Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multicenter, phase II, randomized, controlled trial (MUKfive).

The proteasome inhibitors, carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these proteasome inhibitors in combination with cyclophosphamide and dexamethasone (KCd vs. VCd) in second-line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomized patients (2:1) to KCd (n=201) or VCd (n=99); responding patients on carfilzomib were randomized to maintenance carfilzomib (n=69) or no further treatment (n=72). Primary endpoints were: (i) very good partial response (non-inferiority, odds ratio [OR] 0.8) at 24 weeks, and (ii) progression-free survival. More participants achieved a very good partial response or better with carfilzomib than with bortezomib (40.2% vs. 31.9%, OR=1.48, 90% confidence interval [CI]: 0.95, 2.31; non-inferior), with a trend for particular benefit in patients with adverse-risk disease. KCd was associated with higher overall response (partial response or better, 84.0% vs. 68.1%, OR=2.72, 90% CI: 1.62, 4.55, P=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, P<0.0001), while grade ≥3 cardiac events and hypertension were only reported in the KCd arm (3.6% each). The median progression-free survival in the KCd arm was 11.7 months vs. 10.2 months in the VCd arm (hazard ratio [HR]=0.95, 80% CI: 0.77, 1.18). Carfilzomib maintenance was associated with longer progression-free survival, median 11.9 months vs. 5.6 months for no maintenance (HR 0.59, 80% CI: 0.46-0.77, P=0.0086). When used as fixed duration therapy in first relapase, KCd is at least as effective as VCd, and carfilzomib is an effective maintenance agent. This trial was registered with International Standard Randomised Controlled Trial Number (ISRCTN) identifier: ISRCTN17354232.

Experiences of establishing an academic early phase clinical trials unit.

BACKGROUND: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely, and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This article describes an approach to establishing an academically led early phase trial portfolio, highlighting lessons learned and sharing experiences. METHODS: In 2009, the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK's phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. RESULTS: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focussing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. CONCLUSION: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article.

Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial.

There is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply-treated patients. We report a multi-centre randomized two-stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m2 vs. 100 mg/m2) days 1 and 8, thalidomide (100 mg) days 1-21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28-d cycle. Ninety-four relapsing patients were treated on trial, with a median three prior treatment lines. A pre-planned interim deliverability and activity assessment led to closure of the 100 mg/m2 arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non-haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m2 arm, treatment was deliverable in 61.1% subjects and the partial response rate was 46.3% in the study eligible population, with 7.5 months progression-free survival. This study demonstrates bendamustine at 60 mg/m2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre-treated myeloma patients and has substantial clinical activity.

MUKnine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia.

INTRODUCTION: Multiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients. METHODS AND ANALYSIS: The Myeloma UK nine OPTIMUM trial (MUKnine) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUKnine a), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUKnine b) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUKnine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing. ETHICS AND DISSEMINATION: Ethics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN16847817, May 2017; Pre-results.

Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial.

INTRODUCTION: Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone. PATIENTS AND METHODS: Sixteen patients who had received a median of 1 prior treatment line received bortezomib subcutaneously 1.3 mg/m2 days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle). RESULTS: Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability. CONCLUSION: Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor-based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.

The MUK eight protocol: a randomised phase II trial of cyclophosphamide and dexamethasone in combination with ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor.

BACKGROUND: Multiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD. METHODS: MUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This 'switch' phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment. DISCUSSION: Development of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safety and efficacy of ICD in patients with RRMM demonstrate a toxicity profile consistent with ixazomib in combination with lenalidomide and dexamethasone, whilst the combination showed possible activity in RRMM patients. Further investigation of the anti-tumour effect of this drug in RRMM patients is therefore warranted, especially since no trials comparing CD with ICD have been completed at present. TRIAL REGISTRATION: ISRCTN number: ISRCTN58227268 . Registered on 26 August 2015.

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma.

BACKGROUND: Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. METHODS: MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. DISCUSSION: The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. TRIAL REGISTRATION: The trial is registered under ISRCTN17354232, December 2012.