Search

Background Nanoliposomal irinotecan (nal-IRI) was recently authorized in Japan for unresectable pancreatic cancer after disease progression following chemotherapy. Physicians now consider certain aspects of nal-IRI safety profile as slightly different from conventional irinotecan. This report aims to explore additional aspects of the nal-IRI safety in Japanese phase 2 study. Methods We analyzed the incidence, time to first onset, and time to resolution for adverse events that require special attention and other selected toxicities in the nal-IRI combination group (n = 46). Results Leukopenia/neutropenia (76.1%/71.7%), diarrhea (58.7%) and hepatic dysfunction (41.3%) were the most commonly reported treatment-emergent adverse events, with a median time to onset of 21.0 days (range: 8, 97), 9.0 days (1, 61) and 22.0 days (2, 325), respectively, and a median time to resolution of 8.0 days (95% confidence intervals: 8, 9), 4.0 days (4, 8) and 40.0 days (9, –), respectively. Eight patients experienced Grade ≥ 3 diarrhea and their symptoms were well controlled by dose modification except one patient who had drug withdrawal. The median time to resolution for Grade ≥ 3 and Grade ≤ 2 diarrhea was 17.5 days (95% confidence intervals: 1, 31) and 4 days (3, 7), respectively. Anorexia occurred in 28/46 patients (60.9%) with a median time to onset of 4.0 days (range: 2, 132) and a median time to resolution of 12.0 days (95% confidence intervals: 6, 26). Conclusions We explored safety profile of nal-IRI combination regimen recognized as effective and tolerable treatment for Japanese unresectable pancreatic cancer patients. Although the treatment-emergent adverse events occurred were controllable, patients with prolonged toxicities should be closely managed.

The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1–4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413

Conventional seamless phase 2/3 design with fixed sample size determination (SSD) has gained its popularity in oncology drug development due to attractive features such as significantly shortening the development timeline, minimizing sample size, as well as early decision making. However, this design is not immune to inaccurate treatment effect assumption when only limited efficacy data are available at study design stage. We propose an innovative seamless phase 2/3 study design with flexible SSD for oncology trials, in which the trial is designed under a distribution of treatment effect instead of one single assumption due to huge uncertainty of treatment effect at design stage and the sample size for end of phase 3 analysis is not predetermined at design stage, but rather dynamically determined based on observed treatment effect at phase 2 portion. Some practical sample size determination rules for end of phase 3 analysis will be discussed. The proposed design can lead to reduced sample size or/and improved power compared with conventional seamless phase 2/3 design with fixed SSD. This innovative study design can be especially useful for programs with aggressive development strategy to expedite the process in delivering efficacious treatment to patients.

The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1-4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413.

In the TOURMALINE-MM3 study, post-autologous stem cell transplantation maintenance therapy with the oral proteasome inhibitor ixazomib versus placebo significantly improved progression-free survival (PFS), with a favorable safety profile. With ixazomib versus placebo maintenance, deepening responses occurred in 139/302 (46%) versus 60/187 (32%) patients with very good partial response or partial response (VGPR/PR) at study entry (relative risk 1.41, P = 0.004), and median time to best confirmed deepened response was 19.9 versus 30.8 months (24-month rate: 54.2 versus 41.4%; hazard ratio (HR): 1.384; P = 0.0342). Median PFS in patients with VGPR/PR at study entry was 26.2 versus 18.5 months (HR: 0.636, P, The authors acknowledge Steve Hill PhD of FireKite, an Ashfield company, part of UDG Healthcare plc, for professional medical writing support, which was funded by Millennium Pharmaceuticals Inc, Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and complied with Good Publication Practice-3 (GPP3) guidelines (Battisti WP et al. Ann Intern Med. 2015;163:461–4), and Renda Ferrari, PhD (Millennium Pharmaceuticals, Inc), for contributing to the editorial and scientific content of the manuscript. The TOURMALINE-MM3 study was funded by Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Open access funding provided by Projekt DEAL.

