33%), fatigue (13%), asthenia (12%), pneumonia (11%), upper respiratory tract infection (10%), decreased appetite (9%), neutropenia (8%), pyrexia (8%), nausea (7%), bronchitis (7%), diarrhea (6%), weight decreased (6%), and anemia (5%). Dose reductions of XPOVIO due to an adverse reaction occurred in 64% of patients. Adverse reactions which required dose reductions in >5% of patients included thrombocytopenia (31%), decreased appetite (8%), nausea, fatigue, weight decreased (7% each), and asthenia (6%). The most common adverse reactions (>=20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight decreased, cataract, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia. Table 5 Table 5: Adverse Reactions (>=10%) in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) with a Difference Between Arms of >5% Compared to Vd in BOSTON Key: X=XPOVIO, Vd=bortezomib-dexamethasone a. Fatigue includes fatigue and asthenia. Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, polyneuropathy, peripheral sensorimotor neuropathy, toxic neuropathy, and peripheral motor neuropathy. Upper respiratory tract infection includes upper respiratory infection, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, and viral upper respiratory tract infection. Vision blurred includes blurred vision, visual acuity reduced, and visual impairment. Adverse Reaction Weekly XVd (n=195) Twice Weekly Vd (n=204) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Diarrhea 32 6 25 <1 Vomiting 21 4. 4 0 General Conditions a Pyrexia 15 1. 5 11 1 Metabolism and Nutrition Weight decreased 26 2. 1 12 1 Nervous System b Dizziness 12 <1 3. 9 0 Infections c Eye Disorders Vision blurred d 13 <1 6 0 Clinically relevant adverse reactions in <10% of patients who received XPOVIO in combination with bortezomib and dexamethasone included: Neurologic disorders: Table 6 Table 6: Select Laboratory Abnormalities (>=15%) That Worsened from Baseline in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) in BOSTON The denominator used to calculate the rate varied from 91 to 201 based on the number of patients with at least one post-treatment value. Includes one fatal anemia. Laboratory Abnormality Weekly XVd Twice Weekly Vd All Grades Grade 3 or 4 All Grades Grade 3 or 4 Hematologic Lymphocyte count decrease 77 38 70 27 Hemoglobin decrease 71 17 51 a 12 Neutrophil count decrease 48 12 19 7 Chemistry Phosphate decrease 61 23 42 11 Sodium decrease 58 14 25 3 Calcium decrease 55 2. 1 47 1 Blood urea nitrogen increase 41 5 40 5 Creatinine increase 28 3. 5 Potassium decrease 27 6 22 3. 5 Magnesium decrease 27 <1 23 1. 5 Potassium increase 18 4. 5 Hepatic Albumin decrease 27 <1 35 <1 AST increase 24 1. 5 19 <1 Bilirubin increase 16 1 13 2 ALP increase 12 0 16 <1 XPOVIO in Combination with Dexamethasone (Xd) The safety of XPOVIO in combination with dexamethasone was evaluated in STORM [see Clinical Studies ( 14. 1 Fatal adverse reactions occurred in 9% of XPOVIO treated patients. Serious adverse reactions occurred in 58% of patients. The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65% had the dose of XPOVIO interrupted. Thrombocytopenia was the leading cause of dose modification, resulting in dose reduction and/or interruption in >25% of patients. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. Table 7 Table 7: Adverse Reactions (>=10%) in Patients Who Received XPOVIO in STORM a. Thrombocytopenia includes thrombocytopenia and platelet count decreased. Anemia includes anemia and hematocrit decreased. Neutropenia includes neutropenia and neutrophil count decreased. Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest. Upper respiratory tract infection includes upper respiratory tract infection, respiratory tract infection, pharyngitis, nasopharyngitis, bronchitis, bronchiolitis, respiratory syncytial virus infection, parainfluenza virus infection, rhinitis, rhinovirus infection, and adenovirus infection. Cough includes cough, productive cough, and upper-airway cough syndrome. Mental status changes includes mental status changes, confusional state, and delirium. Hypercreatininemia includes hypercreatininemia and hypercreatinemia. Pneumonia includes pneumonia, atypical pneumonia, lung infection, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia influenzal, and pneumonia viral. Includes fatal event. Adverse Reaction XPOVIO 80 mg twice weekly + Dexamethasone (n=202) All Grades Grades >=3 Thrombocytopenia a 74 61 Fatigue b 73 22 Nausea 72 9 Anemia c 59 40 Decreased appetite 53 4. 5 Weight decreased 47 0. 5 Diarrhea 44 6 Vomiting 41 3. 5 Hyponatremia 39 22 Neutropenia d 34 21 Leukopenia 28 11 Constipation 25 1. 5 Dyspnea e 24 3. 