Purpose: On May 17, 2007, doxorubicin HCl liposome injection (Doxil) in combination with bortezomib (Velcade) received approval from the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory multiple myeloma after at least one prior therapy that has not included bortezomib. Liposomal doxorubicin's efficacy and safety were demonstrated in a phase III, randomized, multicenter, international trial comparing the combination of this agent plus bortezomib vs bortezomib alone in multiple myeloma patients who had not previously received bortezomib and had received at least one prior therapy. Here we summarize the FDA review of the data that support this approval.
Experimental Design and Results: An interim analysis of time to disease progression (TTP), the primary end point, was conducted after 249 TTP events in this study that randomized 324 patients to liposomal doxorubicin plus bortezomib treatment and 322 patients to bortezomib monotherapy. Time to progression was significantly prolonged in the combination arm (median TTP = 9.3 months) compared with bortezomib monotherapy (median TTP = 6.5 months), P < .0001 (log-rank test); hazard ratio = 0.55 (95% confidence interval = 0.43–0.71). The response rates were similar between the two arms and not statistically different; however, among responding patients, the median duration of response was longer with the combination—10.2 months compared to 7.0 months in the monotherapy arm. Adverse reactions occurred more frequently with the combination therapy. As compared to the monotherapy, frequent grade 3/4 adverse reactions with the combination were neutropenia and thrombocytopenia.
Conclusions: Liposomal doxorubicin received FDA approval for use in combination with bortezomib in patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.
The trial randomized 646 patients with progressive multiple myeloma between December 2004 and March 2006 in 123 study centers from 18 countries; 322 were assigned to the bortezomib arm and 324 to the liposomal doxorubicin–plus-bortezomib arm. These 646 patients comprised the intent-to-treat (ITT) population. Of 646 patients, 636 had at least one treatment after their randomization, and were thus included in the population for safety analysis.
The patient characteristics and disease status at enrollment were balanced between the two treatment arms, as shown in Tables 1 and 2. Most patients in both arms experienced disease progression after their response to initial therapy, with some primarily refractory to initial therapy. Two-thirds of patients had more than one line of prior therapy. Notably, two-thirds of patients also had prior treatment with anthracyclines. Disease burden as reflected by the levels of monoclonal proteins appeared similar between the treatment arms as well.
Protocol violations and deviations were similar between the two arms. The major violations and/or deviations that may have affected efficacy assessment were enrollment of patients who did not meet the criteria of measurable disease and use of protocol-contraindicated radiotherapy, other chemotherapeutics, or steroids during the trial. These departures represented 7% of patients in the combination arm and 5% in the bortezomib arm. Sensitivity analyses with exclusion of those patients did not alter the TTP results.
Treatment intensity and duration appeared to be similar between the two arms, with a median number of treatment cycles of five for each arm at the time of interim analysis. The median cumulative dose of liposomal doxorubicin was 147 mg/m2.
The interim analysis of TTP (as prespecified after approximately 230 events) in the ITT population was performed in August 2006 with 249 events (clinical data cutoff: April 28, 2006). The result favored the combination therapy. With the IDMC recommendation, the collection of TTP data ceased and the protocol was amended in September 2006 to allow patients who were actively on bortezomib monotherapy to cross over to the liposomal doxorubicin/bortezomib combination therapy. As shown in Table 3, the results for TTP, response rate, and duration of response were based on the interim analysis of the ITT population.
The primary endpoint of TTP was improved significantly in patients treated with liposomal doxorubicin/bortezomib combination therapy (median = 9.3 months) as compared to bortezomib monotherapy (median = 6.5 months)—hazard ratio = 0.55; 95% confidence interval = 0.43–0.71; P < .0001 (stratified log-rank test). The difference was considered clinically meaningful in this disease setting. The Kaplan-Meier TTP curves are shown in Figure 1. The response rate, including both complete and partial responses, was similar between the liposomal doxorubicin/bortezomib arm and the bortezomib monotherapy arm. However, the median duration of response was longer with combination therapy.
The overall survival analysis was not mature, as only 22% of subjects had died as of the data update at 4 months after the sNDA submission.
Safety was analyzed for the 636 patients who received at least one dose of the study drug. Treatment-emergent adverse reactions (TEARs) were generally comparable between the liposomal doxorubicin/bortezomib combination therapy and bortezomib monotherapy. As shown in Table 4, the most commonly observed adverse reactions, with a frequency of ≥ 25% on either arm, were fatigue, pyrexia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and peripheral neuropathy.
All-grade TEARs occurring with at least a 10% greater frequency in the combination arm compared to the bortezomib-alone arm were hand-foot syndrome, mucositis/stomatitis, and neutropenia. All-grade TEARS occurring with a 5% to 10% greater frequency in the combination therapy arm relative to the bortezomib-alone arm included fatigue, pyrexia, anorexia, thrombocytopenia, nausea, vomiting, diarrhea, weight decrease, and cough.
Grade 3/4 neutropenia occurred in 32% of subjects in the combination arm compared to 16% in the bortezomib arm, and thrombocytopenia occurred in 24% of subjects in the combination arm compared to 17% of subjects in the bortezomib arm. Grade 3 hand-foot syndrome was observed in 6% of subjects in the combination arm, but in no patients in the bortezomib-only arm.
The incidence of heart failure events was about 3% in both treatment arms. However, the protocol-defined decrease in LVEF was observed in 13% of subjects in the doxorubicin/bortezomib combination arm vs 8% in the bortezomib-alone arm.
The incidence of death within 30 days of treatment termination ascribed to study drug–related adverse reactions was 1% in both arms.
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