FOCUS is a phase 3, randomized, open-label, multicenter study comparing 2 treatment regimens for patients with MM for whom no approved alternative therapies are available.
The primary objective of the study is to compare OS in patients with relapsed and refractory MM shown to be refractory to their most recent therapy and who have received all standard approved therapies, randomized to receive carfilzomib or a defined BSC regimen.
Secondary endpoints include PFS, ORR [stringent complete response (sCR)
complete response (CR)
very good partial response (VGPR)
partial response (PR)], CBR (ORR
MR), disease control rate (DCR; CBR
stable disease lasting ≥8 weeks),
DOR (calculated separately for overall response, CBR, and disease control endpoints), and safety.
Eligible patients must be at least 18 years of age and have measurable MM (defined by serum M protein ≥0.5 g/dL or serum quantitative immunoglobulin A ≥750 mg/dL in patients with IgA secretory MM and/or urine Bence Jones protein ≥200 mg/ 24 h), an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–2, and a life expectancy of at least 1 month. Patients must have received 3 or more prior therapeutic regimens, including treatment with bortezomib (defined as ≥4 cycles at full dose if tolerated); must have been responsive to at least 1 line of therapy (defined as a ≥25% decrease in M protein or total protein) and have relapsed disease, defined as progression while on or after at least 1 treatment regimen; and must have been refractory to their most recent therapy, defined as nonresponsive (eg, stable disease only, or progressive disease while on treatment), or disease progression within 60 days of discontinuation from therapy. Prior treatments must have included an immunomodulatory agent, an alkylating agent, and a corticosteroid. Additionally, patients must have adequate hepatic function and creatinine clearance of ≥15 mL/min.
Exclusion criteria include: Waldenström’s macroglobulinemia or IgM myeloma, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome or plasma cell leukemia; major surgery within 21 days prior to randomization; myocardial infarction in previous 3 months, New York Heart Association Class III/IV congestive heart failure; known human immunodeficiency virus seropositivity or active hepatitis; significant neuropathy (Grade ≥3 or Grade 2 with pain) at randomization; other malignancy in past 3 years; and prior carfilzomib treatment.
Study design and treatment
The study will be conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization E6, and any applicable regulatory requirements. The protocol and amendments have been reviewed by an Independent Ethics Committee. Approval has been provided by the Ethics Committee for each institution or city where the clinical trial is being held. Written informed consent will be obtained before any protocol-specific tests or procedures are conducted. Estimated sample size is 302 patients, and randomization will be stratified based on number of previous therapies and geographic location (Europe vs non-Europe). Eligible patients will be randomized in a 1:1 ratio to carfilzomib or BSC regimen (Table ). BSC will initiate on Cycle 1 Day 1 and will include corticosteroid treatment (prednisolone 30 mg every other day, dexamethasone 6 mg every other day, or equivalent), with optional cyclophosphamide 50 mg PO once daily.
Carfilzomib treatment will be given in 28-day cycles at 20 mg/m2 IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m2 IV for Days 8, 9, 15, and 16 of Cycle 1 and continuing at 27 mg/m2 for Cycles 2 through 9. For Cycles 10 and higher, carfilzomib will be given at 27 mg/m2 IV on Days 1, 2, 15, and 16. Oral hydration, IV hydration, and dexamethasone 4 mg PO or IV during Cycle 1 will be included in the treatment regimen. Dosing will be modified as necessary (20 mg/m2, 15 mg/m2, or 11 mg/m2) to manage toxicity.
For all patients randomized to carfilzomib, required concomitant medications during Cycle 1 include dexamethasone (4 mg PO or IV) and ciprofloxacin (500 mg PO QD). Valacyclovir or an equivalent antiviral is also required for patients treated with carfilzomib who have a history of herpes zoster. Additional medications that are permitted include bisphosphonates and other supportive care therapies at the investigator’s discretion. Uric acid-lowering agents, red blood cell and platelet transfusions, erythropoiesis-stimulating agents, and approved growth factors may be given when clinically indicated. Concurrent treatment with any anticancer therapy or radiation to large marrow reserves with therapeutic or palliative intent are not permitted, nor are corticosteroids at doses higher than those stated in the protocol. Plasmapheresis is not permitted.