5 k Upper respiratory tract infection f 21 3 Cough g 16 0 Mental status changes h 16 7 Pyrexia 16 0. 5 Hyperglycemia 15 7 Dizziness 15 0 Insomnia 15 2 Lymphopenia 15 10 Dehydration 14 3. 5 Hypercreatininemia i 14 2 Pneumonia j 13 9 k Epistaxis 12 0. 5 Hypokalemia 12 3. 5 Dysgeusia 11 0 Vision blurred 10 0. 5 Headache 10 0 Diffuse Large B-Cell Lymphoma The safety of XPOVIO was evaluated in SADAL [see Clinical Studies ( 14. 2 Fatal adverse reactions occurred in 3. 7% of patients within 30 days and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reaction was infection (4. 5% of patients). Serious adverse reactions occurred in 46% of patients who received XPOVIO; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients who received XPOVIO. Adverse reactions which results in discontinuation in >=2% of patients included: infection, fatigue, thrombocytopenia, and nausea. Adverse reactions led to XPOVIO dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having 2 or more dose reductions. The median time to first dose modification (reduction or interruption) was 4 weeks, with the leading causes being thrombocytopenia (40% of all patients), neutropenia (16%), fatigue (16%), nausea (10%), and anemia (10%). The median time to first dose reduction was 6 weeks, with 83% of first dose reductions occurring within the first 3 months. The most common adverse reactions, excluding laboratory abnormalities, in >=20% of patients were fatigue, nausea, diarrhea, decreased appetite, weight decreased, constipation, vomiting, and pyrexia. Table 8 Table 8: Adverse Reactions (>=10%), Excluding Laboratory Terms, in Patients with DLBCL Who Received XPOVIO in SADAL a. Edema includes edema, swelling, swelling face, edema peripheral, peripheral swelling, acute pulmonary edema. Diarrhea includes diarrhea, post-procedural diarrhea, gastroenteritis. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. Decreased appetite includes decreased appetite and hypophagia. Cough includes cough and productive cough. Dyspnea includes dyspnea and dyspnea exertional. Upper respiratory tract infection includes upper respiratory tract infection, sinusitis, nasopharyngitis, pharyngitis, rhinitis, viral upper respiratory infection. Urinary tract infection includes urinary tract infection and specific types of urinary tract infection. Dizziness includes dizziness and vertigo. Taste disorder includes taste disorder, dysgeusia, ageusia. Mental status changes include confusional state, amnesia, cognitive disorder, hallucination, delirium, somnolence, depressed level of consciousness, memory impairment. Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, sensory disturbance, paresthesia, neuralgia. Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, pain in extremity, bone pain. Hemorrhage includes hemorrhage, hematoma, hematuria, epistaxis, rectal hemorrhage, injection site hematoma, subdural hematoma, upper gastrointestinal hemorrhage, corneal bleeding. Vision blurred includes vision blurred, visual acuity reduced, visual impairment. Adverse Reaction XPOVIO 60 mg twice weekly (n=134) All Grades Grade 3 or 4 General Conditions a Pyrexia 22 4. 5 Edema b 17 2. 2 Gastrointestinal Diarrhea c 37 3. 0 Constipation 29 0 Vomiting 28 1. 5 Abdominal pain d 10 0 Adverse Reaction XPOVIO 60 mg twice weekly (n=134) All Grades (%) Grade 3 or 4 (%) Metabolism and Nutrition e Weight decreased 30 0 Respiratory f Dyspnea g 10 1. 5 Infections h Pneumonia 10 6 Urinary tract infection i 10 3 Nervous System j Taste disorder k 13 0 Mental status changes l 11 3. 7 Peripheral neuropathy, sensory m 10 0 Musculoskeletal n Vascular Hemorrhage o 10 0. 7 Eye Disorders p Clinically relevant adverse reactions in <10% of patients who received XPOVIO included: Injury: Metabolic and nutrition disorders: dehydration (7%) Neurologic disorders: Infection: Eye disorders: Blood and lymphatic disorders: febrile neutropenia (3%) Cardiac disorders: Table 9 Table 9: Select Laboratory Abnormalities (>=15%) Worsening from Baseline in Patients with DLBCL Who Received XPOVIO in SADAL The denominator used to calculate the rate varied from 107 to 128 based on the number of patients with at least one post-treatment value. Not fasting. CK increase was not associated with reports of myopathy or myalgia. Laboratory Abnormality XPOVIO 60 mg twice weekly All Grades Grade 3 or 4 Hematologic Hemoglobin decrease 82 25 Lymphocyte count decrease 63 37 Neutrophil count decrease 58 31 Chemistry Glucose increase 57 a 5 Creatinine increase 47 3. 9 Phosphate decrease 34 11 Magnesium decrease 30 2. 6 Calcium decrease 30 0. 9 Potassium increase 26 3. 9 Potassium decrease 23 7 CK increase b 21 1. 9 Hepatic Albumin decrease 25 0 AST increase 24 3. 1 Bilirubin increase 16 1.

