Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Daratumumab

Pomalidomide

Dexamethasone acetate

BB 1101

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Carfilzomib 56 mg/m2 on days 1, 8 and 15. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if \< 75 years old on days 1, 8, 15 and 22.

Selinexor 80 mg on days 1, 8 and 15.

Pomalidomide 4 mg po daily for 21 days. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if \< 75 years old on days 1, 8, 15 and 22.

Selinexor 60 mg on days 1, 8 and 15.

Daratumumab on current schedule (16 mg/kg IV days 1, 8, 15 and 22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on).

Dexamethasone 20 mg if ≥ 75 years old and 40 mg if \< 75 years old on days 1, 8, 15 and 22.

Selinexor 100 mg on days 1, 8, 15 and 22.

Selinexor 60 MG

Selinexor 80 MG

Selinexor 100 mg PO on days 1, 8, 15 and 22

Selinexor 100 MG

Carfilzomib

16 mg/kg IV days 1, 8, 15 and 22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on

20 mg if ≥ 75 years old and 40 mg if \< 75 years old on days 1, 8, 15 and 22

Palka Anand

Kristin Ivanovski

Thomas White

Kimberly Doucette, MD

Noa Biran, MD

This is a prospective, 2-arm (with an additional exploratory arm), open-label, multicenter study looking at the response rate of patients receiving selinexor (KPT-330), in combination with carfilzomib, daratumumab or pomalidomide.

Multiple Myeloma patients with documented disease progression or refractory disease while on current treatment with any carfilzomib-containing regimen (arm 1), any pomalidomide-containing regimen (arm 2) or any daratumumab-containing regimen (exploratory arm) will be included in the study. Patients will be assigned to the respective groups according to their current treatment. If a subject has received more than one of the above therapies, then assignment will be made at their physician's discretion (e.g treatment decision can be made based upon patient and physician preferred tolerance.).

Patients will receive treatment until progressive disease (PD), death, toxicity that cannot be managed by standard of care, or withdrawal, whichever occurs first.

This is a Phase 2b, two-arm, open-label, multicenter study of Sd (selinexor 100, 80 or 60 mg) in combination with carfilzomib, or pomalidomide in patients with MM previously treated with carfilzomib or pomalidomide respectively, and refractory to prior treatment. An additional exploratory arm will focus on patients treated with SD in combination with daratumumab.

This study will enroll approximately 96 patients overall (43 in each of the arms and 10 additional patients in the exploratory arm. Patients will be assigned to the respective arms based on their previous treatment.

Patients who are relapsed or refractory to their current carfilzomib-based regimen will be enrolled on Arm 1 and will receive the following treatment regimen on a 28-day cycle:

Carfilzomib 56 mg/m2 on days 1, 8 and 15. They will also receive dexamethasone 40 mg (or 20 mg if patient is ≥ 75 years old) once weekly and Selinexor 80 mg on days 1, 8 and 15.

Patients who are relapsed or refractory to their current pomalidomide-based regimen will be enrolled on Arm 2 and will receive the following treatment regimen on a 28-day cycle:

Pomalidomide 4 mg po daily for 21 days combined with Dexamethasone 40 mg (or 20 mg if patient is ≥ 75 years old) once weekly and Selinexor 60 mg days 1, 8 and 15.

For arms 1 and 2, 13 patients will be accrued in each arm in the first stage. If there are 3 or fewer responses in these 13 patients, the study will be stopped. Otherwise, 30 additional patients will be accrued for a total of 43 (in each arm).

Finally, in the exploratory arm, we will enroll up to 10 patients who are relapsed or refractory to their current daratumumab-based regimen. Patients enrolled on the exploratory arm will receive the following treatment regimen on a 28-day cycle:

Daratumumab on current schedule (16 mg/kg IV days 1,8,15,22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on) combined with Dexamethasone 40 mg once weekly (or 20 mg if patient is ≥ 75 years old) and Selinexor 100 mg once weekly.

The Investigator may remove a patient from study treatment using criteria described in Section 10.2. Patients may decide to discontinue study treatment for any reason. Patients who elect to discontinue study treatment should be encouraged to continue in the study so that follow-up information on disease progression, other antineoplastic therapy, symptoms and survival status may be obtained. However, patients may elect to withdraw consent and decline further participation in the trial at any time.

The Investigator must determine the primary reason for a patient's discontinuation of study treatment and record this information on the electronic case report form (eCRF). Patients who are prematurely withdrawn from study treatment are not eligible to re-initiate study treatment on this protocol at a later date.

A Study of Selinexor, in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma

A Phase 2B Study of Selinexor (KPT-330), in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma Relapsing on Current Therapy

ORR will include patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), based on International Myeloma Working Group (IMWG) response criteria (Kumar 2016)

To identify intestinal microbiota associated biomarkers that predict response and risk for development of treatment-related toxicities at baseline, on-treatment, post-treatment and relapse.

Changes from baseline in immune cell subsets in peripheral blood mononuclear and bone marrow mononuclear cells will be monitored.

