E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Refractory multiple myeloma (RMM) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the efficacy (overall response rate [ORR]) for treatment with selinexor 80 mg plus
low-dose dexamethasone (20 mg) (Sd) twice weekly (four-week cycles) 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 the anti-CD38 mAb daratumumab (herein referred to as penta-refractory MM).
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) for patients with penta-refractory MM in Part 2 (Expansion). |
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E.2.2 | Secondary objectives of the trial |
The following endpoints will be analyzed separately for (a) Part1 patients with quad-refractory MM, (b) Part1 patients with penta-refractory MM, and (c) Part2 (expansion) patients with penta-refractory MM. Additionally, analyses of safety and tolerability will be performed on the overall population of patients from Parts1 and 2 who received at least one dose of study treatment.
- Duration of response
- Clinical Benefit Rate and duration of clinical benefit (Duration from first observation of at least MR to time of disease progression or death due to disease progression, whichever occurs first)
- Disease Control Rate
- Progression Free Survival
- Time to Progression obtained with selinexor plus dexamethasone vs. TTP on most recent prior therapy
- Time to next treatment
- Overall Survival
- Quality of Life
- Safety and tolerability
- Describe the PK properties of selinexor in this patient population(Part1 only)
Exploratory objectives
For details see pages 40 of study protocol |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent in accordance with federal, local, and institutional guidelines.
2. Age ≥ 18 years at the time of signing informed consent.
3. Measurable MM based on IMWG guidelines as defined by at least one of the
following:
a. Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or, for IgA myeloma,
by quantitative IgA
b. Urinary M-protein excretion ≥ 200 mg/24 hours
c. FLC ≥ 100 mg/L, provided that the FLC ratio is abnormal.
d. If serum protein electrophoresis is felt to be unreliable for routine M-protein
measurement, then quantitative Ig levels by nephelometry or turbidometry is
acceptable.
4. Patients 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.
5. 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 daratumumab. Refractory is defined as ≤ 25% response to therapy, or progression during therapy or progression within 60 days after completion of therapy.
6. Multiple myeloma that is refractory to the patient’s most recent anti-MM regimen.
(Documented severe intolerance to the patient’s last therapy is allowed upon approval
by the Medical Monitor.)
7. Any clinically significant non-hematological toxicities (except for peripheral neuropathy
as described in exclusion criterion #17) that patients experienced from treatments in
previous clinical studies must have resolved to Grade ≤ 2 by Cycle 1 Day 1.
8. Adequate hepatic function within 21 days prior to Cycle 1 Day 1: total bilirubin < 2x
upper limit of normal (ULN) (except patients with Gilbert’s syndrome who must have a
total bilirubin of < 3x ULN), AST < 2.5x ULN and ALT < 2.5x ULN.
9. Adequate renal function within 21 days prior to Cycle 1 Day 1: estimated creatinine
clearance of ≥ 20 mL/min, calculated using the formula of Cockroft and Gault.
10. Female patients of childbearing potential must agree to use 2 methods of
contraception (including 1 highly effective and 1 effective method of contraception) and have a negative serum pregnancy test at screening. Male patients must
use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose of study treatment.
11. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
12. Adequate hematopoietic function within 21 days prior to Cycle 1 Day 1 (See Exclusion
Criterion #20 for transfusion washout periods for RBCs and platelets):
a. Total WBC count ≥ 1,000/mm3
b. ANC ≥ 1000/mm3
c. Platelet count ≥ 75,000/mm3 (patients in whom <50% of bone marrow nucleated
cells are plasma cells) or ≥ 50,000/mm3 (patients in whom ≥ 50% of bone marrow
nucleated cells are plasma cells. [Platelet transfusions <1 week prior to Cycle 1 Day
1 are prohibited (see below).]
13. Hemoglobin level ≥ 8.5 g/dL. In certain cases, patients with stable
baseline hemoglobin level >8.0 may be included following approval by the Medical
Monitor. [Red blood cell transfusions <2 weeks prior to Cycle 1 Day 1 are prohibited
(see below).]
14. Confirmation of patient eligibility for specific key criteria for study participation with the Medical Monitor. |
|
E.4 | Principal exclusion criteria |
1. Active smoldering MM.
2. Active plasma cell leukemia.
3. Documented systemic amyloid light chain amyloidosis.
4. Active central nervous system (CNS) MM.
5. Pregnancy or breastfeeding.
6. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks
prior to Cycle 1 Day 1, and radio-immunotherapy 6 weeks prior to Cycle 1 Day 1.
7. Active graft vs. host disease (after allogeneic stem cell transplantation) at Cycle 1 Day 1
8. Life expectancy of < 4 months.
9. Major surgery within four weeks prior to Cycle 1 Day 1.
10. Active, unstable cardiovascular function:
a. Symptomatic ischemia, or
b. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with
ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree
atrioventricular (AV) block or asymptomatic left anterior fascicular block/right
bundle branch block (LAFB/RBBB) will not be excluded), or
c. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3,
or
d. Myocardial infarction (MI) within 3 months prior to Cycle 1 Day 1.
11. Active, uncontrolled hypertension.
12. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals
within one week prior to first dose.
13. Known HIV seropositive.
14. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or
HBsAg (HBV surface antigen).
15. 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 enrollment. Cancer treated with curative intent > 5 years previously and without evidence of recurrence will be allowed.
16. Active GI dysfunction interfering with the ability to swallow tablets, or any GI
dysfunction that could interfere with absorption of study treatment.
17. Grade ≥ 3 peripheral neuropathy, and Grade ≥ 2 painful neuropathy, within 21 days prior
to Cycle 1 Day 1.
18. Serious, active psychiatric or medical conditions which, in the opinion of the
Investigator, could interfere with treatment.
19. Participation in an investigational anti-cancer study within 21 days prior to Cycle 1
Day 1.
20. Receipt of transfusions as follows:
a. Platelet infusion within 1 week prior to Cycle 1 Day 1.
b. RBC transfusion within 2 weeks prior to Cycle 1 Day 1.
21. Receipt of the following blood growth factors within 2 weeks prior to Cycle 1 Day 1:
Granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony
stimulating factor (GM-CSF), erythropoietin (EPO), or megakaryocyte growth factor.
22. Known intolerance to or contraindication for glucocorticoid therapy at Cycle 1 Day 1.
23. Prior exposure to a SINE compound, including selinexor
24.Unable or unwilling to comply with protocol requirements, including providing a 24-
hour urine samples at the required study time points. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary statistical analysis of efficacy will be performed on ORR (achievement of PR,
VGPR, CR or sCR) for the mITT population after the last patient has completed 1 cycle.
|
|
E.5.2 | Secondary end point(s) |
Duration of response; clinical benefit rate and duration of clinical benefit; disease control rate and duration of disease control; progression free survival; time to progression obtained with selinexor plus dexamethasone versus TTP on most recent prior therapy; Time to Next Treatment (TTTNT = Duration from start of study treatment to start of next ant-MM treatment or death due to disease Progression, whichever occurs first; overall survival; quality of life using FACT-MM. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary analysis of efficacy will be performed after the last patient has completed 1 cycle. |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Austria |
Belgium |
France |
Germany |
Greece |
United States |
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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
|
The End of Study (EoS) will occur when all patients have completed the one-year Follow-up Period (i.e., when the last patient has expired, been followed for 12 months after last dose of study drug, been lost to follow-up, or has withdrawn consent, whichever occurs first). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |