Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

Quantitative Benefit–Risk Assessment of Rivaroxaban for the Prevention of Venous Thromboembolism.

Abstract 169 Introduction: Venous thromboembolism (VTE) is a common complication after hip or knee replacement and is associated with significant morbidity and mortality. Anticoagulants reduce the risk of these complications, but can also result in increased bleeding, thus requiring an assessment of benefit–risk. Patients and Methods: To obtain more precise estimates of treatment effects on low frequency events, data were pooled from 4 phase 3 randomized clinical trials (RECORD1–4) of rivaroxaban vs enoxaparin regimens (or enoxaparin/placebo combination in 1 study) for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in total hip and knee replacement. Although the studies were designed to answer slightly different questions and differed in treatment duration and comparator dose, pooling was supported by similar study designs, identical endpoints, identical event ascertainment methods, and the same independent central blinded adjudication committees. Benefit–risk was assessed by comparing the excess number of outcome events for benefits vs that for harms (‘risks'), occurring over the treatment period. Excess number of events was defined as the number of events in a hypothetical population of 10,000 patients treated with enoxaparin minus the number of events in such a population treated with rivaroxaban. A positive value indicates that fewer events occur in the population treated with rivaroxaban. The analysis was undertaken for several clinically comparable pairs of composite benefit and harm outcomes: total VTE (any DVT, non-fatal PE, or death from any cause) vs major and clinically relevant non-major (CRNM) bleeding; major VTE (proximal DVT, non-fatal PE, or VTE-related death) vs major bleeding; and symptomatic VTE/all-cause mortality vs major bleeding. For each pair, pooled Mantel–Haenszel weighted risk differences were used to compute the excess number of benefit and harm events, and the difference between excess numbers of events was used to evaluate net clinical benefit (NCB; Table). In all calculations, benefits and risks were weighted equally. An additional assessment was performed using all treatment-emergent serious adverse events (SAEs) as reported by investigators. Results: Rixaroxaban is associated with statistically significantly fewer total VTE, major VTE, and symptomatic VTE/all-cause mortality events than enoxaparin, whereas enoxaparin is associated with a smaller number of different bleeding events, although no bleeding endpoints, other than the composite of major + CRNM bleeding, were statistically significantly different. In each pairwise comparison, the excess number of bleeding events is less than the excess number of VTE-related events by a factor ranging from 4 to 10 (Table). Enoxaparin was also associated with an excess of 194 treatment-emergent SAEs compared with rivaroxaban out of 10,000 patients. In all cases, there is a positive NCB for rivaroxaban vs enoxaparin with 95% confidence intervals (CIs) excluding 0, suggesting that the benefits of rivaroxaban exceed the risks when compared with enoxaparin. Conclusions: This quantitative benefit–risk approach provides a comparison of interventions in clinically relevant population terms. Using the net clinical benefit approach, for a variety of endpoints defining benefits and harms, the benefit–risk profile for rivaroxaban is consistently improved compared with enoxaparin for patients after elective hip and knee replacement. Disclosures: Levitan: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Employment, Equity Ownership. Yuan:Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Employment, Equity Ownership. Turpie:Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Consultancy; Bayer Schering Pharma AG: Consultancy, Speakers Bureau; sanofi-aventis: Consultancy; GSK: Consultancy; Astellas: Consultancy; Takeda: Consultancy; Portola: Consultancy. Friedman:Boehringer Ingelheim : Consultancy, Research Funding; Johnson & Johnson : Consultancy; Astellas US: Consultancy, Research Funding; Sanofi-Aventis: Consultancy. Homering:Bayer Schering Pharma AG: Employment. Berlin:Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Employment, Equity Ownership. Berkowitz:Bayer HealthCare Pharmaceuticals: Employment. DiBattiste:Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Employment.

Pilot Trial of the Safety, Tolerability, and Retinoid Levels of N-(4-hydroxyphenyl) Retinamide in Combination With Tamoxifen in Patients at High Risk for Developing Invasive Breast Cancer

PURPOSE: N-(4-hydroxyphenyl) retinamide ([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated. RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P ≤ .01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade ≤ 2) reversible toxicities included skin and ocular dryness, fatigue, and mood changes. Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4. Baseline mean ± SD Cp retinol was 708 ± 280 ng/mL. Mean ± SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR were 0.34 ± 0.21 μmol/L, 0.28 ± 0.21 μmol/L, and 282 ± 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM. CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.