Patients will continue randomized study treatment until confirmed disease progression (progressive disease, PD) or unacceptable toxicity. Following confirmation of PD or discontinuation from study treatment, all patients will enter long-term follow-up (LTFU) for survival. Crossover is not allowed upon progression.
Assessment of efficacy
Patients will be evaluated for disease response and progression according to the International Myeloma Working Group (IMWG) response criteria [25
] and for MR according to the European Group for Blood and Marrow Transplantation (EBMT) criteria [26
]. Evaluations will occur on Day 1 of each cycle, at the post-treatment visit, and during LTFU for those who did not have PD prior to discontinuing treatment. PD must be confirmed by 1) 2 consecutive measurements of rising serum or urine M-protein, 2) development of new lesions or definite increase in size of existing bone lesions or soft tissue plasmacytomas, or 3) hypercalcemia attributed solely to MM. Tumor response for all categories must be confirmed by 1) 2 consecutive M-protein measurements, 2) plasmacytoma evaluation where relevant, 3) no evidence of new or progressive bone lesions and 4) bone marrow biopsy for CR/sCR.
Assessment of safety
All patients who receive at least 1 dose of any study-specific treatment will be included in the safety analysis. Adverse event (AE) data will be collected at each visit from the time the patient signs the consent form and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and assigned a severity grade using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 grading scale. The investigator may discontinue study treatments for the following reasons: patient withdrawal of consent, confirmed PD, unacceptable toxicity, noncompliance with study procedures, requirement for alternative therapy, and intercurrent illness or worsening of a chronic condition; however, patients will be encouraged to remain on study for survival assessment. Patients with a dose reduction due to toxicity will remain on study; if the reduced dose is well tolerated, the patient may be rechallenged with the original dose at the start of the next cycle.
The primary endpoint of the study is OS, defined as the time from randomization to death due to any cause. The study will provide 80% power to detect a 30% reduction in the risk of death. The primary inferential comparison for OS between treatment groups will use the log-rank test assessed against an overall 1-sided significance level of 0.025 stratified by the randomization stratification factors (number of prior therapies and geographical location). The hazard ratio for treatment group will be estimated using a stratified Cox proportional hazards model. The distribution of OS times will be summarized using the Kaplan-Meier method.
An independent data monitoring committee (DMC) has been convened for this study and will act in an advisory capacity in safeguarding the interests of study patients, assessing interim safety and efficacy and for monitoring the overall conduct of the trial.
The inferential tests associated with secondary endpoints PFS, ORR, CBR, DCR, and DOR (including duration of clinical benefit and duration of disease control) will be performed in accordance with a closed testing procedure (CTP) to adjust for the multiplicity. Under the CTP, if the null hypothesis for the primary endpoint (OS) is rejected at the 1-sided significance level of 0.025, then testing of the secondary endpoints will proceed in a sequential step-down manner and a 1-sided significance level of 0.025 will be used at each testing step. Testing of secondary endpoints will continue provided the null hypothesis for each of the previously tested secondary endpoints is rejected.
The distribution of PFS times will be summarized descriptively using the Kaplan-Meier method. The inferential comparison between treatment groups will use the log-rank test stratified by the randomization stratification factor. The hazard ratio for treatment group will be estimated using a stratified Cox proportional hazards model. The inferential comparison between treatment groups for the ORR, CBR, and DCR endpoints will be made using the Cochran-Mantel-Haenszel chi-square test, stratified by the randomization stratification factor. The odds ratio to measure the relative treatment effect and the 95% CI will be estimated using the Mantel-Haenszel method. The DOR will be calculated for patients who achieve sCR, CR, VGPR, and PR. The inferential comparison between treatment groups will use the log-rank test stratified by the randomization stratification factors (region: Europe vs non-Europe, and number of prior lines of therapy: 3 vs 4 vs ≥5). The duration of overall response will be summarized descriptively using the Kaplan-Meier method.
The comparisons for the primary and secondary efficacy endpoints will be between the 2 randomized treatments groups (Regimen C vs Regimen BSC) based on the intent-to-treat population (ITT), consisting of all randomized patients.
FOCUS began enrolling patients in September 2010 with a target enrolment of 302 patients. Approximately 100 institutions are being recruited to participate. The study is currently accruing patients in 7 countries and over 40 sites throughout Europe and is expanding to other parts of the world, with 211 patients enrolled as of the end of June 2012.