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

This study will compare the activity of CCD with that of the current standard therapy at relapse, 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.

To assess whether CCD provides non-inferior activity with regard to the short-term outcome measure of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with Carfilzomib to CCD provides superior activity in terms of the longer-term outcome measure of progression-free survival (PFS), as compared to CCD with no maintenance.

The MUK five trial is designed as a phase II randomised, controlled, parallel group, multi-centre clinical trial for participants with symptomatic myeloma at first relapse, or refractory to not more than 1 line of therapy. The trial has received national research ethics approval from the NHS National Research Ethics Service London, Fulham (REC Number: 12/LO/1078). A total of 300 participants will be randomised on a 2:1 basis to either 6 cycles of CCD or 8 cycles of CVD (both equivalent to 24 weeks of therapy), with follow-up to disease progression. Participants in the CCD arm who, at the end of the initial 6 cycles of CCD do not have evidence of disease progression, will be randomised to receive maintenance therapy with Carfilzomib or to receive no further treatment. Participants in the CVD arm will not receive maintenance therapy (Fig. 1). In order to compare the regimens with regard to activity, the trial has been designed to incorporate two co-primary endpoints: response and progression-free survival. This allows the trial to assess the activity of the two regimens within a fixed period of 24 weeks of treatment, i.e. not incorporating the maintenance phase in the CCD arm, and to compare the activity of the whole CCD regimen with and without maintenance therapy, and the whole CCD regimen without maintenance with the CVD regimen by evaluating the longer term endpoint of PFS.

The sample size was calculated according to each of the co-primary endpoints

The primary endpoint analysis is based on a non-inferiority comparison of CCD vs. CVD. Clinical discussion taking into account recent data anticipates a ≥ VGPR rate of approximately 30–40 % with CVD at first relapse [4, 15, 16]. Considerable discussion was given to whether this comparison should be performed as a superiority or non-inferiority comparison, since CCD is expected to improve ≥ VGPR rates by up to 10 %. In this setting, however, a phase II superiority trial to detect this small improvement would likely be unfeasible. A non-inferiority design is therefore used, assuming a ≥ VGPR rate of 35 % with CVD, and a ≥ VGPR rate of 45 % with CCD, with a non-inferiority margin of −5 %. Randomising participants on a 2:1 basis in favour of CCD, a total of 291 participants (CCD = 194, CVD = 97) are required to exclude a difference of −5 % from the 90 % confidence interval with 80 % power (1-sided 5 % significance level).

The primary PFS comparison will be focused on those participants undergoing maintenance randomisation in the CCD arm, to compare maintenance with carfilzomib vs. no maintenance. It is assumed that median PFS with CVD with no maintenance will be approximately 14 months from the time of initial treatment [17]. It is hypothesised that a similar median PFS will be observed with CCD therapy with no maintenance. It is also anticipated that approximately 80 % of participants randomised to receive CCD therapy will be progression-free at the end of 24 weeks of initial treatment [4]. With 80 % power, a 2-sided alpha of 0.2, and assuming follow-up of at least 18 months for all participants from the time of maintenance randomisation, 70 participants per arm (109 events) are required to detect a hazard ratio of 0.67, corresponding to an increase in median PFS of 6 months with Carfilzomib maintenance therapy, from the time of maintenance randomisation. Taking the required sample size for the response rate endpoint it is therefore expected that approximately 160 participants will be eligible for maintenance randomisation, providing a sufficient sample size to assess the maintenance therapy comparison, allowing approximately 10 % dropout.

The trial is expected to take up to 36 months to complete recruitment. Participants will be recruited from NHS hospitals throughout the UK which are approved research sites within the Myeloma UK Early Phase Clinical Trial Network. Participants will be approached during standard clinic visits for management of their disease and will be provided with verbal and written details, in the form of a participant information sheet. Following information provision, participants will have as long as they need to consider participation (normally a minimum of 24 h) and will be given the opportunity to discuss the study with their family and other healthcare professionals before they are asked whether they would be willing to take part in the study.

Participants who satisfy all the study inclusion criteria and none of the exclusion criteria listed in Table 1 will be invited to provide written informed consent.

