Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma

• Register: EUCTR
• Last refreshed on: 7 February 2022
• Main ID: EUCTR2016-003957-14-CZ
• Date of registration: 07/02/2017
• Prospective Registration: Yes
• Primary sponsor: Karyopharm Therapeutics Inc.
• Public title: Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma
• Scientific title: A Phase 3 Randomized, Controlled, Open-label Study of Selinexor, Bortezomib, and Dexamethasone (SVd) versus Bortezomib and Dexamethasone (Vd) in Patients with Relapsed or Refractory Multiple Myeloma (RRMM) - BOSTON
• Date of first enrolment: 20/04/2017
• Target sample size: 364
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003957-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: yes Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: sVd versus Vd Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Bulgaria, Canada, Czech Republic, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Poland, Romania, Russian Federation, Serbia, Spain, Ukraine, United Kingdom, United States

Contacts

• Name: Clinical Trial Information Desk
• Affiliation: Karyopharm Therapeutics Inc.

• Name: Clinical Trial Information Desk
• Affiliation: Karyopharm Therapeutics Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Histologically confirmed MM with measurable disease per IMWG guidelines as defined
by at least 1 of the following:
a. Serum M-protein = 0.5 g/dL (> 5 g/L) by serum protein electrophoresis (SPEP) or for
immunoglobulin (Ig) A myeloma, by quantitative serum IgA levels; or
b. Urinary M-protein excretion at least 200 mg/24 hours; or
c. Serum free light chain (FLC) = 100 mg/L, provided that the serum FLC ratio is
abnormal (normal FLC ratio: 0.26 to 1.65).
2. Had at least 1 prior anti-MM regimen and no more than 3 prior anti-MM regimens.
Induction therapy followed by stem cell transplant and consolidation/maintenance
therapy will be considered as 1 anti-MM regimen.
3. Documented evidence of progressive MM (based on the Investigator's determination
according to the modified IMWG response criteria) on or after their most recent regimen.
4. Prior treatment with bortezomib or other PI is allowed, provided all of the following
criteria are met:
-Best response achieved with prior bortezomib at any time was = PR and with the
last PI therapy (alone or in combination) was = PR, AND
-Participant did not discontinue bortezomib due to Grade = 3 related toxicity, AND
-Must have had at least a 6-month PI-treatment-free interval prior to C1D1 of
study treatment.
5. Must have an ECOG Status score of 0, 1, or 2.
6. Written informed consent in accordance with federal, local, and institutional guidelines.
7. Age = 18 years.
8. Resolution of any clinically significant non-hematological toxicities (if any) from
previous treatments to Grade = 1 by C1D1. Patients with chronic, stable Grade 2
non-hematological toxicities may be included following approval from the Medical
Monitor.
9. Adequate hepatic function within 28 days prior to C1D1:
a. Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert’s
syndrome who must have a total bilirubin of < 3 × ULN), and b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to < 2 × ULN.
10. Adequate renal function within 28 days prior to C1D1 (estimated creatinine clearance
[CrCl] of = 20 mL/min, calculated using the formula of Cockroft and Gault):
(140-Age) × Mass (kg)/(72 × creatinine mg/dL)
Multiply by 0.85 if the patient is female, or if CrCl is = 20 mL/min as measured by
24-hour urine collection.
11. Adequate hematopoietic function within 7 days prior to C1D1: total white blood cell
(WBC) count = 1500/mm3, absolute neutrophil count = 1000/mm3, hemoglobin =
8.5 g/dL and platelet count = 75,000/mm3 (patients for whom < 50% of bone marrow
nucleated cells are plasma cells) or = 50,000/mm3 (patients for whom = 50% of bone
marrow nucleated cells are plasma cells).
a. Patients receiving hematopoietic growth factor support, including erythropoietin,
darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte
macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (e.g.,
eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between
growth factor support and the Screening assessments, but they may receive growth
factor support during the study.
b. Patients must have:
-At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and
-At least a 1-week interval from the last platelet transfusion prior to the Screening
platelet assessment.
However, patients may receive RBC and/or platelet transfusions as clinically indicated
per institutional guidelines during the study.
12. Fema
Exclusion criteria:
1. Prior exposure to a SINE compound, including selinexor.
2. Prior malignancy that required treatment, or has shown evidence of recurrence (except
for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during
the 5 years prior to randomization. Cancer treated with curative intent for > 5 years
previously and without evidence of recurrence will be allowed.
3. Has any concurrent medical condition or disease (e.g., uncontrolled active hypertension,
uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with
study procedures.
4. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals
within 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled
infection within 1 week prior to C1D1 are acceptable.
5. Active plasma cell leukemia.
6. Documented systemic light chain amyloidosis.
7. MM involving the central nervous system.
8. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes (POEMS) syndrome.
9. Spinal cord compression.
10. Greater than Grade 2 peripheral neuropathy or Grade = 2 peripheral neuropathy with pain at baseline,
regardless of whether or not the patient is currently receiving medication.
11. Known intolerance, hypersensitivity, or contraindication to glucocorticoids.
12. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy (including investigational therapies) = 2 weeks prior to C1D1. Localized radiation to a single site at least 1 week before C1D1 is
permitted. Glucocorticoids within 2 weeks of C1D1 are permitted. Patients on long-term
glucocorticoids during Screening do not require a washout period but must be able to
tolerate the specified dexamethasone dose in this study.
13. Prior autologous stem cell transplantation < 1 month or allogeneic stem cell
transplantation < 4 months prior to C1D1.
14. Active graft versus host disease (after allogeneic stem cell transplantation) at C1D1.
15. Pregnant or breastfeeding females.
16. BSA < 1.4 m2 at baseline, calculated by the Dubois (Dubois 1916) or Mosteller (Mosteller, 1987) method.
17. Life expectancy of < 4 months.
18. Major surgery within 4 weeks prior to C1D1.
19. Active, unstable cardiovascular function:
a. Symptomatic ischemia, or
b. Uncontrolled clinically significant conduction abnormalities (eg, patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with first-degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle
branch block will not be excluded), or
c. Congestive heart failure of New York Heart Association Class = 3 or known left ventricular ejection fraction < 40%, or
d. Myocardial infarction within 3 months prior to C1D1.
20. Known active human immunodeficiency virus (HIV) infection or HIV seropositivity.
21. Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus
ribonucleic acid (RNA) or hepatitis B virus surface antigen.
22. Any active gastrointestinal dysfunction interfering with the patient’s ability to swallow
tablets, or any active gastrointestinal dysfunction that could interfere with absorption of
study treatment.
23. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.
24. Contraindication to any of the required concomitant drugs or supportive treat