549 Background: Based on a phase II study conducted in Japanese metastatic pancreatic cancer (NCT02697058) and a global phase III study, nal-IRI obtained market authorization in March 2020 in Japan for "Unresectable pancreatic cancer after disease progression following cancer chemotherapy". After one year of practice, physicians have a sense that some of the safety profile of nal-IRI to be slightly different from conventional irinotecan. The purpose of this report is to explore additional points of the nal-IRI safety in the Japanese study. Methods: This analysis with the safety population of nal-IRI+5-FU/ l-LV group was done for the incidence, time to first onset (TTO), and time to resolution (TTR) for the events associated with 12 identified risks in the Risk Management Plan (RMP)(Table) and other selected GI toxicities. Prophylaxis used were also analyzed. Results: Myelosuppression (82.6%), diarrhoea (58.7%) and hepatic dysfunction (41.3%) were commonly reported of the 12 identified risks. The median (m) TTO of these TEAEs was 16 days (range: 6, 73), 9 days (1, 61), and 22days (2,325) respectively. As for the mTTR, it was 8.0 days (95% CI: 8.00, 9.00), 4.0 days (4.00, 8.00), and 40.0 days (9.00, -) respectively. For the myelosuppression, there were 4 patients who received G-CSF for the treatment of ≥ grade 3 myelosuppression. The 8 patients who experienced diarrhoea leading to dose reduction had no recurrence of ≥grade3 diarrhoea after intervention. For other GI toxicities, anorexia occurred in 28/46 patients (60.9%) with mTTO 4.0 days (range: 2, 132) and mTTR 12.0 days (95% CI: 6.00, 26.00). Summary of TTO for the events associated with identified risks in the RMP. * Intestinal obstruction, enteritis, disseminated intravascular coagulation, interstitial lung disease, ventricular extrasystoles are also included in the RMP but not observed. Discussion: This is the first report of nal-IRI safety profile details such as timing in Japanese patients. It is interesting to note that some TEAEs appear different in practice regarding TTR in comparison with conventional irinotecan. This difference can be due to the unique PK profile of nal-IRI as a result of utilizing liposomal technology but needs to be further elucidated. Conclusions: Although the TEAEs occurred with nal-IRI+5-FU/ l-LV were controllable with proper management in Japanese patients, some with prolonged toxicities should be carefully managed. Clinical trial information: NCT02697058. [Table: see text]

There is a need for efficacious, convenient treatments with long-term tolerability for patients with relapsed/refractory multiple myeloma (RRMM). This phase 2 study evaluated the all-oral combination of ixazomib, cyclophosphamide and dexamethasone (ICd). Patients with RRMM received ixazomib 4 mg and cyclophosphamide 300 mg/m2 on days 1, 8 and 15, and dexamethasone 40 mg on days 1, 8, 15 and 22 in 28-day cycles. The primary endpoint was overall response rate (ORR). Seventy-eight patients were enrolled (median age 63·5 years). At data cut-off, patients had received a median of 12 treatment cycles; 31% remained on treatment. ORR was 48% [16% very good partial response or better (≥VGPR)]. ORR was 64% and 32% in patients aged ≥65 and

In recent years, there has been an increasing trend in conducting seamless phase 2/3 clinical trials for drug development in the pharmaceutical industry due to the visible advantages compared with traditional approaches for separate phase 2 and 3 development. Innovative study designs have been proposed for seamless phase 2/3 trials, which mainly focus on the traditional aspects of study design, such as how to control the Type I error rate, sample size re-estimation after the phase 2 portion, and how to make treatment selection at the end of the phase 2 portion. However, there are still some questions unresolved such as how to determine the go/no-go boundary and how to plan the phase 2 portion sample size. In this paper, we discuss how to determine the phase 2 portion and phase 3 portion sample sizes as well as the corresponding go/no-go criteria for a seamless phase 2/3 oncology trial based on Probability of Success. In addition, we further expand the methodology to include designs with an interim look within the phase 2 portion to speed up the go/no-go decision-making process. In case of overwhelming efficacy, this design would further shorten the overall trial duration. In case of inefficacy, this design can stop the trial earlier without exposing more patients to inefficacious treatment.

In recent years, there is an increasing trend to conduct multi-regional clinical trials (MRCT) for drug development in pharmaceutical industry. A carefully designed MRCT could be used in supporting the new drug's approval in different regions simultaneously. The primary objective of an MRCT is to investigate the drug's overall efficacy across regions while also assessing the drug's performance in some specific regions. In order to claim the study drug's efficacy and get drug approval in some specific region(s), the local regulatory authority may require the sponsors to provide evidence of consistency in the treatment effect between the overall patient population and the local region. Usually, the regional specific consistency requirement needs to be pre-specified before the study conduct and the consistency in treatment effect between the region(s) of interest and overall population will be evaluated at the final analysis. In this article, we evaluate the consistency requirements in multi-regional...

The failure rate for phase III trials in oncology is high; quantitative predictive approaches are needed. We developed a model-based meta-analysis (MBMA) framework to predict progression-free survival (PFS) from overall response rates (ORR) in relapsed/refractory multiple myeloma (RRMM), using data from seven phase III trials. A Bayesian analysis was used to predict the probability of technical success (PTS) for achieving desired phase III PFS targets based on phase II ORR data. The model demonstrated a strongly correlated (R2 = 0.84) linear relationship between ORR and median PFS. As a representative application of the framework, MBMA predicted that an ORR of ∼66% would be needed in a phase II study of 50 patients to achieve a target median PFS of 13.5 months in a phase III study. This model can be used to help estimate PTS to achieve gold-standard targets in a target product profile, thereby enabling objectively informed decision-making.

