| 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 |
The study has 2 parts.
The overall primary objective of the study is to compare progression-free survival (PFS) of the
selected optimal dose of SPd vs. EloPd based on the International Myeloma Working Group (IMWG) response criteria.
The main objective of Part 1 of the study is to assess the safety and tolerability of 40 mg and 60
mg doses of selinexor plus Pd (SPd-40 and SPd-60), to confirm the optimal dose of selinexor for
Part 2 of the study. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objective:
- To compare clinical efficacy of SPd versus EloPd
- To assess the safety and tolerability of SPd versus EloPd
- To compare the impact of treatment on health-related quality of life (HR-QoL)
- To characterize PK of selinexor and pomalidomide.
Exploratory objective:
- To identify predictive biomarkers of response to treatment and explore treatment mechanism of action
- To evaluate exposure response relationship for applicable efficacy and safety endpoints |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Correlative Study #1: Immuno-characterization and preclinical development of multi-specific nanobodies (optional)
Immune cells of patients with MM undergoing selinexor treatment will be profiled at different timepoints (after inclusion and 6 months of treatment or time point of progression). For identification of the most relevant targets via multiparametric flow cytometry analysis of the TIGIT axis and purinergic signaling, two bone marrow and peripheral blood aspirates per patient (20 patients on selinexor, 20 patients without selinexor) will be assessed. The monitoring of immune cell-proliferation and their conversion of ATP to ADO with and without blockade of CD38, CD39 and CD73 by using nanobodies will be assessed for bone marrow and peripheral blood aspirates (5 patients on selinexor, 5 patients without selinexor) by analyses of the cell-titer glo, AMP glo and HPLC. The evaluation of the functional relevance of the multi-enzymatic inhibition with a combinatorial blockade of the TIGIT pathway will be conducted by using half-life extended Nbs and hcAbs lacking Fc effector function (LALAPG mutants) to block CD38, CD39 and CD73 alone or in combination to reduce conversion of proinflammatory ATP to anti-inflammatory ADO. Established cancer cell killing assays will be performed for evaluation of the multi-specific Nbs using allogeneic T cells sorted from primary MM samples (bone marrow and peripheral blood aspirate of 10 patients on selinexor, 10 patients without selinexor), healthy donors and MM cell cell lines. Direct targeting of CD38, CD39 and CD73 alone and in combination with inhibition of TIGIT, PVR, PVRL2 expressing cells like MM cells and regulatory T cells by ADCC and CDC will be evaluated in vitro using new engineered hcAbs carrying wildtype or enhanced Fc effector functions (ADES mutants). ADCC assays with NK-92-CD16 effector cell and CDC assays using human serum as source of complement (bone marrow and peripheral blood aspirate per patient (12 patients on selinexor, 12 patients without selinexor) will be performed.
Correlative Study #2: Monitoring Multiple myeloma bone marrow inflammation at the single cell level (optional)
The effects of selinexor treatment on the pro-tumor stromal inflammation and on the myeloma immune environment will be analyzed. Specifically: identification of changes in the stromal and immune microenvironment, as well as in the tumor cells in response to selinexor treatment; identification of changes in bone marow inflammation in patients responding to selinexor therapy.
Single cell RNA sequencing will be used to map the response of inflammatory stromal cells, together with the bone marrow immune environment and the myeloma cells to selinexor at the single cell level. Multiplex immunoassays will be performed to track bone marrow inflammation.
Experiments will be performed on set of patients to identify alterations associated with selinexor response. Patients reaching MRD-negativity will be compared to patients who do not reach MRD-negativity.
Correlative Study #3: Lambda translocations in RRMM patients treated with SPd vs EPd (optional)
Using an additional FISH probe (XL 22q11 Ig lambda Break Apart, Metasystems) the percentage of lambda translocated patients in the RRMM setting will be defined and it will be investigated whether Selinexor or Elotuzumab added to IMiDs backbone can revert the high-risk behavior of lambda translocated patients.