Lactation 8. 2 Risk Summary Based on findings in animal studies and its mechanism of action [see Clinical Pharmacology ( 12. 1 (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data In an embryo-fetal development study in pregnant rats, daily oral administration of selinexor at 0, 0. 75, or 2 mg/kg throughout organogenesis caused incomplete or delayed ossification, skeletal variations, and reduced fetal weight compared with controls at a dose of 0. 75 mg/kg (approximately 0. 08-fold of human area under the curve [AUC] at the recommended dose). Malformations were observed at 2 mg/kg, including microphthalmia, fetal edema, malpositioned kidney, and persistent truncus arteriosus. Risk Summary There is no information regarding the presence of selinexor or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with XPOVIO and for 1 week after the last dose. XPOVIO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8. 1 Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating XPOVIO [see Use in Specific Populations ( 8. 1 Contraception Females Advise females of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose. Males Advise males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose. Infertility Females and Males Based on findings in animals, XPOVIO may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology ( 13. 1 The safety and effectiveness of XPOVIO have not been established in pediatric patients. In BOSTON, of the 195 patients with multiple myeloma who received XPOVIO in combination with bortezomib and dexamethasone, 56% were 65 years of age and older, while 17% were 75 years of age and older. No overall differences in effectiveness were observed between these patients and younger patients. When comparing patients 65 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and a higher incidence of serious adverse reactions (56% vs 47%). In STORM, of the 202 patients with multiple myeloma who received XPOVIO, 49% were 65 years of age and older, while 11% were 75 years of age and older. No overall difference in effectiveness was observed in patients over 65 years of age, including patients over 75 years of age, when compared with younger patients. When comparing patients 75 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (44% vs 27%), higher incidence of serious adverse reactions (70% vs 58%), and higher incidence of fatal adverse reactions (17% vs 9%). Among 134 patients with DLBCL who received XPOVIO in SADAL, 61% were 65 years of age and older, while 25% were 75 years of age and older. Clinical studies of XPOVIO in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with selinexor. Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay. Fertility studies in animals have not been conducted with selinexor. In repeat-dose oral toxicity studies, selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed in rats at >=1 mg/kg, decreased ovarian follicles were observed in rats at >=2 mg/kg, and single cell necrosis of testes was observed in monkeys at >=1.5 mg/kg. These dose levels resulted in systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure (AUC last
CLINICAL STUDIES
XPOVIO Combination with Bortezomib and Dexamethasone (XVd) The efficacy of XPOVIO in combination with bortezomib and dexamethasone was evaluated in BOSTON (NCT03110562). BOSTON was a global, randomized, open label, active-controlled trial in adult patients who had received 1 to 3 prior anti-MM regimens. Prior treatment with bortezomib or other PI was allowed. Patients with Grade 2 or higher peripheral neuropathy at study entry were excluded. Patients were randomized to receive one of the following: XPOVIO 100 mg orally once weekly on Days 1, 8, 15, 22, 29 in combination with bortezomib 1. 3 mg/m 2 Bortezomib 1. 