Official Title
A Phase 1b/2 Study of Selinexor (KPT-330) in Combination With Backbone Treatments for Relapsed/Refractory Multiple Myeloma and Newly Diagnosed Multiple Myeloma
Summary:
This study will independently assess the efficacy and safety of 10 combination therapies in
11 arms, in dose-escalation/-evaluation and expansion phases, for the treatment of patients
with relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM).
The combinations to be evaluated are:
- Arm 1: Selinexor + dexamethasone + pomalidomide (SPd)
- Arm 2: Selinexor + dexamethasone + bortezomib (SVd); enrollment complete
- Arm 3: Selinexor + dexamethasone + lenalidomide (SRd) in RRMM; enrollment complete
- Arm 4: Selinexor + dexamethasone + pomalidomide + bortezomib (SPVd)
- Arm 5: Selinexor + dexamethasone + daratumumab (SDd); enrollment complete
- Arm 6: Selinexor + dexamethasone + carfilzomib (SKd)
- Arm 7: Selinexor + dexamethasone + lenalidomide (SRd) in NDMM
- Arm 8: Selinexor + dexamethasone + ixazomib (SNd)
- Arm 9: Selinexor + dexamethasone + pomalidomide + elotuzumab (SPEd)
- Arm 10: Selinexor + dexamethasone + belantamab mafodotin (SBd)
- Arm 11: Selinexor + dexamethasone + pomalidomide + daratumumab (SDPd)
Selinexor pharmacokinetics:
- PK Run-in (Days 1-14):
Starting in protocol version 8.0, patients enrolled to any arm in the Dose Escalation Phase
(i.e., Arm 4 [SPVd], Arm 6 [SKd], Arm 8 [SNd], Arm 9 [SPEd], Arm 10 [SBd], and Arm 11 [SDPd])
will also first be enrolled to a pharmacokinetics (PK) Run-in period until 9 patients have
been enrolled to this period to evaluate the PK of selinexor before and after
co-administration with a strong CYP3A4 inhibitor.
Trial Description
Primary Outcome:
- Phase 1 (Dose-escalation): Maximum Tolerated Dose (MTD)
- Phase 1 (Dose-escalation): Recommended Phase-2 dose (RP2D)
- Phase 1 (Dose-escalation): Maximum Plasma Concentration (Cmax) of Selinexor
- Phase 1 (Dose-escalation): Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Selinexor
- Phase 1 (Dose-escalation): Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated) (AUC0-inf)
- Phase 2 (Expansion): Overall response rate (ORR)
- Phase 2 (Expansion): Duration of response (DOR)
- Phase 2 (Expansion): Clinical Benefit Rate (CBR)
This is a multi-centre, open-label, clinical study with Dose Escalation (Phase 1) and
Expansion (Phase 2) to independently assess the MTD, efficacy , and safety of 10 combination
therapies in 11 arms in patients with RRMM and NDMM. Patients will be assigned to treatment
arms based on their diagnoses and treatment histories. For 9 patients, a PK Run-in period
will precede Cycle 1 (DLT evaluation) to assess selinexor PK when co-administered with a
strong CYP3A4 inhibitor. In the Dose Escalation Phase (Phase 1): (a) in Arm 1 (SPd), Arm 2
(SVd), and Arm 3 (SRd in RRMM), patients will be randomized to either QW or BIW selinexor
dosing cohorts; (b) in Arm 5 (SDd), patients will be sequentially assigned in blocks of 3 to
either QW or BIW selinexor dosing; (c) in Arm 4 (SPVd), Arm 6 (SKd), Arm 7 (Srd in NDMM), Arm
8 (SNd), Arm 9 (SPEd), Arm 10 (SBd), and Arm 11 (SDPd) patients will be assigned to QW
selinexor dosing.
Cohort 1.4 is included from Version 10 to study safety and tolerability of SPd with selinexor
40 mg QW, is lower than RP2D (ie, selinexor 60 mg QW) in combination with pomalidomide 4 mg.
Cohort 1.4 is a different expansion cohort from the one with RP2D (ie, Cohort 1.3). In Cohort
1.4, 20 patients will be enrolled in total.
Starting in protocol Version 8.0, patients enrolled to the Dose Escalation Phase of Arm 4
(SPVd), Arm 6 (SKd), Arm 8 (SNd), Arm 9 (SPEd), Arm 10 (SBd), and Arm 11 (SDPd) will first be
enrolled to a 14-day PK Run-in period (selinexor +/- clarithromycin) until 9 patients have
been enrolled. During this 14-day PK Run-in period, selinexor 40 milligrams (mg) will be
administered alone on Day 1, clarithromycin 500 mg twice daily (BID) will be administered on
Days 2-8, and selinexor 40 mg will again be administered on Day 8 with the morning
clarithromycin dose. Blood samples for PK analysis will be collected pre-dose and 1 (± 10
min), 1.5 (± 10 min), 2 (± 10 min), 3 (± 10 min), 4 (± 10 min), 5 (± 10 min), 6 (± 10 min), 8
(± 10 min), and 24 h (± 30 min) hours after selinexor is dosed on Day 1 (without
clarithromycin) and Day 8 (with clarithromycin). Patients will then proceed to the DLT
evaluation period that will begin after the completion of the 14-day PK Run-in period; this
day will be designated as Cycle 1 Day 1 (C1D1) in the Dose Escalation Phase.
View this trial on ClinicalTrials.gov
