|- candidate number||20829|
|- NTR Number||NTR4869|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||29-okt-2014|
|- Secondary IDs||EMC-MM-KPT-330-001 |
|- Public Title||A Phase II study of Selinexor (KPT-330) combined with bortezomib and dexamethasone (SVd) for induction and
consolidation for patients with progressive or refractory Multiple Myeloma.|
|- Scientific Title||A Phase II study of Selinexor (KPT-330) combined with bortezomib and dexamethasone (SVd) for induction and
consolidation for patients with progressive or refractory Multiple Myeloma.|
|- ACRONYM||The Selvedex trial|
|- hypothesis||In this protocol we will study the value of selinexor as the third agent based on its unique mechanism of action and reported synergy with bortezomib in patients with progressive or refractory MM.|
|- Healt Condition(s) or Problem(s) studied||Multiple myeloma (Kahler's disease), Chemotherapy, Progressive|
|- Inclusion criteria||- The subject must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.|
- Age ≥ 18 years at the time of signing the informed consent form.
- Able to adhere to the study visit schedule and other protocol requirements.
- Documented diagnosis of multiple myeloma and measurable disease (serum M-protein ≥ 5 g/L or urine M-protein ≥ 200 mg/24 hours or abnormal FLC ratio with involved free light chain (FLC) > 100 mg/L);
- Documented progression as per the IMWG uniform response criteria (Durie, 2006) during or after the anti-myeloma regimen; or never achieved a response better than PD after at least 2
cycles of their previous anti-myeloma regimen.
- At least one prior anti-myeloma regimen. Induction therapy followed by autologous stem cell transplant (ASCT) and consolidation/ maintenance will be considered as one regimen.
- Normal renal function with a Creatinine Clearance > 30mL/min according to the Modification of Diet in Renal Disease (MDRD) equation for estimation of Glomerular Filtration Rate (GFR)
- WHO performance status score of 0, 1 or 2 (see Appendix B).
- Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing
potential. Acceptable methods of contraception are condoms with contraceptive foam, oral,
implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm
with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout
the study and for three months following the last dose.
- All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
- All subjects must agree not to share medication.
|- Exclusion criteria||- Prior resistance/refractory disease to bortezomib|
- Systemic AL amyloidosis
- Non secretory myeloma
- Known CNS involvement
- Absolute neutrophil count (ANC) <1.0 x 109/L, unless related to MM.
- Platelet count < 50 x 109/L.
- Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L).
- Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC transfusion or recombinant human
erythropoietin use is permitted).
- Significant hepatic dysfunction (Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal
(ULN) or serum total bilirubin > 2 x ULN unless due to inheritable syndrome such as Gilbert’s)
- Prior history of malignancies, other than MM, unless the subject has been free of the disease
for ≥ 5 years. Exceptions include the following:
o Basal or squamous cell carcinoma of the skin.
o Carcinoma in situ of the cervix or breast.
o Incidental histological finding of prostate cancer (TNM stage of T1a or T1b).
- Hypersensitivity to bortezomib or dexamethasone (this includes ≥ Grade 3 rash during prior
- Peripheral neuropathy ≥ Grade 2 at time of registration.
- Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell
transplant less than 12 months prior to initiation of study treatment
- Congestive heart failure (NY Heart Association Class III or IV) (see appendix C).
- Myocardial infarction within 12 months prior to starting study treatment
- Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris.
- Subjects who received any of the following within the last 14 days of initiation of study
o Major surgery (kyphoplasty is not considered major surgery).
o Use of any anti-myeloma drug therapy at the time of registration in the trial.
- Use of any investigational agents within 28 days or five half-lives (whichever is longer) of
- Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent
the subjects from signing the informed consent form.
- Any active uncontrolled infections
- Pregnant or breastfeeding females.
- Known human immunodeficiency virus (HIV) positivity, active infectious hepatitis A, B or C or
chronic hepatitis B or C.
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||Single arm|
|- planned startdate ||1-nov-2014|
|- planned closingdate||1-mrt-2023|
|- Target number of participants||49|
|- Interventions||The following treatments will apply:|
Patients who have not previously received an autologous transplant and who are eligible for ASCT will be treated with 4 cycles of selinexor, bortezomib and
dexamethasone. After induction they will receive High Dose Melphalan (HDM) and unde rgo an Autologous Stem Cell
Transplantation (ASCT). Stem cell harvest will be performed using high-dose Cyclophosphamide and standard G-CSF. Following hematologic recovery, these
patients will receive 4 cycles of consolidation treatment with selinexor, bortezomib and dexamethasone.
Patients who have previously received an autologous transplant or who are transplant ineligible will be treated with 4 cycles of selinexor, bortezomib and dexamethasone
followed by 4 cycles of consolidation treatment with selinexor, bortezomib and dexamethasone.
In Part I of the study, the maximum tolerated dose (MTD) or highest administered dose of selinexor when combined with bortezomib & dexamethasone will be determined in 6
patients per dose level. A maximum of 3 dose levels will be evaluated.
Escalation to a higher dose level is allowed if 0 or 1 dose limiting toxicity (DLT) is experienced in a dose level. Dose
escalation stops as soon as at least 2 patients in a dose level experience a DLT.
Part II of the study will be performed at the highest dose level where 0 or 1 DLT have occurred.
|- Primary outcome||Part I: Evaluate the safety and tolerability of selinexor at 3 different dose levels in combination with bortezomib/dexamethasone & determine the recommended dose level (RDL) of selinexor for Part II
Part II: Evaluate the efficacy of the combination of selinexor, bortezomib and dexamethasone (SVd) for induction and consolidation in subjects with
progressive or refractory multiple myeloma (MM). This objective will be investigated after 4 induction cycles and after 8 cycles.
|- Secondary outcome||Evaluate the response (sCR, CR, VGPR, PR) after 8 cycles of selinexor, bortezomib and dexamethasone.
Evaluation of biomarkers, including baseline markers predictive of response to selinexor combined with bortezomib and dexamethasone.|
Evaluate effect on quality of stem cell transplant.
Evaluate the gene expression profiles in particular of
nuclear pore transporters in relation to the treatment
Evaluate pharmacodynamic (PDn) changes in XPO1
and related markers in peripheral blood leukocytes and
in plasma cytokine levels following selinexor dosing.
Evaluate limited pharmacokinetics (PK) of selinexor in
combination with bortezomib and/or dexamethasone.
|- Timepoints||Expected durations of therapies:|
- Induction therapy 4 months
- Transplantation and recovery 2 – 4 months
- Consolidation therapy 4 months
- All patients will be followed until a maximum of 5 years after registration.
|- Trial web site||http://www.erasmusmc.nl/hematologie/research2/|
|- CONTACT FOR PUBLIC QUERIES|| E. Asselbergs|
|- CONTACT for SCIENTIFIC QUERIES||Prof. Dr. P. Sonneveld|
|- Sponsor/Initiator ||Erasmus Medical Center|
(Source(s) of Monetary or Material Support)
|- Brief summary||Standard regimens in multiple myeloma are 4 – 6 induction cycles of induction therapy (bortezomib/dexamethasone)
followed by High Dose melphalon (HDM) and autologous stem cell transplantation (ASCT).|
Preferably a third agent is
added to the bortezomib/dexamethasone. In this protocol we will study the value of selinexor as the third agent based on
its unique mechanism of action and reported synergy with bortezomib in patients with progressive or refractory MM.
|- Main changes (audit trail)|
|- RECORD||29-okt-2014 - 26-nov-2014|