Objectives To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. Methods Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. Results A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. Conclusions Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

391 Background: Few data are available regarding real-world treatment patterns and outcomes for metastatic PDAC (mPDAC) in Europe. Methods: This retrospective, observational, chart-review study involved medical oncologists and gastroenterologists from France, Germany, Italy, Spain, and the UK. Physicians completed online patient (pt) reports for 20 consecutive pts diagnosed with PDAC between 01 and 10/2016. Here, the analysis is focused on treated pts diagnosed with mPDAC. Reports provided information on general disease and pt characteristics, diagnosis, and treatment of metastatic disease. Outcomes included median PFS and OS according to each line of metastatic therapy. In addition, how baseline performance status (PS) and treatment sequence affected OS and PFS were assessed. Results: 304 physicians (France [n=62], Germany [n=60], Italy [n=63], Spain [n=66], UK [n=53]) participated and enrolled 6,000 pts with PAC, of whom 3827 had mPDAC. Of the 3827, 3432 were treated for their metastatic disease. The most common first-line therapies were modified FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%), while the most common second-line therapies were gemcitabine monotherapy (25.0%), 5-FU + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). The longest median PFS and OS were obtained when using mFOLFIRINOX as first-line therapy, with gemcitabine-based combinations as second-line therapy. However, pt characteristics were more favorable with FOLFIRINOX compared with the other regimens used in first line. The most common treatment in first line for patients with a worse baseline PS (PS >1) was gemcitabine monotherapy (571 patients [46%]); in addition, having a worse baseline PS was predictive of shorter survival in second line. The most common reason for discontinuation of either line was disease progression. The study showed that the choice of first- and second-line treatment among European physicians is in accordance with current ESMO guidelines; in contrast, the choice of subsequent line was more heterogeneous, according to local practices. Additional data concerning first and second line OS and PFS per treatment regimen will be presented at the meeting. Conclusions: This large real-life study highlights a clear picture of treatment patterns in European real-world clinical practice and outcomes for metastatic PDAC, which may help in more effectively managing such patients in the future. Further univariate and multivariate analysis will complete this first description.

Carbon fiber (CF), graphene oxide (GO)-deposited CF (GO-CF), and reduced GO-deposited CF (rGO-CF) were introduced into wood plastic composite (WPC). The electromagnetic interference (EMI) shielding effectiveness (SE) of WPC in the X-band region (8.2–12.4 GHz) was studied. The results showed that GO-CF and rGO-CF were more effective than CF in improving EMI SE of WPC. The rGO sheets were beneficial to the dispersion of CF in matrix and could build of a more effective electric network. The WPC with 4 wt% rGO-CF and a shielding thickness of 4 mm had the SE of 29 dB. Compared with the SE of WPC with CF (23 dB), WPC with rGO-CF had a 26% increase. The WPC filled with rGO-CF has a promising prospect in EMI shielding materials. POLYM. COMPOS., 2016. © 2016 Society of Plastics Engineers

Background: Novel efficacious treatments with long-term tolerability are needed for transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. This phase 2 study evaluated the safety and efficacy of all-oral ixazomib-cyclophosphamide-dexamethasone (ICd) followed by single-agent ixazomib maintenance. Patients and methods: Patients were randomised (1:1) to receive 4.0 mg of ixazomib, 300 (Arm A) or 400 (Arm B) mg/m2 of cyclophosphamide (days 1, 8, and 15), and 40 mg of dexamethasone (days 1, 8, 15, and 22) as induction (up to 13 × 28-day cycles), followed by single-agent ixazomib maintenance (28-day cycles) until progressive disease, death, or unacceptable toxicity. Primary end-point was complete response (CR) + very good partial response (VGPR) rate for ICd induction. Results: Seventy patients were enrolled (n = 36 Arm A; n = 34 Arm B); median age was 73 years (range, 61–87). At data cut-off, 66% of patients had completed 13 induction cycles followed by ixazomib maintenance. Median overall treatment duration was 19 cycles (range, 1–29); 21% of patients discontinued treatment during induction and 3% during maintenance due to adverse events (AEs). During induction, among 67 response-evaluable patients, CR+VGPR rate was 25%, and overall response rate (ORR) was 73%. Including the maintenance phase, CR+VGPR rate was 33%, and ORR was 76%. Median progression-free survival was 23.5 months (median follow-up: 26.1 months). The most common all-grade AE was neutropenia (31%). Grade ≥3 AEs were reported by 73% of patients. Five on-study deaths occurred (not treatment-related). Conclusions: ICd treatment followed by ixazomib maintenance is tolerable and active in elderly, transplant-ineligible NDMM patients. Trial registration number: NCT02046070.

