Phase III Trial of Pixantrone Dimaleate Compared with Other Agents as Third-Line, Single-Agent Treatment of Relapsed Aggressive Non-Hodgkin's Lymphoma (EXTEND): Results From the Treatment and Follow-up Periods.

Nearly half of patients with aggressive non-Hodgkin's lymphoma (NHL) relapse or are refractory to initial therapy. With each subsequent therapy, the probability of response decreases and the responses are less durable. An agent currently in development, pixantrone dimaleate (pixantrone), is a novel aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. The clinical activity and safety profile of pixantrone are promising in patients heavily pretreated for relapsed aggressive NHL and who received prior treatment with up to 450 mg/m² of doxorubicin.

This phase 3, randomized, multicenter, controlled, open-label study enrolled patients who had ≥1 prior anthracycline-containing regimen and failed 2 prior treatment regimens for relapsed aggressive (de novo or transformed) NHL. Seventy patients were randomized to a treatment group administered pixantrone 85 mg/m² on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles. Seventy patients were randomized to the investigator's choice of a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, or mitoxantrone; in the US only, gemcitabine and rituximab were permitted). Patients in both groups were followed up to 18 months after last treatment. The primary endpoint, CR/CRu rate, was assessed by an independent assessment panel (IAP). Other efficacy endpoints were overall response rate (ORR), responses lasting ≥4 months, progression-free survival (PFS), overall survival (OS), duration of response, and time to response. This report includes the results from the treatment period and updated results from the follow-up period, which is still ongoing.

A total of 140 patients were randomized with 70 patients in each treatment group. Of the 140 patients, 96% received treatment (n=68 for pixantrone, n=67 for comparator). The median number of treatment cycles that patients in the pixantrone group received was 4 compared with 3 for the comparator group. The percentage of patients who received all 6 treatment cycles in the pixantrone group was 32.4% compared with 28.4% for the comparator. The primary endpoint, CR/CRu rate (assessed by IAP), in the ITT population was 20.0% for the pixantrone group compared with 5.7% for the comparator (P = 0.021). The ORR for the pixantrone group was 37.1% compared with 14.3% for the comparator (P = 0.003), and the percentage of patients with objective responses lasting at least 4 months for the pixantrone group was 25.7% compared with 8.6% for the comparator (P =0.012). The median number of months of PFS in the pixantrone group was 4.7 compared with 2.6 for the comparator (HR= 0.60, log rank P = 0.007). The median number of months of OS, while not fully mature, was 8.1 for the pixantrone group compared with 6.9 for the comparator (HR=0.88, log rank P = 0.554). Subgroup assessments of the CR/CRu rate and ORR, by risk factor, were consistently higher in the pixantrone group than in the comparator group. These subgroup assessments included prior exposure to anthracyclines ('300 mg/m² or ≥300 mg/ m²) and rituximab (treated or not treated), IPI score ('1 or ≥2), and NHL diagnosis (refractory or relapsed), and age ('65 or ≥65). In the pixantrone group, neutropenia and leukopenia were the most common (≥10%) grade 3/4 adverse events and the incidence of febrile neutropenia was 7.4%. The percentage of patients with cardiac disorder SAEs was 8.8% in the pixantrone group compared with 4.5% for the comparator.

In this phase 3, randomized, multicenter study, patients with relapsed aggressive NHL administered single-agent pixantrone achieved superior efficacy, compared with other single-agent chemotherapeutic agents, as measured by CR/CRu rate, ORR, responses lasting ≥4 months, and PFS. Positive trends were observed in OS and duration of response. Patients in the pixantrone group tended to reach CR sooner than patients in the comparator group. Pixantrone has a tolerable safety profile in heavily pretreated patients with relapsed aggressive NHL.

Cernohous:Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment.