Phase 2 Trial of the Combination of Ixazomib, Thalidomide and Dexamethasone (ITD) in Relapsed/Refractory Myeloma: Planned Preliminary Analysis

Introduction: Despite improved survival outcomes in multiple myeloma (MM), disease relapse is inevitable and further therapeutic options are required. Therapy with bortezomib (a proteasome inhibitor (PI)), thalidomide and dexamethasone (VTD) has been shown to be highly effective in relapsed/refractory MM (RRMM). Ixazomib (an oral PI) in combination with lenalidomide and dexamethasone (IRD) has been shown to increase progression-free survival (PFS) in RRMM. Currently there are limited data on the efficacy/tolerability of the combination of ixazomib, thalidomide and dexamethasone (ITD). ITD may prove to be an attractive "all oral" therapeutic alternative particularly in jurisdictions with less access to high cost therapeutics.

Aim: To evaluate the efficacy and safety of the combination of ixazomib, thalidomide and dexamethasone (ITD) in RRMM.

Methods: This is a planned preliminary analysis of a multi-centre, single arm, open label, phase 2 study of the combination of ITD in RRMM patients with 1-3 prior lines of therapy. ITD (Ixazomib: 4mg orally D1, 8, 15, Thalidomide 100mg orally nocte D1-28, Dexamethasone 40mg orally D1, 8, 15, 22 of a 28-day cycle) was continued until disease progression or unacceptable toxicity.

We plan to enrol 45 patients and to date data for 33 patients who have received 4 cycles of therapy or are off study were available for analysis. Baseline characteristics, therapy/safety, response and outcome data were analysed. The primary endpoint is overall response rate (ORR) defined as at least a partial response (PR). As specified in the protocol, we calculated the posterior distribution for ORR using the currently available data and a minimally informative prior distribution (Bayesian updating of the posterior could commence after 12 patients became evaluable) and we report a 95% credible interval (CI) for ORR and also for the clinical benefit rate (CBR) defined as at least a minimal response (MR). We also report an interim summary of PFS. Analyses were performed using R and SAS9.4.

Results: Thirty-three patients were enrolled from 2 Australian sites (M:F 24:9), median age: 66 years (41-85). Median number of prior lines of therapy was 1 (1-3). Patients received a median of 6 cycles (1-20). Nine patients (27.3%) received <4 cycles. ISS stage at diagnosis: 1: 12, 2: 14, 3: 4 (3 unknown). Of patients with known cytogenetic/FISH data (n=22) 8 had high risk features (del17p, +1q21, t(14;16), t(4;14)). Twenty patients had IgG disease (IgA: 7, Light chain only: 6).

The ORR was 18/33 (54.5%; 95% CI: 37.6 - 70.1%) including complete response (CR) in 2 patients (6.1%). The posterior probability that the true ORR exceeds 45% is currently 86%. Median time to best response was 83 days for responders and 99 days when non-responders were censored at their dates of last contact. The CBR was 23/33 (69.7%; 95% CI: 52.4 - 82.5%). The posterior probability that the true CBR exceeds 45% is currently > 99%. Both median PFS and OS have not been reached.

Safety/tolerability: Fourteen patients (42.4%) tolerated ITD dosing as per protocol with thalidomide dose reduced/ceased in 15 patients (reduced: 8, ceased: 7) and dexamethasone dose reduced in 6 patients. No patients remaining on study have dose reduced/ceased ixazomib. Eighteen patients remain on study therapy with 15 ceasing therapy (progressive disease (PD): 9, adverse event (AE): 2, consent withdrawal: 2, lack of response: 1, new diagnosis of AML: 1). Twenty-two patients experienced a total of ninety-two (all-grade) AEs regardless of relatedness to study treatment with new/worsening peripheral neuropathy (12/92, 13.0%) and infection (11/92, 12.0%) most common. Two patients had grade 3 adverse events (epistaxis/thrombocytopenia:1, constipation: 1).

Conclusion: The combination of ITD is efficacious and tolerable in RRMM and would represent an attractive all oral therapeutic option for RRMM particularly in jurisdictions with limited access to other therapeutics such as lenalidomide.

Figure 1. Progression-free survival (PFS) and conventional 95% confidence intervals in months from the date of day 1 of the first cycle of ITD (FAS¹).

¹ Up to the cutoff date (23JUL2018)

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