Written informed consent for entry in to the trial must be obtained and eligibility must be confirmed prior to randomisation. Randomisation will be administered by telephone by the University of Leeds Clinical Trials Research Unit (CTRU), using an automated 24 h telephone system. Participants will be randomised on a 2:1 basis to either the CCD or CVD trial arm. A computer generated minimisation program that incorporates a random element will be used to ensure treatment groups are well-balanced for the following characteristics: β2 microglobulin at trial entry (<3.5, 3.5-5.5, >5.5); prior bortezomib (Velcade®) treatment (y/ n); prior ASCT (y/n); timing of first relapse or primary refractory disease (primary refractory, first relapse: < 12 months, first relapse: ≥ 12 months).

Participants on the CCD arm only, who have no evidence of progressive disease at the response assessment at the end of CCD therapy, will be randomised again to receive either carfilzomib maintenance or no maintenance treatment, provided they fulfil the eligibility criteria listed in Table 2. Participants will be randomised on a 1:1 basis to either carfilzomib maintenance or no maintenance. A computer generated minimisation program that incorporates a random element will be used to ensure treatment groups are well-balanced for the following characteristics: response category at the end of treatment with CCD (PR, MR or SD vs. VGPR or CR); prior ASCT (y/n).

Participants randomised to CVD will receive the following regimen: bortezomib subcutaneous 1.3 mg /m² (days 1, 4, 8 and 11), cyclophosphamide oral 500 mg (days 1, 8 and 15), dexamethasone oral 40 mg (days 1, 8 and 15). The cycle is repeated every 21 days. Response should be assessed at the end of each cycle and, in the absence of disease progression or intolerance, participants should receive 8 cycles of treatment. Participants randomised to CCD will receive the following regimen: carfilzomib IV 20 mg/m²(cycle 1, days 1 and 2 only) / 36 mg/m² (cycle 1, days 8, 9, 15 and 16, and cycle 2 onwards, days 1, 2, 8, 9, 15 and 16), cyclophosphamide oral 500 mg (days 1, 8 and 15), dexamethasone oral 40 mg (days 1, 8, 15 and 22). The cycle is repeated every 28 days. Response should be assessed at the end of each cycle and, in the absence of disease progression or intolerance, participants should receive 6 cycles of treatment.

Participants in the CCD arm, who are randomised to receive carfilzomib maintenance, will receive carfilzomib IV 36 mg/m² (days 1, 2, 15 and 16) for 6 months, after which the frequency of dosing will be reduced to carfilzomib IV 36 mg/m² (days 1 and 2) for a further 12 months.

Each drug may be reduced due to toxicity. If no resolution of toxicity is seen after adjustment to the lowest dose level, treatment will be discontinued.

Baseline investigations are to be performed within 14 days prior to randomisation, after written informed consent has been obtained. The required baseline assessments include a physical examination, medical history, ECOG performance status and ISS stage, as well as haematology, biochemistry, radiological and bone marrow sample assessments.

Assessments during treatment, including a physical examination, safety and laboratory tests will be performed at multiple time-points during cycles 1 – 6 for the CCD regimen and cycles 1 – 8 for the CVD regimen. Response assessments will be carried out at the end of treatment phase (6 months in each arm), according to International Myeloma Working Group (IMWG) criteria, and will include bone marrow examination for MRD using multi-parameter flow cytometry.

During maintenance in the CCD arm, assessments will be performed on days 1, 2, 15 and 16 of each cycle (or days 1 and 2 if administering the reduced schedule) and will include a physical examination and laboratory tests. Assessments at 6 and 12 months will also include bone marrow sampling for MRD assessment.

Assessments at the end of initial and maintenance treatment include a physical examination, laboratory tests and a bone marrow aspirate (post-initial treatment). Follow-up will be performed 4-weekly until disease progression, and will involve a physical examination and laboratory tests.

The study has two co-primary endpoints, the proportion of participants achieving at least VGPR 24 weeks post initial randomisation and progression-free survival. A key secondary endpoint is the proportion of participants experiencing ≥ grade 3 neuropathy or ≥ grade 2 neuropathy with pain during the initial treatment period (8 cycles of CVD or 6 cycles of CCD). All secondary endpoints are listed in Table 3.

Participants will be grouped as follows for analysis:

The trial has received national research ethics approval from the NHS National Research Ethics Service London, Fulham (REC Number: 12/LO/1078)

All patients provide written informed consent prior to randomisation in to the trial.

Not applicable

Not applicable – this is a protocol paper outlining the study being conducted. All data supporting the development of the study is outlined in the manuscript.