Waste fiber reinforced polymer (FRP) combined with corn straw fiber was recycled and incorporated in wood plastic composite (WPC). The synergistic enhancement effect of glass fiber and corn straw fiber was investigated. The results show that there was a good physical interlocking structure among glass fiber of waste FRP, corn straw fiber and poly(vinyl chloride) (PVC) in WPC, which led to the enhancement of mechanical properties of WPC. With 30 phr (parts per hundreds of resin) waste FRP, the tensile strength and flexural strength of WPC were improved to 24 MPa and 66 MPa, increased by 31% and 23% with respect to starting WPC. This study reveals that waste FRP and corn straw fiber can be good alternative for wood fiber in the production of WPC. POLYM. COMPOS., 2015. © 2015 Society of Plastics Engineers

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib.

Background Adipokines are elaborated by adipose tissue and are associated with glycemic, lipid, and vascular traits. We hypothesized that in a cross‐sectional analysis circulating adipokines are altered among subsets of obesity stratified by presence versus absence of metabolic syndrome (MetS) and prospectively predict the incidence of MetS. Methods and Results Participants in the community‐based Framingham Third Generation Cohort who attended examination cycle 1 were included in the study (2002–2005; N=3777, mean age, 40 years; 59% women). Circulating adiponectin, leptin, leptin receptor, fetuin‐A, fatty acid–binding protein 4, and retinol binding protein 4 were assayed and related to incident MetS in follow‐up (mean 6 years). The adipokines were compared among individuals with excess body weight (body mass index ≥25 kg/m 2 ) and prevalent MetS, excess body weight without MetS (metabolically healthy obese), and normal‐weight with MetS (metabolically obese, normal‐weight) with normal‐weight participants without MetS as a referent. Metabolically healthy obese individuals (n=1467) had higher circulating levels of fetuin‐A and fatty acid–binding protein 4 but lower levels of leptin, leptin receptor, and adiponectin ( P P =0.002). Higher circulating concentrations of retinol‐binding protein 4 and fetuin‐A were associated with incidence of MetS (odds ratio per 1‐ SD increment log marker, 1.21; 95% CI , 1.03–1.41 [ P =0.02] and 1.17; 95% CI, 1.01–1.34 [ P =0.03], respectively). Conclusions In our community‐based sample of young to middle‐aged adults, metabolically healthy obese individuals demonstrated an adverse adipokine profile. Higher circulating levels of retinol‐binding protein 4 and fetuin‐A marked future cardiometabolic risk.

To speed up the process of bringing a new drug to the market, more and more clinical trials are being conducted simultaneously in multiple regions. After demonstrating the overall drug's efficacy across regions, the regulatory and drug sponsor may also want to assess the drug's effect in specific region(s). Most of the recent approaches imposed a uniform criterion to assess the consistency of treatment effects between the interested region(s) and the entire study population regardless of the number of regions in multiregional clinical trials (MRCT). As a result, the needed sample size to achieve the desired probability of satisfying the regional requirement could be huge and implausible for the trial sponsors to implement. In this paper, we propose a unified additional requirement for regional approval by differing the parameters in the additional requirement depending on the number of planned regions. In particular, the values of the parameters are determined by a reasonable sample size increase with the desired probability satisfying the additional requirement. Considering the practicality of the global trial or sample size increase, we recommend specific values of the parameters for a different number of planned regions. We also introduce the assurance probability curve to evaluate the performance of different regional requirements.

In recent years, there is an increasing trend to conduct multi-regional clinical trials (MRCT) for drug development in Pharmaceuticals industry. A carefully designed MRCT could be used in supporting the new drug’s approval in different regions simultaneously. The primary objective of an MRCT is to investigate the drug’s overall efficacy across regions while also assessing the drug’s performance in some specific regions. In order to claim the study drug’s efficacy and get drug approval in some specific region(s), the local regulatory authority may require the sponsors to provide evidence of consistency in the treatment effect between the overall patient population and the local region. Usually, the regional specific consistency requirement needs to be pre-specified before the study conduct and the consistency in treatment effect between the region(s) of interest and overall population will be evaluated at the final analysis. In this paper, we evaluate the consistency requirements in multi-regional clinical trials for different endpoints, i.e., continuous, binary and survival endpoints. We also compare the different consistency requirements of the same endpoint/measurement if multiple consistency requirements are enforced and our recommendations for each endpoint/measurement will be made based on the comprehensive consideration.