3 mg/m 2 2 Treatment continued in both arms until disease progression or unacceptable toxicity. Randomization was stratified based on prior proteasome inhibitor therapies exposure (yes versus no), number of prior regimens (1 versus >1), Stage (III versus I or II) according to the Revised-International Staging System (RISS) and region. Upon confirmed progressive disease (PD), patients in the Vd arm could receive XPOVIO in combination with bortezomib and dexamethasone (XVd) or XPOVIO 100 mg taken orally on Days 1, 8, 15, 22, 29 with dexamethasone 20 mg taken orally on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle. A total of 402 patients were randomized: 195 to XVd arm and 207 to Vd arm. Baseline patient demographics and disease characteristics are summarized in Table 11 Table 12 Table 11: Baseline Demographics (BOSTON) Characteristic XVd Vd Median age, years (range) 66 (40, 87) 67 (38, 90) Age distribution, n (%) 65 en dash 74 years 75 (38) 85 (41) >=75 years 34 (17) 47 (23) Sex, n (%) Female 80 (41) 92 (44) Race, n (%) Black or African American 4 (2) 7 (3) Asian 25 (13) 25 (12) Other 0 1 (0. 5) Missing 5 (3) 9 (4) Table 12: Disease Characteristics (BOSTON) a. Includes any of del (17p)/p53, t (14;16), t (4;14), 1q21. Parameter XVd (n=195) Vd (n=207) Median years from diagnosis to randomization (range) 3. 0) ECOG performance status score, n (%) >=2 20 (10) 16 (8) Creatinine Clearance, n (%), mL per minute 30 to 59 53 (27) 60 (29) >=60 139 (71) 137 (66) Revised International Staging System at Baseline, n (%) II 117 (60) 125 (60) III 12 (6) 16 (8) Unknown 10 (5) 14 (7) Number of Prior Therapies, n (%) Type of known prior therapy, n (%) Stem Lenalidomide 77 (39) 77 (37) Pomalidomide 11 (6) 7 (3) Bortezomib 134 (69) 145 (70) Carfilzomib 20 (10) 21 (10) Daratumumab 11 (6) 6 (3) Median weeks since end of last prior therapy, (range) 48 (1, 1088) 42 (2, 405) Known high-risk cytogenetics a 97 (50) 95 (46) Efficacy was based on progression free survival (PFS) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma, as assessed by an Independent Review Committee (IRC). Efficacy results based on a preplanned PFS interim analysis, are shown in Table 13 Figure 1 Table 13: Efficacy Results per IRC in Multiple Myeloma (BOSTON) a. Hazard ratio is based on stratified Cox''s proportional hazard regression modeling, p-value based on stratified log-rank test. Median follow up of 15. 1 months at the time of the analysis. The pre-planned PFS interim analysis boundary of statistical significance was defined as a p-value <0. Includes sCR + CR + VGPR + PR, p value based on Cochran-Mantel-Haenszel test. Includes sCR + CR + VGPR, p value based on Cochran-Mantel-Haenszel test. XVd Vd Progression Free Survival (PFS) a One-sided p-value b 0. 7, Not Reached) 9. 8) Overall Response Rate (ORR) c , n (%) 149 (76. 3) 95% CI (69. 9) One-sided p-value 0. 0012 19 (10) 13 (6) Complete Response (CR) 14 (7) 9 (4) Very Good Partial Response (VGPR) 54 (28) 45 (22) Partial Response (PR) 62 (32) 62 (30) >= VGPR Response Rate d , n (%) 87 (44. 4) 95% CI (37. 2) One-sided p-value 0. 0082 Figure 1: Kaplan-Meier Curve of PFS (BOSTON) The median time to response was 1. 4 months in the XVd arm and 1. 6 months in the Vd arm. The median duration of response, among responding patients, was 20. 3 months and 12. 9 months in the XVd and Vd arms, respectively. Figure 1 XPOVIO Combination with Dexamethasone (Xd) The efficacy of XPOVIO plus dexamethasone was evaluated in STORM (KCP-330-012; NCT02336815). STORM was a multicenter, single-arm, open-label study of adults with relapsed or refractory multiple myeloma (RRMM). STORM Part 2 included 122 patients with RRMM who had previously received three or more antimyeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy. In STORM Part 2, a total of 122 patients received XPOVIO 80 mg orally in combination with dexamethasone 20 mg orally on Days 1 and 3 of every week. Treatment continued until disease progression or unacceptable toxicity. Eighty-three patients had RRMM that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. Baseline