Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study

We conducted exposure–response analyses using safety, efficacy, and PK data from a phase 1 trial of single-agent, weekly ixazomib in relapsed/refractory MM in order to determine an appropriate dose for a phase 3 randomized, double-blind maintenance study (NCT02181413). The phase 3 trial will aim to assess the efficacy and safety of ixazomib maintenance versus placebo in patients with newly diagnosed MM who have achieved ≥PR to prior proteasome inhibitor and/or immunomodulatory drug-based induction therapy followed by HDT-ASCT. The primary endpoint will be progression-free survival, with overall survival a key secondary endpoint.

Long-term treatment in settings like maintenance therapy of myeloma will require selection of doses that provide the right balance between offering bioactive exposures associated with disease control and a tolerable safety profile without toxicities that adversely impact QoL [26, 30]. Therefore, based on the findings from the present logistic regression analyses, it was decided that ixazomib maintenance therapy will be initiated at a once-weekly dose of 3 mg. At a weekly ixazomib dose of 3 mg, the analysis predicted that the probabilities of grade ≥ 3 hematologic and grade ≥ 2 non-hematologic AEs would be reduced compared to the 4 mg dose. Further, the 3 mg dose is within the clinically active range for ixazomib (as indicated by the relationship between ixazomib exposure and clinical benefit at this dose, where the probability of achieving clinical benefit [≥SD] was predicted to be 37 %). This represents one dose level below the starting dose (4 mg) used in ongoing phase 3 trials in relapsed/refractory (NCT01564537) [13] and previously untreated (NCT01850524) MM, and the dose that is indicated for use in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed and/or refractory MM [12]. Notably, in three maintenance clinical trials of the immunomodulatory drug lenalidomide as maintenance therapy for MM, lenalidomide was also administered at a reduced starting maintenance dose (10 mg) [31‐33], relative to the 25 mg dose that is recommended in the front-line or relapsed settings [34].

Various phase 1/2 trials have characterized the clinical pharmacology, safety and efficacy of ixazomib in MM [6‐10]. Although most of these trials utilized body surface area (BSA)-based dosing, a recent analysis has shown that it is feasible to switch from BSA-based to fixed dosing of ixazomib with negligible effects on the PK characteristics of the drug [28]. As such, all ixazomib studies now employ a fixed-dosing approach and this is reflected in the United States Prescribing Information for ixazomib [12].

In addition to informing the starting dose used in phase 3 clinical trials, performing dose comparison assessments in early phase trials can be used to define dose-modification strategies in subsequent phase 3 trials [26, 35]. To provide patients in the phase 3 trial of ixazomib maintenance therapy the opportunity to derive maximum clinical benefit (without prohibitive toxicity), the starting dose of 3 mg will be increased to 4 mg after 4 cycles (i.e. at cycle 5, day 1) based on the observed tolerability at the 3 mg dose in individual patients. Such a posology was selected instead of starting treatment at the 4 mg dose in all patients in order to optimize the overall benefit/risk profile in the maintenance setting, where long-term therapy without excessive toxicity is an important consideration. While starting all patients at a 4 mg weekly dose is appropriate in the treatment setting due to the need to rapidly induce a clinical response, such an approach was not considered in the maintenance therapy setting as it may lead to a significant impact on QoL in the early stage of treatment, which may impact the long-term treatment adherence, and even result in early discontinuation. The ixazomib dose will only be increased if, during cycles 3 and 4, there have been no drug-related non-hematologic grade ≥ 2 AEs, no drug-related dose interruptions, and no drug-related delays of >1 week in starting a cycle. Patients who have had any dose reduction will not dose escalate. Selection of the time point for dose escalation in patients tolerating ixazomib was based the time course of treatment discontinuation due to AEs in previous ixazomib clinical studies in MM. A review of aggregate data from 275 patients participating in five phase 1/2 ixazomib MM studies (data cut-off, February 15, 2013) found 31 (12 %) patients who had discontinued due to AEs [7‐10, 17]. Of these 31 patients, 27 (87 %) had discontinued by the end of cycle 4. This finding provides the rationale for dose escalation after 4 cycles in patients who are tolerating treatment. The study design for the phase 3 maintenance study, including the planned dosing schedule, is presented in Fig. 3. Adaptive dosing protocols that include provisions for individualized intra-patient titration based on safety and tolerability have informed dose-modification strategies for many recently approved oncology drugs, an approach that is considered useful in determining the optimal benefit–risk balance, particularly when long-term treatment to enable durable disease control is important [26, 36, 37]. This approach can maximize the proportion of patients who achieve bioactive exposures without undue risk for excessive toxicity [26].

The particular phase 1 study used for this analysis was selected because complete PK and efficacy/safety data were available for an adequately sized population of patients with MM who had been treated with single agent oral ixazomib. However, as the phase 1 population had relapsed/refractory MM and the phase 3 population will have newly diagnosed MM, there is a potential for some differences in response and tolerance. Patients with relapsed and/or refractory MM generally have significant tumor burden, whereas patients after ASCT and those in remission are likely to have less or no tumor burden, which may affect both the efficacy and toxicity of ixazomib. For example, interpretation of the exposure–safety analysis is based on the assumption that patients on the maintenance trial will have a similar risk of AEs to patients in the phase 1 study. However, patients enrolled in the phase 1study (N = 60) had received a median of 6 prior regimens over a median of 4.9 years since MM diagnosis [6], whereas patients receiving ixazomib in the maintenance setting following transplant will have received fewer prior therapies, which could result in a reduced risk of AEs, particularly a reduced risk of hematologic toxicities associated with less compromise of the bone marrow reserve.

To ensure that learnings from this population can be applied to the phase 3 maintenance study, non-hematologic AEs were categorized into two groups (≥grade 2 versus ≥grade 1) because patients on maintenance therapy will receive ixazomib for a long duration, at a time when they have asymptomatic MM and are therefore expected to have reasonable QoL with tolerable drug side effects. Under these conditions, even grade 2 toxicities (particularly non-hematologic toxicities) may have a significant impact on QoL. In addition, efficacy data were categorized into ≥SD versus PD because SD was considered to represent a therapeutic drug effect in this heavily treated relapsed and/or refractory MM population.

In conclusion, these exposure–response analyses indicate that a favorable benefit/risk balance may be achieved at ixazomib doses of 3 mg and 4 mg weekly, below the previously established MTD of 5.5 mg [6]. In the planned phase 3 maintenance trial, patients with newly diagnosed MM who have responded to induction therapy and HDT-ASCT will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability is established after 4 cycles, to provide maximum clinical benefit.