Introduction Maintenance therapy has been extensively explored as a strategy for prolonging the duration of disease control and potentially survival following ASCT. To date, only lenalidomide has been approved for this indication. However, lenalidomide maintenance is associated with the development of second primary malignancies and tolerability issues. PIs are a backbone of MM treatment, and bortezomib-based maintenance has shown promising activity post-ASCT, yet the benefit of PI-based maintenance has not been demonstrated in a phase 3 trial vs placebo. Moreover, the feasibility of bortezomib maintenance in routine clinical practice is limited due to tolerability and the need for regular parenteral administration. There is a need for an oral PI maintenance therapy that can be administered for a prolonged period, improve depth of response without cumulative or late-onset toxicity, and improve convenience for patients. Methods The phase 3, double-blind, placebo-controlled, multicenter TOURMALINE-MM3 study (NCT02181413) compared weekly ixazomib vs placebo maintenance in NDMM patients who had at least a partial response (≥PR) to induction therapy with a PI and/or immunomodulatory drug (IMiD) followed by single ASCT. Patients were randomized (3:2) to receive ixazomib or matched placebo on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease (PD) or unacceptable toxicity. Randomization was stratified by induction regimen (PI without IMiD vs IMiD without PI vs PI+IMiD), pre-induction ISS stage (I vs II or III), and post-ASCT response (complete response [CR] or very good partial response [VGPR] vs PR). Patients were ineligible if they had received post-ASCT consolidation or tandem ASCT. The ixazomib dose was 3.0 mg during cycles 1-4, increasing to 4 mg from cycle 5 if tolerated during cycles 1-4. The primary endpoint was PFS per independent review committee (IRC), who were blinded to treatment assignment. The key secondary endpoint was OS. Here, we report data from the final analysis for PFS (data cut-off: April 16, 2018). Results 656 patients were randomized (395 ixazomib; 261 placebo). Patient demographics were balanced between groups; overall median age was 57 years (range, 24-73), 37% vs 63% had ISS I vs II or III, 59%/11%/30% had received PI without IMiD / IMiD without PI / PI+IMiD induction therapy, 34%/45%/21% had achieved CR / VGPR / PR following induction/ASCT, and 18% had high-risk cytogenetics [del(17p), t(4;14), or t(14;16)]. After a median follow-up of 31 months with 54% of PFS events, there was a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib vs placebo (median 26.5 vs 21.3 months; hazard ratio [HR] 0.72; 95% CI: 0.582, 0.890; p=0.002; Figure). In a landmark analysis from ASCT, PFS was 30.7 vs 24.9 months (HR 0.684; 95% CI: 0.551, 0.848; p Conclusions This study demonstrated a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib maintenance, with deepening of responses and increased conversions to MRD negativity over control, as well as a favorable safety profile, including an absence of risk of second primary malignancies and low rates of peripheral neuropathy, supporting ixazomib as a valuable option for maintenance therapy in responding patients post-ASCT. Figure. Figure. Disclosures Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Takeda Celgene, Amgen, BMS, and Roche: Other: Advisor; Janssen, Amgen, Takeda, Celgene, BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Schjesvold:Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Beksac:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Goldschmidt:Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; ArtTempi: Honoraria; Mundipharma: Research Funding. Maisnar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chng:Merck: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Aslan: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding. Kaiser:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Iida:Janssen: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Astellas: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Toyama Chemical: Research Funding; MSD: Research Funding; Gilead: Research Funding; Teijin Pharma: Research Funding; Sanofi: Consultancy. Morgan:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation. Dash:Takeda Pharmaceuticals International Co.: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Background There is increasing evidence for the clinical benefit of long-term, continuous therapy for NDMM pts. Proteasome inhibitors (PIs) form a backbone of therapy in MM; however, long-term therapy with some PIs may be limited due to toxicity and the need for regular parenteral