patient demographics and disease characteristics of these 83 patients are summarized in Table 14 Table 15 Efficacy was based on overall response rate (ORR), as assessed by an Independent Review Committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. The approval of XPOVIO was based upon the efficacy and safety in a prespecified subgroup analysis of the 83 patients whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, as the benefit-risk ratio appeared to be greater in this more heavily pretreated population than in the overall trial population. Overall response rate results are presented in Table 16 Table 14: Baseline Demographics (STORM) Demographic STORM (n=83) Median age, years (range) 65 (40, 86) Age category, n (%) <65 years 40 (48) 65 en dash 74 years 31 (37) >=75 years 12 (15) Sex, n (%) Male 51 (61) Female 32 (39) Race, n (%) White 58 (70) Black or African American 13 (16) Asian 2 (2) Native Hawaiian or other Pacific Islander 1 (1) Other 6 (7) Missing 3 (4) Table 15: Disease Characteristics (STORM) a. Includes any of del(17p)/p53, t(14; 16), t(4; 14), 1q21. Parameter STORM (n=83) Median years from diagnosis to start of study treatment (range) 7 (1, 23) Prior treatment regimens, median (range) 8 (4, 18) Documented refractory status, n (%) Pomalidomide 83 (100) Bortezomib 83 (100) Carfilzomib 83 (100) Daratumumab 83 (100) Documented refractory status to specific combinations, n (%) Daratumumab in any combination 57 (69) Daratumumab as single agent (+/- dexamethasone) 26 (31) Previous stem cell transplant, n (%) 67 (81) Revised International Staging System at Baseline, n (%) II 56 (68) III 17 (21) Unknown 0 High-risk cytogenetics a 47 (57) Table 16: Efficacy Results per IRC in Relapsed or Refractory Multiple Myeloma (STORM) a. Includes sCR + CR + VGPR + PR. Response STORM (n=83) Overall Response Rate (ORR) a , n (%) 21 (25. 3) 95% CI 16. 4, 36 Stringent Complete Response (sCR) 1 (1) Complete Response (CR) 0 Very Good Partial Response (VGPR) 4 (5) Partial Response (PR) 16 (19) The efficacy of XPOVIO monotherapy was evaluated in SADAL (KCP-330-009; NCT02227251). SADAL was a multicenter, single-arm, open-label study of adults with relapsed or refractory DLBCL, not otherwise specified (NOS), after 2 to 5 systemic regimens. Eligible patients were not candidates for autologous hematopoietic stem cell transplantation (HSCT). The study required a minimum of 60 days since last systemic therapy, with a minimum of 98 days in patients with refractory disease (defined as less than partial response) to last systemic therapy. Patients received XPOVIO 60 mg orally on Days 1 and 3 of each week. Of 134 patients evaluated, the median age was 67 years (range: 35-91), 59% were male, 79% were White, and 7% were Asian. Most patients (88%) had an ECOG performance status of 0 or 1. The diagnosis was de novo DLBCL not otherwise specified (NOS) in 75% and transformed DLBCL in 23%. The median number of prior systemic therapies was 2 (range: 1-5), with 63% of patients receiving 2 prior systemic therapies, 24% receiving 3 prior therapies, and 10% receiving 4 or 5 prior therapies. Twenty-eight percent had documented refractory disease to the most recent therapy; 30% had prior autologous HSCT. The median time from last systemic therapy to the start of XPOVIO was 5. 4 months overall and 3. 6 months in the patients with refractory disease. Efficacy was based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using Lugano 2014 criteria ( Table 17 Table 17: Efficacy Results per IRC in Relapsed or Refractory DLBCL (SADAL) Parameter XPOVIO 60 mg twice weekly (n=134) ORR per Lugano criteria, n (%) 39 (29) Complete Response 18 (13) Partial Response 21 (16) Duration of Response Patients maintaining response at 6 months, n/N (%) 15/39 (38) Patients maintaining response at 12 months, n/N (%) 6/39 (15).

Karyopharm Therapeutics Inc.

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