| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory multiple myeloma (RRMM) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To compare PFS based on the IRC’s disease outcome assessments in patients randomized to the SVd Arm versus the Vd Arm
|
|
| E.2.2 | Secondary objectives of the trial |
-To compare the ORR (≥ PR) based on the IRC’s response outcome assessments, in patients randomized to the SVdArm versus the VdArm
-To compare the incidence of any Gr. ≥2 peripheral neuropathy events (total Grade≥ and separately for Gr. 2, 3, and 4) in patients randomized to the SVdArm vs patients randomized to the VdArm
-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 SVdArm vs the VdArm
-To compare OS in all patients randomized to the SVdArm vs the VdArm
-To compare the DOR in patients randomized to the SVdArm vs the VdArm
-To compare OS in patients randomized to the SVdArm vs patients randomized to the VdArm who do not cross over to SVdX or SdX(Vd patients who cross over will be censored at the date of crossover) (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 SVdArm versus the VdArm
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 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 (eg,
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. Female patients of childbearing potential must have a negative serum pregnangy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 3 month following the last dose of study treatment. Highly effective methods of contraception are listed in the Protocol Section 10.8.1 |
|
| E.4 | Principal 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 (eg, 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 ≤ 2 (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 treatments.
25. Patients unwilling or unable to comply with the protocol, including providing 24-hour
urine samples for urine protein electrophoresis at the required time points. |
|
| E.5 End points |
| E.5.1 | 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.
|
|
| E.5.1.1 | 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 an IRC according to the IMWG criteria. |
|
| E.5.2 | 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 desease 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
- 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 or SdX; Vd patients who cross over will be censored at the date of crossover
- ORR, PFS, and DOR (for patients with 1 prior anti-MM regimen versus > 1 prior anti-MM regimen)
- 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 Endpoints:
- 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 EORTC-QLQ-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).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Bulgaria |
| Canada |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Italy |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 33 |
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