Clinical trial NCT02336815: Selinexor Treatment of Refractory Myeloma
Official title: A Phase 2b, Open-Label, Single-Arm Study of Selinexor (KPT-330) Plus Low-Dose Dexamethasone (Sd) in Patients With Multiple Myeloma Previously Treated With Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib, and an Anti-CD38 Monoclonal Antibody (mAb) Daratumumab, and Refractory to Prior Treatment With Glucocorticoids, an Immunomodulatory Agent, a Proteasome Inhibitor, and an the Anti-CD38 mAb Daratumumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple myeloma
Karyopharm
KPT-330
Selinexor
Refractory
Bortezomib
Carfilzomib
Lenalidomide
Pomalidomide
Dexamethasone
STORM
Daratumumab
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2015-01-13
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 2b, single-arm, open-label, multicenter study of selinexor 80 mg plus dexamethasone 20 mg (Sd) dosed twice weekly in four-week cycles, in patients with penta-refractory MM (Parts 1 and 2) or quad refractory MM (Part 1 only).

Detailed description: This is a Phase 2b, single-arm, open-label, multicenter study of selinexor 80 mg plus dexamethasone 20 mg (Sd), both dosed twice weekly in each four-week cycle, in patients with MM 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 daratumumab.

This study consists of two parts:

* Part 1 enrolled patients with both quad-refractory MM and penta-refractory MM.
* Part 2 will enroll patients with penta-refractory MM only.

Eligibility criteria: Inclusion Criteria:

Measurable MM based on modified IMWG guidelines. Defined by at least one of the following:

1. Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA myeloma, by quantitative IgA
2. Urinary M-protein excretion ≥ 200 mg/24 hours
3. Free Light Chain (FLC) ≥ 100 mg/L, provided that the FLC ratio is abnormal
4. If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative Ig levels by nephelometry or turbidimetry are acceptable

   * Must have previously received ≥ 3 anti-MM regimens including: an alkylating agent, lenalidomide, pomalidomide, bortezomib, carfilzomib, daratumumab, and a glucocorticoid. There is no upper limit on the number of prior therapies provided that all other inclusion/exclusion criteria are met.
   * MM refractory to previous treatment with one or more glucocorticoids, parenteral PI (i.e., bortezomib and/or carfilzomib), IMiD (i.e., lenalidomide and/or pomalidomide), and the anti-CD38 mAb, daratumumab. Refractory is defined as ≤ 25% response to therapy, or progression during therapy or progression within 60 days after completion of therapy.

Exclusion Criteria:

* Active smoldering MM.
* Active plasma cell leukemia.
* Documented systemic amyloid light chain amyloidosis.
* Active CNS MM.

