Study of Selinexor (KPT- 330), Lenalidomide, & Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients

Study Overview
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Brief Summary
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This is an open-label, randomized clinical study with two stages to assess the maximum tolerated dose (MTD), efficacy, and safety of selinexor, lenalidomide, and dexamethasone (SLd) in patients with relapsed/refractory (RR) multiple myeloma (MM). The stages are dose escalation (Phase 1) and expansion (Phase 2).

Detailed Description
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In Phase 1 (Dose Escalation), patients will be randomized to either once-weekly (Arm A) or twice- weekly (Arm B) dosing with selinexor. Dose escalation will be performed within each arm for both lenalidomide and selinexor to determine the selinexor MTD for that arm. Each arm will be expanded until approximately 17 patients have been treated at the MTD in each arm. The Sponsor and Investigator will review the MTD, efficacy, and safety data from Phase 1 to determine which dose schedule (Arm A or B) to be used as the RP2D dose in the Expansion Phase. In Phase 2 (Expansion), patients who had received the MTD dose that was nominated for RP2D will continue at the same dose. Patients who did not receive the RP2D for that arm will stay on their Phase 1 dose. Additional patients will be accrued, as needed, to achieve the target population size of approximately 34 patients at the RP2D.

Official Title
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A Multi-Center, Phase 1/2, Open-Label Study of Selinexor (KPT- 330), Lenalidomide, and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Selinexor
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis, measurable disease and evidence of disease progression of MM. Relapsed or refractory to the most recently received therapy. Relapsed is defined as documented evidence of PD after achieving at least SD for ≥ 1 cycle. Refractory disease is defined as ≤ 25% response (i.e., patients never achieved minimal response or better) or progression during therapy or within 60 days after completion of therapy. Symptomatic MM, based on IMWG guidelines. Patients must have measurable disease. Exclusion Criteria: Smoldering MM. Multiple myeloma that does not express M-protein or FLC (i.e., non-secretory MM is excluded), and quantitative immunoglobulin levels cannot be used instead. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome Active MM involving the central nervous system (CNS).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Selinexor (1x/week), Lenalidomide, & Dexamethasone<br>Lenalidomide will be dosed initially at 15 mg daily, and if that dose is tolerated per dose-limiting toxicity (DLT criteria,) it will be increased to 25 mg for that arm. Selinexor will be started at 80 mg ( 45 mg/m2) once weekly in combination with dexamethasone 40 mg once weekly with each dose of selinexor. If the selinexor 80 mg dose is tolerated per DLT criteria, the dose will be increased to 100 mg ( 60 mg/m2) and evaluated for MTD, tolerability and efficacy. | Drug: Selinexor<br>* Two different dosing schedules will be tested, once weekly and twice weekly. If the selinexor 80 mg dose is tolerated, the dose will be increased to 100 mg.<br>* Other names: KPT-330;Drug: Lenalidomide<br>* In both arms, lenalidomide will be started at 15 mg/day (Dose Level 1) and, if tolerated per DLT criteria, will be escalated to 25 mg/day (Dose Level 2).<br>Drug: Dexamethasone<br>* Dexamethasone will be given in combination with each dose of selinexor on the once weekly treatment arm. For the twice weekly arm dexamethasone will be given in combination with each dose of selinexor and will also be given without selinexor on Days 22 and 24.<br>|
| Experimental: B: Selinexor (2x/week), Lenalidomide, & Dexamethasone<br>Lenalidomide will be dosed initially at 15 mg daily, and if that dose is tolerated per DLT criteria, it will be increased to 25 mg for that arm. Selinexor will be started at 60 mg ( 35 mg/m2) twice weekly in combination with dexamethasone 20 mg twice weekly with each dose of selinexor; dexamethasone 20 mg will also be given, without selinexor, on Days 22 and 24. If the selinexor 60 mg dose is tolerated per DLT criteria, the dose will be increased to 80 mg ( 45 mg/m2) and evaluated for MTD, tolerability and efficacy. | Drug: Selinexor<br>* Two different dosing schedules will be tested, once weekly and twice weekly. If the selinexor 80 mg dose is tolerated, the dose will be increased to 100 mg.<br>* Other names: KPT-330;Drug: Lenalidomide<br>* In both arms, lenalidomide will be started at 15 mg/day (Dose Level 1) and, if tolerated per DLT criteria, will be escalated to 25 mg/day (Dose Level 2).<br>Drug: Dexamethasone<br>* Dexamethasone will be given in combination with each dose of selinexor on the once weekly treatment arm. For the twice weekly arm dexamethasone will be given in combination with each dose of selinexor and will also be given without selinexor on Days 22 and 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine maximum tolerated dose (MTD) | Determine the maximum tolerated dose (MTD) of selinexor in the combination SLd in patients with RR MM, as determined by dose limiting toxicities (DLTs), efficacy, and safety | 12 months | 
| Overall response rate (ORR) | According to the International Myeloma Working Group [IMWG] criteria, Overall Response Rate (ORR) includes: stringent complete response [sCR], complete response [CR], very good partial response [VGPR], and partial response [PR] | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KPT-330, Selinexor, Multiple Myeloma, Relapsed/refractory, Lenalidomide, Dexamethasone, Karyopharm