Correlative Study #4: Bone marrow aspirates (mandatory)
A portion of the bone marrow aspirates collected at Screening will be shipped to a central laboratory for exploratory studies. This portion of bone marrow aspirate will have CD138 + and CD138- cells isolated. They are to be frozen in dimethyl sulfoxide until sequencing of RNA and DNA is performed. Studies may include transcriptomic, genomic, and/or proteomic analyses to identify predictive biomarkers of selinexor response and to characterize the mechanism of action of selinexor. |
|
| E.3 | Principal inclusion criteria |
There is no difference in the patient population enrolled in Part 1 or Part 2 of the study. This trial
will enroll patients who meet all of the inclusion criteria and none of the exclusion criteria.
Inclusion Criteria:
1. Relapsed or refractory MM per IMWG criteria with measurable disease 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 or D myeloma, by quantitative serum IgA or IgD levels ≥0.5
g/dL.
b. Urinary M-protein excretion ≥200 mg/24 hours.
c. Serum free light chain (FLC) ≥100 mg/L, provided that the FLC ratio is abnormal
(normal FLC ratio: 0.26 to 1.65).
2. Received at least 1 and no more than 4 prior anti-MM lines of therapy. Induction therapy
followed by stem cell transplant and consolidation/maintenance therapy will be
considered as 1 line of therapy.
3. Patients must have prior therapy which must include an anti-CD38 mAb, and ≥2
consecutive cycles of the following agents given alone or in combinations: lenalidomide,
proteasome inhibitor.
4. Patients must have prior therapy with anti-CD38 mAb in one of the following ways:
a. Received anti-CD38 mAb as their immediate last treatment prior to study entry (50%
of patients).
b. Received prior anti-CD38 mAb other than in immediate last treatment prior to study
entry (50% of patients).
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
6. Resolution of any clinically significant non-hematological toxicities (if any) from
previous treatments to Grade ≤1 by Cycle 1 Day 1 (C1D1). Patients with clinically
significant Grade 2 neuropathy from previous treatments may be included.
7. Adequate hepatic function within 28 days prior to C1D1:
a. Total bilirubin <2 × upper limit of normal (ULN) (except patients with Gilbert's
syndrome who must have a total bilirubin of <3 × ULN)
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 × ULN
8. Adequate renal function within 28 days prior to C1D1 (estimated creatinine clearance
[CrCl] of ≥15 mL/min (not requiring dialysis), calculated using the formula of Cockcroft
and Gault or measured by 24-hour urine collection).
9. Adequate hematopoietic function within 7 days prior to C1D1 defined as absolute
neutrophil count ≥1.5 x 10^9/L, hemoglobin ≥8.5 g/dL, and platelet count ≥100 x 10^9/L
(patients for whom <50% of bone marrow nucleated cells are plasma cells) or ≥75 x
109/L (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., romiplostim, or
eltrombopag) 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.
10. Female patients of childbearing potential must have a negative serum pregnancy test
within 10 to 14 days and a second test within 24 hours prior to the first dose of study
treatment. Female patients of childbearing potential and fertile male patients who are
sexually active must use highly effective methods of contraception throughout the study
and for 3 months following the last dose of study treatment.
11. Age ≥18 years at the time of signing informed consent.
12. Written informed consent signed in accordance with federal, local, and institutional
guidelines.
13. Patients must be able and willing to take enteric-coated aspirin according to clinical
practice, or if history of prior thrombotic disease, must be fully anticoagulated with
warfarin (international normalized ratio [INR] 2-3) or be treated with full-dose, low
molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary
embolism (PE) at the Investigator's discretion. For patients on warfarin, INR should be
repeated as clinically indicated. |
|
| E.4 | Principal exclusion criteria |
There is no difference in the patient population enrolled in Part 1 or Part 2 of the study. This trial
will enroll patients who meet all of the inclusion criteria and none of the exclusion criteria.
Exclusion Criteria:
1. Smoldering MM.
2. Plasma cell leukemia.
3. Documented active systemic amyloid light chain amyloidosis.
4. Active central nervous system MM.
5. Prior treatment with:
a. a selective inhibitor of nuclear export (SINE) compound, including selinexor.
b. pomalidomide or elotuzumab.
6. Any concurrent medical condition or disease that is likely to interfere with study
procedures.
7. 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.
8. Known intolerance, hypersensitivity, or contraindication to any of the study treatments.
9. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy including
investigational therapies and high dose dexamethasone (i.e., 40 mg daily for 4 days per
week) ≤2 weeks prior to C1D1. 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.
10. Prior autologous stem cell transplantation <60 days or allogeneic stem cell
transplantation <4 months prior to C1D1.
11. Major surgery within 4 weeks prior to C1D1.
12. Active graft versus host disease after allogeneic stem cell transplantation.
13. Pregnant or breastfeeding females.
14. In the opinion of the Investigator, patients who are below their ideal body weight and
would be unduly impacted by changes in their weight.
15. Clinically significant cardiac disease, including:
a. Myocardial infarction within 6 months before C1D1, or unstable or uncontrolled
disease/condition related to or affecting cardiac function (e.g., unstable angina,
congestive heart failure, New York Heart Association Class III-IV).
b. Uncontrolled cardiac arrhythmia (CTCAE v. 5.0 Grade 2 or higher) or clinically
significant electrocardiogram (ECG) abnormalities.
c. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's
formula (QTcF [APPENDIX 4]) >470 msec.
16. 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.
17. 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.
18. Contraindication to any of the required concomitant drugs or supportive treatments.
19. Patients unwilling or unable to comply with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS), defined as time from date of randomization until the date of first confirmed progressive disease (PD), per IMWG response criteria, or death due to any cause,
whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the study. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints:
• Overall response rate (ORR), defined as
any response ≥ partial response (PR)
(i.e., PR [partial response], VGPR [very
good partial response], CR ([complete
response], or sCR [stringent complete
response])
• Overall survival (OS)
Additional Secondary Efficacy Endpoints
• Clinical benefit rate (CBR), defined as
response ≥ minimal response (MR)
• Duration of response (DOR)
• Time to next treatment (TNT)
• Time to initial response (TTR)
• Time to best response (TTBR)
• Time to second disease progression (PFS2)
Safety and tolerability of study treatment will
be evaluated based on AE reports, vital signs,
clinical laboratory results, electrocardiogram
(ECG) and physical examination findings, by
means of the occurrence, nature, and severity of
AEs as categorized by the CTCAE v5.0.
Patient-reported quality of life (QoL), as
measured by the European Organisation for
Research and Treatment of Cancer- Quality of
Life (EORTC-QLQ-C30), EORTC-QLQMY20,
and EQ-5D-5L instruments.
Selinexor and pomalidomide PK parameters,
estimations of maximum plasma concentration,
area under the concentration versus time curve
(AUC), and apparent clearance, if feasible.
Exploratory endpoints:
Correlative studies (see Protocol APPENDIX 5) to
evaluate response to treatment with selinexor as
related but not limited to the following:
• Cytogenetic and fluorescence in situ
hybridization (FISH) of prognostic
biomarkers, including p53 abnormalities
(i.e., del 17p13) and other chromosomal
aberrations (e.g., t[4;14], t[14;16],
gain/amp[1q21], del1p32,and MM
cytogenetic classifications).
• Genetic analysis including but not limited to
DNA and RNA sequencing of bone marrow
samples.
Relationships between selinexor exposure
metrics such as Cmax and AUC and efficacy and
safety endpoints
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the study. |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| impact on health-related quality of life |
|
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| adaptive; 2 Parts (Part 1 to confirm the optimal dose of selinexor for Part 2 of the study); |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Spain |
| 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
|
| The End of Study (EoS) will be upon completion of the follow-up period for the last patient. This will occur when all patients in the trial have been followed for 36 months after enrollment, has died, has been lost to follow-up, has withdrawn consent, or Sponsor decision to terminate the trial, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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