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsed or refractory multiple myeloma (RRMM)
MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Selinexor
Product Code: KPT-330
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Selinexor
CAS Number: 1393477-72-9
Current Sponsor code: KPT-330
Other descriptive name: SELINEXOR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Trade Name: Velcade 3.5mg, power for solution for injection
Product Name: Bortezomib
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: BORTEZOMIB
CAS Number: 179324-69-7
Other descriptive name: bortezomib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3.5-

Trade Name: Dexamethason 4mg JENAPHARM, tablets
Product Name: Dexamethasone
Pharmaceutical Form: Tablet
INN or Proposed INN: DEXAMETHASONE
CAS Number: 50-02-2
Other descriptive name: Dexamethasone
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Trade Name: Velcade 3.5mg, powder for solution for injection
Product Name: Bortezomib
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: BORTEZOMIB
CAS Number: 179324-69-7
Other descriptive name: bortezomib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3.5-

Trade Name: Dexamethason 4 mg JENAPHARM, tablets
Product Name: Dexamethasone
Pharmaceutical Form: Tablet
INN or Proposed INN: DEXAMETHASONE
CAS Number: 50-02-2
Other descriptive name: Dexamethasone
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Trade Name: Dexamethason-ratiopharm 4mg, tablets
Product Name: Dexamethasone
Pharmaceutical Form: Tablet
INN or Proposed INN: DEXAMETHASONE
CAS Number: 50-02-2
Other descriptive name: Dexamethasone
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Trad

Primary Outcome(s)

Main Objective: - To compare PFS based on the IRC’s disease outcome assessments in patients randomized to the SVd Arm versus the Vd Arm

