Doxorubicin HCl liposome injection (Doxil) received accelerated approval in November 1995 for the treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy. In June 1999, the drug received accelerated approval for the treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel(Drug information on paclitaxel)- and platinum-based chemotherapy regimens, which was followed by regular approval in January 2005 for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.
Relapsed/refractory multiple myeloma constitutes a major challenge for both patients and oncologists.[1,2] Therapeutic options for this disorder include retreatment with initial chemotherapy regimens such as vincristine, doxorubicin(Drug information on doxorubicin), and dexamethasone(Drug information on dexamethasone), thalidomide(Drug information on thalidomide) (Thalomid), bortezomib(Drug information on bortezomib) (Velcade), lenalidomide (Revlimid), and autologous or allogeneic hematopoietic cell transplantation. With thalidomide accepted as front-line therapy for a number of patients, bortezomib and lenalidomide have become treatment options for relapsed or refractory disease.
In a randomized, open-label phase III trial in patients with multiple myeloma previously treated with at least one prior therapy, patients receiving bortezomib alone demonstrated a median time to progression of 6.2 vs 3.5 months with dexamethasone.[3,4] In addition, two randomized, double-blind, placebo-controlled phase III trials showed that the combination of lenalidomide with dexamethasone was associated with a prolonged time to progression compared with placebo plus dexamethasone in patients with multiple myeloma who had received at least one prior therapy.[5,6] Various combinations have been studied incorporating bortezomib or lenalidomide with the aim of enhancing efficacy.[1,7] The study supporting this supplemental new drug application (sNDA) combined pegylated liposomal doxorubicin with bortezomib to treat patients with relapsed and/or refractory multiple myeloma who have received at least one prior therapy.
The protocol for this study in patients with progressive multiple myeloma was submitted and reviewed by the US Food and Drug Administration (FDA) prior to its initiation. The protocol was activated in August 2004. In December 2004, liposomal doxorubicin received orphan drug designation for the treatment of patients with multiple myeloma whose disease has progressed after at least one prior therapy or was refractory to initial therapy. In November 2006, the sNDA was submitted and received a designation for priority review (resulting in a 6-month review timeline). Here we summarize the FDA analysis of the study results.
Study Design for DOXIL-MMY-3001
This liposomal doxorubicin sNDA was based primarily on the results of the DOXIL-MMY-3001 study, an open-label, randomized, multicenter international trial of liposomal doxorubicin plus bortezomib vs bortezomib alone in patients with relapsed or refractory multiple myeloma who have had at least one prior therapy. Prior to randomization, patients were stratified based on beta2-microglobulin level (≤ 2.5 mg/L; > 2.5 mg/L and ≤ 5.5 mg/L; or > 5.5 mg/L) and their response to prior treatment (relapsed vs refractory). Randomization was in a 1:1 allocation within each stratum to the two treatment arms.
Inclusion criteria mainly included the following: (1) patients with confirmed diagnosis of multiple myeloma that was measurable as determined by monoclonal protein in serum (> 1g/dL) or urine (> 200 mg/24 h); (2) progressive disease or primary refractory disease following at least one prior therapy, as defined by > 25% increase in monoclonal protein or development of new or worsening lytic bone lesions, plasmacytoma, or hypercalcemia; (3) adequate bone marrow, renal, and hepatic function as reflected by baseline creatinine clearance ≥ 30 mL/min, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × upper limit of normal, absolute neutrophil count ≥ 1.00 × 109/L, platelet count ≥ 75 × 109/L, hemoglobin ≥ 8.0 g/dL, and serum calcium, corrected < 12 mg/dL or ionized calcium < 6.5 mg/dL; (4) left-ventricular ejection fraction (LVEF) within institutional normal limits; and (5) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 with a life expectancy of at least 3 months.
Exclusion criteria are summarized as follows: (1) history of treatment with bortezomib; (2) prior treatment with doxorubicin or other anthracycline at cumulative doses greater than 240 mg/m2; (3) nonsecretory or nonmeasurable disease; (4) progressive disease while receiving an anthracycline-containing regimen or no change in disease status during initial therapy; (5) peripheral neuropathy of grade 2 or higher severity; (6) cardiac conditions such as myocardial infarct within 6 months before enrollment, symptomatic heart failure, or uncontrolled angina; (7) treatment with other chemotherapeutics, radiation therapy, or major surgery within 21 to 30 days before randomization; (8) seropositive for human immunodeficiency virus, or active hepatitis A, B, or C infection; or (9) other poorly controlled medical conditions that could interfere with adherence to or completion of the study.
The primary efficacy endpoint was time to progression (TTP), defined as the interval between the date of randomization and the date of disease progression or death due to progression. The date of disease progression was determined as the date of the first indication of progression. Patients who were progression-free (including those who died without documented progression) at the time of data cutoff were censored for TTP at the time of their last tumor assessment. Disease progression was assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria established in 1998 and confirmed by an independent data-management committee (IDMC). Secondary endpoints included overall survival, response rate, and duration of response.
The study was designed to detect an improvement in median TTP from 6 months with bortezomib monotherapy to 7.8 months with combination therapy. With 80% power and an overall significance level of 5% (two-sided), the estimated sample size was to have approximately 630 subjects (315 per treatment arm) randomized to observe 460 events (progression or death due to progression). An interim analysis of TTP was planned after approximately 230 events were observed. The collection of TTP data was planned to stop should the data strongly favor treatment with the combination liposomal doxorubicin plus bortezomib as compared to bortezomib alone.
Patients assigned to the combination therapy were to receive liposomal doxorubicin every 3 weeks at a dose of 30 mg/m2 as a 1-hour intravenous infusion on day 4 following bortezomib. Bortezomib at 1.3 mg/m2 was administrated in both arms as an intravenous bolus on days 1, 4, 8, and 11, every 3 weeks. Treatment continued until disease progression, ≥ 14 days delay in starting a new cycle, the occurrence of unacceptable treatment-related toxicity, or for up to a total of eight cycles of therapy, with the exception of a continuing decrease in monoclonal protein > 25% from course to course.
For bortezomib-related neuropathy, dose modifications followed the bortezomib label; for liposomal doxorubicin–related hand-foot syndrome and stomatitis, dose modifications followed the liposomal doxorubicin label. For cardiac toxicities, doxorubicin was supposed to be discontinued if patients experienced symptomatic arrhythmia, congestive heart failure, or an absolute decrease ≥ 15% in LVEF, or LVEF decrease to less than an institution's lower normal limit and absolute decrease ≥ 5%.
Patients underwent clinical and laboratory evaluations every 3 weeks for the first 42 weeks, then every 6 weeks until progression. Serum and urine protein measurements were assayed in a central laboratory, and the results were used by all investigators for assessing response.
Patients were permitted to receive supportive therapies such as bisphosphonates, hematopoietic cytokines (not used prophylactically), blood product transfusions, and antiemetics.