Primary outcomes:
measure: Part 2: Percentage of Participants With Overall Response Rate (ORR) Per International MyelomaWorking Group (IMWG) as Assessed by an Independent Review Committee (IRC)
timeFrame: Baseline until disease progression/discontinuation from the study, or death, whichever occurred first (maximum duration of 17 months)
Secondary outcomes:
measure: Part 1: Duration of Response (DoR) Per IMWG as Assessed by IRC
timeFrame: First response subsequently confirmed to disease progression/discontinuation from the study, or death, whichever occurred first (maximum duration of 13 months)
measure: Part 2: Duration of Response (DoR) Per IMWG as Assessed by an IRC
timeFrame: First response subsequently confirmed to disease progression/discontinuation from the study, or death, whichever occurred first (maximum duration of 17 months)
measure: Part 1: Percentage of Participants With Clinical Benefit Rate (CBR) ) Per IMWG as Assessed by IRC
timeFrame: Baseline up to a maximum of 13 months
measure: Part 2: Percentage of Participants With Clinical Benefit Rate (CBR) Per IMWG as Assessed by IRC
timeFrame: Baseline up to a maximum of 17 months
measure: Part 1: Duration of Clinical Benefit Per IMWG as Assessed by IRC
timeFrame: First response subsequently confirmed to disease progression, or death, whichever occurred first (maximum duration of 13 months)
measure: Part 2: Duration of Clinical Benefit Per IMWG as Assessed by IRC
timeFrame: First response subsequently confirmed to disease progression, or death, whichever occurred first (maximum duration of 17 months)
measure: Part 2: Disease Control Rate (DCR)
timeFrame: Every 12 weeks until progressive disease or death due to any cause, up to 17 months
measure: Part 1: Progression Free Survival (PFS) Per IMWG as Assessed by IRC
timeFrame: From start of study treatment to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 13 months)
measure: Part 2: Progression Free Survival (PFS) Per IMWG as Assessed by IRC
timeFrame: From start of study treatment to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 17 months)
measure: Part 1: Time to Progression (TTP) Per IMWG as Assessed by IRC
timeFrame: From start of study treatment to progression of disease or death, whichever occurred first (maximum duration of 13 months)
measure: Part 2: Time to Progression (TTP) Per IMWG as Assessed by IRC
timeFrame: From start of study treatment to progression of disease or death, whichever occurred first (maximum duration of 17 months)
measure: Part 1: Time to Next Treatment (TTNT)
timeFrame: From start of study treatment to start of next anti-MM treatment or death due to disease progression, whichever occurs first (maximum duration of 13 months)
measure: Part 2: Time to Next Treatment (TTNT)
timeFrame: From start of study treatment to start of next anti-MM treatment or death due to disease progression, whichever occurs first (maximum duration of 17 months)
measure: Part 1: Overall Survival (OS)
timeFrame: From start of study treatment to death (maximum duration of 13 months)
measure: Part 2: Overall Survival (OS)
timeFrame: From start of study treatment to death (maximum duration of 17 months)
measure: Part 2: Change From Baseline in Health-related Quality of Life (HRQL) Score Based on Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) Questionnaire
timeFrame: Baseline, Day 1 of Cycle 2 to Cycle 20 (up to a maximum of 17 months)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAE) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
timeFrame: Baseline to 30 days after last dose of study treatment (maximum duration of 18 months)
measure: Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (TEAEs) of Grade 3/4, Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
timeFrame: Baseline to 30 days after last dose of study treatment (maximum duration of 18 months)
measure: Apparent Clearance (CL/F) of Selinexor in Plasma
timeFrame: Cycle 1: Day 1: Pre-dose, 1, 2 and 4 hours post-dose; Day 8 and 15: Pre-dose and 1 hour post-dose; Cycle 2: Day 1: Predose, 1, 2 and 4 hours post-dose
measure: Volume of Distribution (V/F) of Selinexor in Plasma
timeFrame: Cycle 1: Day 1: Pre-dose, 1, 2 and 4 hours post-dose; Day 8 and 15: Pre-dose and 1 hour post-dose; Cycle 2: Day 1: Predose, 1, 2 and 4 hours post-dose
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic (AZ)
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: Jonnsson Comprehensive Cancer Center / University of Los Angeles
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health Cancer Center- Shands Cancer Center Hospital
state: Florida
city: Miami
country: United States
facility: Sylvester, University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University / Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Honolulu
country: United States
facility: Kaiser Permanente- Hawaii
state: Hawaii
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute / Wayne State University
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University St. Louis
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center / John Therurer Cancer Center
