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

Abstract

BackgroundMultiple 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.MethodsMUK 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.DiscussionThe 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 registrationThe trial is registered under ISRCTN17354232, December 2012.

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 (MUK<i>five</i>)

“…The full trial protocol, including eligibility criteria and sample size, have already been published. 15 The trial received national research ethics approval from the NHS National Research Ethics Service London, (REC number: 12/LO/1078). Three hundred participants were randomized (2:1) to KCd or VCd, using minimization with a random element.…”

Carfilzomib boosted combination therapy for relapsed multiple myeloma

“…The primary objective of the study is to report noninferiority activity through response rate after 24 weeks of treatment. 33 Another study, NCT02056756, is evaluating the MTD of the combination of carfilzomib with bendamustine and dexamethasone for RRMM after at least one prior line of therapy. 34 Results of this study are awaited within the next year.…”

Experiences of establishing an academic early phase clinical trials unit

“…Within the first 6 years of establishing the Myeloma UK Clinical Trials Network and Coordinating Office, a total of 13 trials have been developed, [6][7][8] two of which did not open due to safety concerns during development and withdrawal of industry support. During this time we have learnt that, due to the early phase nature of these studies and working closely with industry, there is a significant time investment in developing a study while negotiations are ongoing.…”

“…Leeds CTRU was successfully awarded a grant to become the Clinical Trials Coordinating Office for the Myeloma UK Clinical Trials Network, providing infrastructure funding to lead the design, central coordination, data management, and analysis of the Network's trial portfolio. Since then, a portfolio of 6 phase I and 7 phase II protocols have been developed through the Network, [6][7][8] funded through industry partnerships and Myeloma UK, and the CTRU has expanded its early phase research into other disease areas, including the initiation of the Yorkshire Cancer Research Centre for Early Phase Clinical Trials.…”