administration, increasing the treatment burden. Ixazomib, the first oral PI, has been studied in NDMM pts in 4 phase 1/2 studies in which approximately 1 year of induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd) was followed by single-agent ixazomib maintenance. Here we report an integrated analysis of pts from these studies who did not undergo autologous stem cell transplant (ASCT) and received ixazomib maintenance therapy. Methods Pts from 4 studies were included: 1) weekly IRd, 12x28-d cycles IRd (weekly ixazomib 1.68-3.95 mg/m² in phase 1, recommended phase 2 dose [RP2D] 4.0 mg; C16005, NCT01217957; ASCT-eligible/-ineligible pts); 2) twice-weekly IRd, 16x21-d cycles IRd (twice-weekly ixazomib 3.0-3.7 mg in phase 1, RP2D 3.0 mg; C16008, NCT01383928; ASCT-eligible/-ineligible pts); 3) IMP, 9x42-d or 13x28-d cycles IMP (weekly/twice-weekly ixazomib 3.0-5.5/3.0-3.7 mg in phase 1, RP2D of weekly ixazomib 4.0 mg; C16006, NCT01335685; ASCT-ineligible pts); 4) ICd, 13x28-d cycles ICd (weekly ixazomib 4.0 mg; C16020, NCT02046070; ASCT-ineligible pts). In all 4 studies, pts completing induction without progressive disease (PD) and, in the IRd studies, not withdrawn for ASCT, could receive single-agent ixazomib maintenance at the last tolerated dose during induction until PD or unacceptable toxicity. Results 121 pts received ixazomib maintenance (25, 18, 35, and 43 in weekly IRd, twice-weekly IRd, IMP, and ICd studies, respectively). Median age was 72 yrs (range 34-90 yrs; 83% aged ≥65 yrs), 62% had IgG myeloma, 47/34/19% had ISS disease stage I/II/III, 40/49% had Eastern Cooperative Oncology Group performance status 0/1. Combined median progression-free survival (PFS) was 33.8 months from time of study entry and 21.4 months from start of maintenance (Figure). Median PFS from the start of maintenance seemed to be longer for the two IRd studies than for IMP, while median PFS for ICd had not yet been reached. 4-yr OS from time of study entry/3-yr OS from the start of maintenance was 82%. Overall response rate was 93% after induction and 94% after maintenance. Best response rate of CR+VGPR after induction was 57% (22% CR), which increased to 63% (35% CR/sCR) after maintenance; 24 pts (20%) improved their response during maintenance (4 pts with CR improved to sCR; 14 VGPR to CR/sCR; 5 partial response [PR] to VGPR/CR; 1 stable disease to PR). Combined mean dose intensity during maintenance was 89.1%. At time of analysis, median duration of maintenance therapy was 2.2 yrs for weekly IRd, 1.0 yr for twice-weekly IRd, and 0.9 yr for IMP and ICd; maximum duration was 4.8, 3.8, 3.9, and 1.6 yrs respectively. 78% of pts had discontinued maintenance, primarily due to PD (55%), and only 7% due to adverse events (AEs). 15% of pts had ixazomib dose reductions during maintenance. Grade ≥3 AEs (48% vs 74%), drug-related grade ≥3 AEs (24% vs 62%), serious AEs (SAEs; 21% vs 43%), and drug-related SAEs (5% vs 19%) were less common during maintenance than during induction. Common grade ≥3 AEs are shown in the Table. Other AEs of clinical interest were also generally similar or less common during maintenance than during induction, including cardiac arrhythmias (13% vs 21%), pneumonia (12% vs 17%), acute renal failure (7% vs 8%), hypotension (4% vs 7%), myocardial infarction (0 vs Conclusions In this integrated analysis, single-agent ixazomib maintenance therapy following an ixazomib-based induction regimen was associated with deepening of responses and good long-term outcomes in NDMM pts not undergoing ASCT. Single-agent ixazomib is feasible for long-term administration, with limited new-onset grade ≥3 AEs. These outcomes appear similar to other studies involving maintenance approaches in NDMM and support the ongoing phase 3 investigation of ixazomib maintenance therapy. Disclosures Dimopoulos: Novartis: Consultancy, Honoraria; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding. Laubach: Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Hofmeister: Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Roche: Research Funding; Karyopharm: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. San Miguel: Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria. Lu: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng: Array Pharmaceuticals: Equity Ownership; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Liu: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Byrne: Oncopeptides AB: Consultancy; Takeda: Consultancy. Berg: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. van de Velde: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson: Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees.

