Phase-I randomized trial of doxorubicin hydrochloride liposome injection versus Caelyx® in multiple myeloma

The adjuvant use of liposomal doxorubicin (DXR) remains a well-documented treatment for multiple myeloma [1,2] and has demonstrated a beneficial therapeutic effect (in terms of overall response rate [ORR], progression-free survival [PFS] and duration of response) in a number of clinical studies [3–6]. In two studies of newly diagnosed patients, the ORR ranged from 57%, when liposomal DXR was used in combination with bortezomib, to 91% in standard-risk patients treated with cyclophosphamide/bortezomib/ dexamethasone, to 100% in high-risk patients treated with the same regimen [3,4]. In a long-term ( 5 years) study with relapsed/refractory patients treated with lenalidomide/liposomal DXR/dexamethasone/vincristine (DVd), the ORR was 53.0%, durable in the long term and DVd had an overall acceptable toxicity profile [5]. Finally, an interim analysis of a phase-III study of liposomal DXR/bortezomib versus bortezomib alone found similar response rates; however, time to progression and duration of response were significantly longer (9.3 vs. 6.5 months [p< .0001] and 10.2 vs. 7.0 months, respectively) [6]. To gain approval from regulatory agencies around the world, it is necessary for generic liposomal formulations of drugs to meet stringent requirements for bioequivalence with the reference drug [7]. Sun Pharmaceutical Industries Limited (SPIL; Mumbai, India) developed a generic DXR hydrochloride liposome injection, which has been shown to be equivalent to the reference drug (CaelyxR ; Janssen-Cilag International NV, Beerse, Belgium) based on an extensive series of physicochemical characterization assessments. It is proposed for the same indications (and doses) as CaelyxR , including an indication in multiple myeloma (in combination with bortezomib). The aim of this study was to monitor the safety and assess the head-to-head bioequivalence of generic DXR hydrochloride liposomal injection compared with CaelyxR in terms of total, encapsulated and free DXR. It was an open-label study because blood concentration levels cannot be influenced by knowledge of the treatment. A randomized crossover design is typically employed in bioequivalence studies and considered to be the most appropriate for this study. This two-treatment, two-period, two-sequence, single-dose, crossover study was conducted under fed conditions in patients with multiple myeloma at five sites across India. The design of the study, which included 21 days of washout between doses, was approved by the Drug Controller General of India and was conducted in accordance with the Guidelines for Good Clinical Practice (GCP) and the Declaration of Helsinki. All patients provided written informed consent before participating in the study. The study was registered at www.clinicaltrials.gov as #NCT00863174. Eligibility criteria included: multiple myeloma with one prior therapy but naive to bortezomib; 18 years of age; no other underlying disease; performance 2 on the Eastern Cooperative Oncology Group (ECOG) performance scale; normotensive; and adequate organ and immune function. Exclusion criteria included current or recent treatment with CYP inhibitors or inducers, enzyme-modifying drugs, anticancer chemotherapy and hormonal contraception; signs of clinically significant illness (including cardiac disease, HIV, hepatitis B and/or C); current pregnancy or lactation; and participation in any other clinical trials within 90 days. Patients were randomized to receive test or reference product first according to the randomization schedule generated by SASR software (release 9.1.3; SAS Institute, Cary, NC), at SPIL, Vadodara, India. They fasted for at least 10 h before eating a normal, low-fat breakfast 30min before administration of the study drug. All patients received dexamethasone 8mg intravenously (IV) 45min before administration, and granisetron 2mg IV and bortezomib 1.3mg/m IV 30min before administration. The test and reference products were administered