Secondary Objective: To compare the overall response rate (ORR) (= partial response [PR]) based on the IRC’s response outcome assessments in patients randomized to the SVd Arm versus the Vd Arm
-To compare the incidence of any Grade = 2 peripheral neuropathy
events in patients randomized to the SVd Arm vs patients randomized to the Vd Arm
-To compare the number of patients with response = VGPR, = CR, = sCR,
or MRD negative (for patients who achieve CR or sCR) in patients
randomized to the SVd Arm vs the Vd Arm
-To compare OS in all patients randomized to the SVd Arm vs the Vd Arm
-To compare the DOR in patients randomized to the SVd Arm vs the Vd Arm
-To determine ORR1 (ORR during SVdX treatment only)
-To determine PFS1 (PFS during SVdX treatment only)
- To compare time-to-next-treatment (TTNT) in patients randomized to the SVd Arm versus the Vd Arm who receive post SVd/Vd/SVdX/SdX
treatment
- To compare time-to-response (TTR) in patients randomized to the SVd Arm versus the Vd Arm

Primary end point(s): PFS, defined as time from date of randomization until the first date of
PD, per IMWG response criteria, or death due to any cause, whichever
occurs first. For the purposes of PFS determination, PD will be
determined by the IRC.

Timepoint(s) of evaluation of this end point: The primary End Point is PFS which is defined as either date of Death or date of Disease Progression when approved by and IRC according to the IMWG criteria.

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy Endpoints
Key Secondary Efficacy Endpoints
• ORR, defined as any response =PR (ie, PR, VGPR, CR, or sCR) based on
the IRC's response outcome assessments, according to the IMWG
response criteria. All changes in MM disease assessments will be based on baseline MM disease assessments.
• Response rates at any time prior to PD or death due to any cause,
pooled and separately for the following responses: =VGPR, =CR, =sCR,
or MRD negative (for patients who achieve CR or sCR)

Non-Key Secondary Efficacy Endpoints
• OS, defined as time to death or lost to follow-up, measured from the
date of randomization until death due to any cause or until lost to follow up, for all patients
• DOR, defined as the duration of time from first occurrence of IRC confirmed response =PR until the first date of IRC-confirmed PD or
death due to any cause, whichever occurs first
• ORR1 (ORR for SVdX patients only)
• PFS1 (PFS for SVdX patients only), defined as the duration of time
from date of first dose of SVd treatment after crossover from the Vd Arm until the first date of PD, or death due to any cause
• TTNT, defined as duration of time from date of last dose of study
treatment until the date of first dose of post-SVd/Vd/SVdX/SdX
treatment
• TTR, defined as duration of time from randomization until the date of first documented response (=PR) per IMWG response criteria
• PFS2 (PFS for patients who receive post-SVd/Vd/SVdX treatment),
defined as the duration of time from the date of first dose of post-
SVd/Vd/SVdX treatment until the first date of PD on post SVd/Vd/SVdX treatment, or death due to any cause

Secondary Safety Endpoints

Key Secondary Safety Endpoint
• Incidence of any Grade =2 peripheral neuropathy events in patients
randomized to the SVd Arm versus patients randomized to the Vd Arm.
The incidence of any Grade =2 peripheral neuropathy events will be
compared between the SVd Arm and the Vd Arm (using only events that occurred prior to crossover) as a secondary endpoint using the safety population.

Non-Key Secondary Safety Endpoints
• Safety and tolerability of study treatment based on AE reports,
physical examination results (including vital signs), Eastern Cooperative Oncology Group (ECOG) performance status score, 12-lead electrocardiogram (ECG) results, ophthalmic examination results, and clinical laboratory results

Secondary HR-QoL Endpoint
• Patient-reported peripheral neuropathy, as measured by the EORTCQLQ-
CIPN20 instrument

Exploratory Endpoints
• Time to discontinuation of SVd and Vd treatment
• HR-QoL, as measured by the EORTC-QLQ-C30 and the EQ-5D-5L
instruments
• Disease response to SdX treatment according to the IMWG response
criteria
PK Endpoints
• Bortezomib and selinexor PK parameters may include, but are not
limited to, estimations of maximum plasma concentration (Cmax), area under the concentration versus time curve (AUC), and time to peak plasma concentration (tmax).

Timepoint(s) of evaluation of this end point: as per protocol

Secondary ID(s)

2016-003957-14-HU

KCP-330-023

Source(s) of Monetary Support

Karyopharm Therapeutics Inc.

Ethics review

Status: Approved
Approval date: 30/03/2017
Contact: