Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma

• Register: EUCTR
• Last refreshed on: 3 April 2017
• Main ID: EUCTR2016-003957-14-HU
• Date of registration: 25/01/2017
• 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: 14/03/2017
• Target sample size: 364
• Recruitment status: Authorised-recruitment may be ongoing or finished
• 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, France, Germany, Greece, Hungary, Israel, Italy, Netherlands, Poland, 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 in
Exclusion criteria:
1. Has received selinexor or another XPO1 inhibitor previously.
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 neuropathy or = Grade 2 neuropathy with pain at baseline,
regardless of whether or not the patient is currently receiving medication.
11. Intolerance, hypersensitivity, or contraindication to glucocorticoids.
12. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy = 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 (e.g., 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 treatments.
25. P

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

Health Condition(s) or Problem(s) studied

Relapsed or refractory multiple myeloma (RRMM)
MedDRA version: 19.1 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-

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-

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-

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-

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-

Primary Outcome(s)

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.
• ORR, defined as any response = PR based on the IRC’s response outcome
assessments, according to the IMWG response criteria

Timepoint(s) of evaluation of this end point: ORR for the primary analysis will be assessed on the ITT population after the last patient randomized has had the opportunity to complete at least 2 post-C1D1 MM evaluations

Main Objective: - To compare PFS based on the Independent Review Committee’s (IRC’s) disease
outcome assessments in patients randomized to the SVd Arm versus the Vd Arm
- To compare the ORR (= PR) based on the IRC’s response outcome assessments, in patients randomized to the SVd Arm versus the Vd Arm

Secondary Objective: -To compare the incidence of any = Grade 2 neuropathy events (total = Grade 2 and
separately for Grades 2, 3, and 4) in patients randomized to the SVd Arm vs
patients randomized to the Vd Arm
-To compare the no of patients with response = very good partial response
(VGPR), = complete response (CR), = stringent complete response (sCR), or minimal
residual disease (MRD) negative (for patients who achieve CR or sCR) in patients
randomized to the SVd Arm versus the Vd Arm
-To compare the DOR in patients randomized to the SVd Arm vs the Vd Arm
-To compare OS in patients randomized to the SVd Arm vs patients randomized to
the Vd Arm who do not cross over to SVdX (OS1)
-To compare ORR, PFS, and DOR for patients with 1 prior anti-MM regimen versus
> 1 prior anti-MM regimen in patients randomized to the SVd Arm vs the Vd Arm
-To determine ORR1 (ORR during SVdX treatment)
-To determine PFS1 (PFS during SVdX treatment)

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints:
- 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)
-DOR, defined as the duration of time from first occurrence of response = PR until the
first date of PD or death, whichever occurs first
-OS1, defined as time to death, measured from date of randomization until death due
to any cause, for patients randomized to the Vd Arm who do not cross over to SVdX
-ORR, PFS, and DOR (for patients with 1 prior anti-MM regimen versus > 1 prior
anti-MM regimen)
-ORR1 (ORR for SVdX patients)
-PFS1 (PFS for SVdX patients), 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 treatment
-TTR, defined as time from the date of first dose of study treatment until the date of
first documented response (any response and best response) 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
-Incidence of all grades and any = Grade 2 neuropathy events (total = Grade 2 and
separately for Grades 2, 3, and 4) in patients randomized to the SVd Arm versus
patients randomized to the Vd Arm. The incidence of any = Grade 2 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.
-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 EORTC-QLQ-CIPN20
instrument
Exploratory Endpoints
-OS, measured from date of randomization until death due to any cause, for all
randomized patients
-PFS (in patient subsets based on R-ISS criteria [Palumbo 2015], International Staging
System (ISS) criteria, and single cytogenetic alterations included in
the R-ISS plus 1q21 amplifications)
-ORR (in patient subsets based on R-ISS criteria, ISS criteria, and single cytogenetic alterations included in the R-ISS plus 1q21 amplifications)
-Treatment discontinuation rate
-HR-QoL, as measured by the EORTC-QLQ-C30 and the EQ-5D-5L instruments

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

Secondary ID(s)

KCP-330-023

Source(s) of Monetary Support

Karyopharm Therapeutics Inc.