state: New Jersey
city: Paramus
country: United States
facility: Valley Hospital
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: NYU Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Mt Sinai NYC
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: UNC-Chapel Hill
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Portland
country: United States
facility: Kaiser Permanente Northwest OR
state: Oregon
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Krems
country: Austria
facility: University Hospital Krems, Department of Internal Medicine II
city: Salzburg
country: Austria
facility: Salzburg Regional Hospital Müllner
city: Vienna
country: Austria
facility: Medical University Vienna, Department of Internal Medicine I
city: Antwerp
country: Belgium
facility: ZNA Stuivenberg
city: Brugge
country: Belgium
facility: General Hospital Saint-Jan
city: Brussels
country: Belgium
facility: Jules Bordet Institute
city: Brussels
country: Belgium
facility: UCL Saint-Luc
city: Ghent
country: Belgium
facility: University Hospital Ghent
city: Leuven
country: Belgium
facility: University Hospital Leuven, Campus Gasthuisberg
city: Yvoir
country: Belgium
facility: UCL Mont-Godinne
city: Lille
country: France
facility: Claude Huriez Hospital, Department of Blood Diseases
city: Lyon
country: France
facility: South Lyon Hospital Center, Department of Clinical Hematology
city: Nancy
country: France
facility: Brabois Adults Hospital
city: Nantes
country: France
facility: Nantes University Hospital Center
city: Paris
country: France
facility: Hopital Saint-Antoine, Service d´Hematologie Clinique et Therapie Cellulaire
city: Paris
country: France
facility: La Pitie-Salpetriere University Hospital, Department of Clinical Hematology
city: Paris
country: France
facility: Necker Children's Hospital
city: Dresden
country: Germany
facility: BAG Oncology Gemeinschaftspraxis
city: Freiburg
country: Germany
facility: University Hospital Freiburg, Department of Internal Medicine I
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg Medizinische Klinik V
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes Klinik für Innere Medizin I
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Tübingen
country: Germany
facility: University hospital of Tuebingen, Internal Medicine II
city: Würzburg
country: Germany
facility: Med. Klinik und Poliklinik II Universitätsklinikum
city: Athens
country: Greece
facility: National & Kapodistrain University of Athens School of Medicine, Alexandra Hospital
Study officials:
References:
citation: Tremblay G, Daniele P, Breeze J, Li L, Shah J, Shacham S, Kauffman M, Engelhardt M, Chari A, Nooka A, Vogl D, Gavriatopoulou M, Dimopoulos MA, Richardson P, Biran N, Siegel D, Vlummens P, Doyen C, Facon T, Mohty M, Meuleman N, Levy M, Costa L, Hoffman JE, Delforge M, Kaminetzky D, Weisel K, Raab M, Dingli D, Tuchman S, Laurent F, Vij R, Schiller G, Moreau P, Richter J, Schreder M, Podar K, Parker T, Cornell RF, Lionel K, Choquet S, Sundar J. Quality of life analyses in patients with multiple myeloma: results from the Selinexor (KPT-330) Treatment of Refractory Myeloma (STORM) phase 2b study. BMC Cancer. 2021 Sep 6;21(1):993. doi: 10.1186/s12885-021-08453-9.
citation: Nikolaou A, Ambavane A, Shah A, Ma W, Tosh J, Kapetanakis V, Willson J, Wang F, Hogea C, Gorsh B, Gutierrez B, Sapra S, Suvannasankha A, Samyshkin Y. Belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma in heavily pretreated patients: a US cost-effectiveness analysis. Expert Rev Hematol. 2021 Dec;14(12):1137-1145. doi: 10.1080/17474086.2021.1970522. Epub 2021 Sep 20.
citation: Chari A, Florendo E, Mancia IS, Cho H, Madduri D, Parekh S, Richter J, Dhadwal A, Thomas J, Jiang G, Lagana A, Bhalla S, Jagannath S. Optimal Supportive Care With Selinexor Improves Outcomes in Patients With Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2021 Dec;21(12):e975-e984. doi: 10.1016/j.clml.2021.07.014. Epub 2021 Jul 18.
citation: Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, Dimopoulos M, Stewart AK, Richter J, Vij R, Tuchman S, Raab MS, Weisel KC, Delforge M, Cornell RF, Kaminetzky D, Hoffman JE, Costa LJ, Parker TL, Levy M, Schreder M, Meuleman N, Frenzel L, Mohty M, Choquet S, Schiller G, Comenzo RL, Engelhardt M, Illmer T, Vlummens P, Doyen C, Facon T, Karlin L, Perrot A, Podar K, Kauffman MG, Shacham S, Li L, Tang S, Picklesimer C, Saint-Martin JR, Crochiere M, Chang H, Parekh S, Landesman Y, Shah J, Richardson PG, Jagannath S. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019 Aug 22;381(8):727-738. doi: 10.1056/NEJMoa1903455.
citation: Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, Zonder J, Baz R, Nooka A, Richter J, Cole C, Vij R, Jakubowiak A, Abonour R, Schiller G, Parker TL, Costa LJ, Kaminetzky D, Hoffman JE, Yee AJ, Chari A, Siegel D, Fonseca R, Van Wier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin JR, Picklesimer CD, Choe-Juliak C, Stewart AK. Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2018 Mar 20;36(9):859-866. doi: 10.1200/JCO.2017.75.5207. Epub 2018 Jan 30.