Background Ixazomib, the first oral proteasome inhibitor (PI), is approved by the US FDA, in combination with lenalidomide-dexamethasone (Rd), for the treatment of pts who have received at least 1 prior therapy. Lenalidomide is a common partner agent in regimens for RRMM; however, due to increasing use of lenalidomide treatment to progression as a standard of care in the first-line setting, novel PI-based combinations without lenalidomide are needed for RRMM. Combinations of a PI, an alkylating agent, and dexamethasone have been shown to be active, with manageable side effects, in RRMM patients (e.g. VCD - bortezomib, cyclophosphamide, dexamethasone), but require SC or IV administration of the PI. The all-oral combination of ICd may offer activity, tolerability, and more convenient administration. This open-label, multicenter phase 2 study (NCT02046070) assessed the safety and efficacy of ICd in pts with RRMM. Methods Adult pts with RRMM after 1-3 prior lines of therapy, who had ECOG performance status 0-2, were not PI-refractory, had adequate hematologic, renal, cardiac, and hepatic function, and did not have grade ≥2 peripheral neuropathy (PN) or grade 1 PN with pain, were eligible. Pts received oral ixazomib 4.0 mg and oral cyclophosphamide 300 mg/m2 on days 1, 8, and 15, plus oral dexamethasone 40 mg (20 mg for pts aged >75 yrs) on days 1, 8, 15, and 22, in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥partial response [PR]); secondary endpoints included safety, pharmacokinetics (PK), complete response (CR) plus very good PR (VGPR) rate, CR rate, time to response (TTR), duration of response (DOR), and progression-free survival (PFS). Results 78 pts were enrolled; median age was 64 yrs (40% aged >65 yrs), 53% were male, median time from initial diagnosis was 53.4 months (range, 12.9-142.7), and 24%/27% had ISS stage II/III disease at diagnosis. Median number of prior therapies was 2, including prior bortezomib, lenalidomide, and stem cell transplant (SCT) in 45 (58%), 38 (49%), and 50 (64%) pts, respectively; 17% were immunomodulatory-drug-naive. At data cut-off (June 20, 2016), pts had received a median of 12 treatment cycles (range, 1-22). A total of 51 (65%) pts had discontinued treatment, primarily due to disease progression (26 pts, 33%) and AEs (13 pts, 17%). Overall, 92% of pts reported AEs, including 59% with grade ≥3 AEs (51%/71% in pts aged ≤65/>65 yrs), and 29% with serious AEs (30%/29%). Common AEs are listed in Table 1. AEs resulted in dose reductions of any study drug in 28 (36%) pts (28%/48% of pts aged ≤65/>65 yrs) and treatment discontinuation in 11 (14%) pts (15%/13% aged ≤65/>65 yrs). Ixazomib, cyclophosphamide, and dexamethasone were dose modified in 83%, 85%, and 87% of pts, respectively. Median ixazomib relative dose intensity was 96%. There were 3 on-study deaths: cardiac arrest, severe pulmonary edema, and cerebral hemorrhage secondary to thrombocytopenia, with the latter considered treatment-related. PK data showed that ixazomib exposures were comparable to those in pts treated with IRd in the TOURMALINE-MM1 study, suggesting no PK interaction with Cd. ORR was 49%, including 16% CR+VGPR (Table 2); in pts with/without prior SCT, ORR was 41%/61% (15%/18% CR+VGPR). Median TTR in responding pts was 2.14 months; median DOR was not reached, with response durations of up to 17 months. After a median follow-up of 12.5 months, median PFS was not reached; 12-month PFS rate estimate was 57.5%. Subgroup analysis showed a higher ORR (68% vs 35%), a higher CR+VGPR rate (23% vs 12%), and a significant PFS improvement in pts aged >65 yrs vs pts aged ≤65 yrs (12-month PFS rate estimate 67.2% vs 50.7%; HR=0.43, p=0.028) (Figure). Although pts aged >65 yrs were less likely to have had prior SCT than those aged ≤65 yrs (22% vs 78%), this did not appear to account fully for the difference in outcomes (PFS in pts without vs with prior SCT, HR=0.82, p=0.6). Conclusions All-oral triplet therapy with ICd appears to have activity in RRMM pts, with a toxicity profile consistent with that seen with ixazomib in combination with Rd (Moreau, et al; N Engl J Med 2016). Preliminary best response and PFS data suggest there may be preferential benefit in elderly pts compared to younger patients (possibly related in part to more limited use of prior high-dose alkylator [melphalan] exposure associated with SCT in elderly pts) albeit with additional toxicity. Disclosures Kumar: Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Grzasko:Celgene: Honoraria; Munipharma: Honoraria; Janssen: Honoraria. Jędrzejczak:Novartis: Consultancy, Research Funding; BMS: Research Funding; Janssen-Cilag: Consultancy; Celgene: Consultancy; Angelini: Consultancy; Roche: Consultancy, Research Funding; Amgen: Research Funding; Sandoz: Consultancy. Kyrtsonis:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Array: Equity Ownership. Byrne:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