Cytokines will be quantified in plasma samples by multiplex ELISA and other readout assays.

Chemokines will be quantified in plasma samples by multiplex ELISA and other readout assays.

Inflammation/anti-inflammation markers will be quantified in plasma samples by multiplex ELISA and other readout assays.

Bacterial translocation markers will be quantified in plasma samples by multiplex ELISA and other readout assays.

Basic peripheral blood laboratory value of absolute and relative lymphocytes obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Basic peripheral blood laboratory value of absolute and relative eosinophils obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Basic peripheral blood laboratory value of absolute and relative monocytes obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Basic peripheral blood laboratory value of absolute and relative neutrophils obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Basic peripheral blood laboratory value of absolute and relative basophils obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Basic peripheral blood laboratory value of LDH obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Basic peripheral blood laboratory value of absolute neutrophil-to-lymphocyte ratio (NLR) obtained in routine clinical care will be evaluated prior to treatment, on-treatment, post-treatment, relapse and at development of severe AE (\>3 score).

Exploratory analysis to identify molecular genomic determinants of response or resistance to selinexor in the treatment combinations to define biomarkers

Exploratory analysis to identify mechanisms of de novo or acquired resistance to selinexor in combination with carfilzomib, pomalidomide or daratumumab.

Duration from start of study treatment to PD or death \[regardless of cause\], whichever comes first

Duration from start of study treatment to death

Rate of achievement of minimal residual disease (MRD) by multiparametric flow cytometry

Incidence of Adverse Events \[Safety and Tolerability\] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.

Duration from start of study treatment to next treament

Karyopharm Therapeutics Inc

Hackensack Meridian Health

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Micronutrients

Pembrolizumab

Docetaxel

Leucovorin

Fluorouracil

Irinotecan

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

(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.

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.

(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).

(Closed for Enrollment)

Selinexor 80 mg oral does QW and pembrolizumab 200 mg IV every 3 weeks (Colorectal cancer \[CRC\] Patients).

(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).

100-mg 2 formulations:

* 5 × 20-mg tablets (Tablet A)
* 1 × 100-mg tablet (Tablet B)

Selinexor 100 mg

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

FOLFIRI

Selinexor 40 mg

Selinexor 80 mg

Selinexor 60 mg

Karyopharm Medical Information

Larissa Ryvo, MD

Julia Dudnik, MD

Valerya Seminesty, MD

Talia Shentzer Kutiel, MD

Nir Peled, MD

Aviad Zick, MD

Maya Gottfried, MD

Anton Ouryvaev, MD

Idit Peretz, MD

Ravit Geva, MD

Talia Golan, MD

This is a Phase 1/2, two-part, multi-arm, open-label study in patients with normal Hepatic Function (HF), with either Non-small cell lung cancer (NSCLC), who have had 1-2 prior lines of treatment, with 1 line containing a checkpoint Inhibitor (CPI); or patients with normal HF, with colorectal cancer (CRC) who have had 1-3 prior lines (KRAS wild-type \[WT\]) or 1-2 prior lines (mutant KRAS) of treatment with no CPI; or patients with impaired HF, with any solid tumor, who have had at least 1 prior line of treatment.

The study will comprise 2 treatment periods (monotherapy and combination therapy).

The purposes of this study, during Monotherapy period, are: (1) to determine the relative bioavailability of the 100 milligrams (mg) (Tablet B) and 20 mg (Tablet A) tablets of selinexor at 100 mg once weekly (QW) dose in patients with normal hepatic function; and (2) to assess the PK of selinexor after a single dose of 40 mg (2 × 20 mg), among patients with moderate and severe hepatic impairment, relative to 100 mg (5 × 20 mg), among patients with normal hepatic function; and, during the Combination therapy period, to assess the preliminary anti-tumor activity of selinexor in combination with docetaxel in patients with NSCLC and with pembrolizumab or folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) in patients with CRC.

Up to 120 patients will be enrolled, of which, 20 with normal HF will be able to continue from Monotherapy to Combination therapy and up to 106 patients with normal HF will receive combination therapy in total. Patients with impaired hepatic function can only participate in the Monotherapy part of the study.

Monotherapy Period:

For the Monotherapy Period of Study KCP-330-027, patients with normal hepatic function (n=20), will be allocated to one of two test formulation treatment arms, and will receive a cross-over once weekly oral dosing, with either 1x100 mg or 5x20 mg selinexor, for 2 weeks, and then will have the option to move on to the combination treatment part of the study. Patients with either moderately or severely impaired hepatic functions will be treated with 2x20 mg selinexor weekly (with an option to increase the dose every 3 weeks by 20 mg increments, up to 80 mg).

For the assessment of hepatic impairment, participants with any type of advanced or metastatic solid tumor who have moderate or severe hepatic impairment will be enrolled in Moderate Hepatic Impairment (MHI) (n=8) and Severe Hepatic Impairment (SHI) (n=6) arms, respectively and will be treated with 2 × 20 mg selinexor, weekly.

For Weeks 1 and 2, following an overnight fast of at least 10 hours, patients will be fed a standard low-fat meal 30 minutes prior to administration of once weekly selinexor. Patients should finish the meal in 30 minutes or less; however, selinexor dose should be administered 30 minutes after start of the meal.

Blood sampling for selinexor PK analyses will be collected ≤10 minutes (m) pre selinexor dose, and at 15m (±5m), 30m (±5m), 1 hour (h) (±5m), 1.5h (±5m), 2h (±10m), 3h (±10m), 4h (±10m), 5h (±10m), 6h (±10m), 8h (±20m), 10h (±20m; optional), 24h (±1h), 30h (±1h), and 48h (±2h) post selinexor dose. Practitioners must record the actual clock time for selinexor dose, and each sample drawn.

If a patient experiences emesis during the first 6 hours of the PK sampling, the PK results for that week will be excluded from the PK analysis dataset, and all testing timepoints must be re-collected during the following week (in this case, the same dosing formulation should be repeated on the following week, and other dosing formulation will be given the week after that).

Patients who will complete the Monotherapy Period will be reassessed for continuation to the Combination Therapy Period, as long as their Hepatic Function remains normal.

If a patient experiences significant toxicity related to selinexor and can't start the combination therapy immediately following monotherapy, dose interruption and weekly retesting are allowed for up to 21 days after the end of Monotherapy treatment visit. Patients requiring \>21 days to recover from toxicities related to selinexor should be discussed with the Sponsor's Medical Monitor for documented approval to continue to the Combination Therapy Period. Reassessment may be extended then and following Medical Monitor approval up to 28 days.

Combination Therapy Period:

In the combination treatment period of the study, patients with normal hepatic functions will be allocated to one of 3 arms (with Arm C divided into 2 cohorts): Arm A (n= up to 40): Patients with NSCLC who have had up to 2 lines of prior systemic treatment with 1 line containing a CPI will receive 60 mg selinexor weekly, in combination with docetaxel 75 milligrams per meter square (mg/m\^2) once every 3 weeks; Arm B (n= up to 40): Patients with CRC (KRAS WT) who have had up to 3 lines of prior systemic treatment or patients with CRC (KRAS mutant \[KRAS Mut\]) who have had up to 2 lines of prior systemic treatment, with no lines containing a checkpoint inhibitor (CPI) will receive 80 mg selinexor weekly, in combination with pembrolizumab 200 mg once every 3 weeks; Arm C (n\<=26): Patients with CRC (regardless of KRAS status) who have had up to 2 lines of prior systemic treatment (regardless of CPI use) will receive either: (Cohort 1) selinexor 40 mg on days 1, 3, 15 and 18 in 28-day cycle + FOLFIRI; or (Cohort 2) selinexor 80 mg on days 1 and 15 in 28-day cycle + FOLFIRI.

Combination Therapy Period Patients will receive combination treatment until progressive disease (PD) or intolerable toxicity.

During both study periods, safety will be assessed through continuous reporting of adverse events (AEs), treatment-emergent adverse events (TEAEs), regularly scheduled clinical laboratory tests (hematologic and chemical), and physical examinations.

Tumor assessment will be performed with either computed tomography (CT) or magnetic resonance imaging (MRI) (CT with contrast preferred; for each patient, the imaging method should remain the same throughout the study).

Following treatment, patients will come in for a safety visit (approximately 30 days after the last dose of combination therapy) and will be followed for up to 2 years after that. Patients who discontinued due to PD will be followed for survival, and patients who discontinued for reasons other than PD will have tumor assessments until PD or until the start of new anti-neoplastic therapy, after which they will be followed for survival.

Two part study (monotherapy period and combination therapy period).

Relative Bioavailability/Bioequivalence of Different Formulations of Selinexor, the Impact of Hepatic Impairment on Selinexor Pharmacokinetics, Tolerability and Antitumor Activity of Selinexor Combination Treatment

Open-Label, Phase 1/2 Study Evaluating the Relative Bioavailability/Bioequivalence of Different Formulations of Selinexor, the Impact of Hepatic Impairment on Selinexor Pharmacokinetics, and the Tolerability and Antitumor Activity of Selinexor Combination Treatment (SPRINT)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Selinexor, in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma	NCT04661137	Multiple Myelom...	Selinexor 60 MG Selinexor 80 MG Selinexor 100 M... Carfilzomib Pomalidomide Daratumumab Dexamethasone	18 Years -	Hackensack Meridian Health
Relative Bioavailability/Bioequivalence of Different Formulations of Selinexor, the Impact of Hepatic Impairment on Selinexor Pharmacokinetics, Tolerability and Antitumor Activity of Selinexor Combination Treatment	NCT04256707	Non-Small Cell ... Colorectal Canc... Other Solid Tum...	Selinexor 100 m... Docetaxel Pembrolizumab FOLFIRI Selinexor 40 mg Selinexor 80 mg Selinexor 60 mg	18 Years -	Karyopharm Therapeutics Inc

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