2580Background: This is an open-label, multi-arm, dose-escalation study (NCT01862328) of pev (TAK-924/MLN4924) plus chemotherapy in pts with solid tumors. Safety and preliminary efficacy results ha...

SummaryBackground Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date. Methods We prospectively evaluated 254 elderly men (mean age, 75·5 years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5- and 10-year follow-up. Results We observed no association between baseline concentrations of sex steroids, gonadotrophins and their trajectories with incident clinical CVD over 5- and 10-year follow-up. Although higher baseline TT concentrations were associated with lower mortality risk at 5 years (hazard ratio per quartile increment, 0·74; 95% confidence interval, 0·56–0·98), correction for multiple statistical testing (P

Background Ixazomib is the first orally administered PI to be studied in the clinic. The feasibility of combining a PI with cyclophosphamide and dexamethasone has been demonstrated with the PI bortezomib (Reeder et al Leukemia 2009; Mai et al Leukemia 2015). This open-label, multicenter, phase 2 study is evaluating the all-oral triplet combination of ICd, with two different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible pts with NDMM, and is the first study to assess ICd for the frontline treatment of MM. Methods Adult pts with previously untreated, symptomatic NDMM who were ineligible for stem cell transplantation due to age and/or comorbidities, had ECOG PS 0-2, and adequate hematologic, hepatic, and renal function, were included. Pts were randomized 1:1 to receive up to 13 x 28-day cycles of induction therapy with ixazomib 4.0 mg PO on days 1, 8, and 15, plus cyclophosphamide 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (ICd-400 arm) PO on days 1, 8, and 15, plus dexamethasone 40 mg PO (20 mg in pts aged >75 years) on days 1, 8, 15, and 22. A safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable pts in each arm after cycle 1. The primary endpoint was the combined rate of complete response plus very good partial response (CR+VGPR). Secondary endpoints included overall response rate (ORR; CR+VGPR+ partial response [PR]) and safety (adverse events [AEs]). Response was investigator-assessed at the end of every cycle per IMWG criteria. Sample size (n=70) was determined to provide 80% power for the primary endpoint of CR+VGPR rate (1-sided alpha=0.10). Here we present a preliminary analysis of data post-induction (data cut-off: July 1, 2015). Results 70 pts were randomized (36 to ICd-300, 34 to ICd-400): median age 72.5 and 75.5 years; 42% and 53% male; 64% and 59% ISS stage II/III (92% and 79% Durie-Salmon stage II/III), respectively. Mean duration of follow-up was 7.0 months in both arms. Response data are summarized in the Table. Best unconfirmed CR+VGPR rates across all 13 cycles were 27% (ICd-300) and 23% (ICd-400); ORRs were 80% and 73%. Best M-protein reductions are shown in the Figure. Twelve pts (6 ICd-300; 6 ICd-400) were DLT-evaluable; no DLTs were observed in either arm. Pts received a median of 6.0 (1-13) and 6.5 (1-13) cycles in the ICd-300 and ICd-400 arms, respectively. Mean ixazomib relative dose intensity was 90.7% in the ICd-300 arm and 89.8% in the ICd-400 arm. Across all 13 cycles of treatment (ICd-300 and ICd-400, respectively), rates of Gr ≥3 AEs were 53% and 62%, serious AEs 33% and 53%, AEs leading to dose reduction in any study drug 17% and 21%, discontinuation of all study drugs due to AEs 14% and 12%, and on-treatment deaths 2 pts (cardiac arrest; upper gastrointestinal hemorrhage) and 1 pt (pneumonia) which were not deemed as treatment-related. In the ICd-300 and ICd-400 arms, respectively, rates of anti-emetic use were 36% and 44% (8% and 18% for AEs) and G-CSF use 11% and 50% (11% and 35% for AEs); erythropoietin was used in only 1 pt (ICd-300 arm). Thrombocytopenia events occurred in 5 pts (no Gr ≥3) in the ICd-300 arm and 4 pts (3 Gr ≥3) in the ICd-400 arm. Most common AEs (>15% all pts) were anemia (19% and 29%), neutropenia (17% and 32%), nausea (14% and 24%), peripheral neuropathy (PN; 17% and 21%), diarrhea (19% and 15%), vomiting (14% and 21%), constipation (17% and 15%), and fatigue (14% and 18%). Most common Gr ≥3 AEs were neutropenia (14% and 32%), anemia (11% and 15%), and pneumonia (8% and 9%); no Gr ≥3 PN was observed. Conclusion These preliminary data suggest that the all-oral triplet combination of ICd is tolerable in transplant-ineligible pts with NDMM, with a manageable toxicity profile in line with that previously seen with ixazomib and with manageable myelosuppression. Comparably high response rates were reported in both the ICd-300 and ICd-400 arms. Toxicity rates appeared higher with ICd-400, suggesting that ICd-300 may be a more preferable regimen for elderly NDMM pts. Updated data, including long-term outcomes after additional follow-up will be presented at the meeting. Table. Best unconfirmed response by IMWG criteria during cycles 1-13 (response-evaluable pts) Response, n (%) ICd-300(n=30) ICd-400(n=30) CR 3 (10) 3 (10) PR 21 (70) 19 (63) VGPR 5 (17) 4 (13) CR+VGPR 8 (27) 7 (23) ORR (CR+VGPR+PR) 24 (80) 22 (73) SD 6 (20) 8 (27) SD, stable disease Disclosures Dimopoulos: Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with cyclophosphamide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are transplant-ineligible.. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.