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Coltuximab ravtansine monotherapy in DLBCL
44 patients were evaluable for response, the study had 90% power to reject the null hypothesis of an ORR of 20% with a one- sided a=0.05. An ORR of less than 20% was considered clinically uninteresting based on available observations from coltuximab ravtansine and new agents in relapsed/refractory non-Hodgkin lymphoma and/or DLBCL, for which activity ranged between 15% and 30% in phase II studies.22-28 The primary end point (ORR), was assessed in the per protocol (PP) population (all treated patients who had an evaluable response assessment during or at the end of treatment or who died due to PD before response assessment, without any important protocol deviations affecting efficacy at study entry). ORR was also assessed in the biomarker- evaluable population (all patients with results of biomarker analy- sis from a fresh or archival sample). DOR and PFS were assessed in the PP population, and OS and safety were assessed in all treat- ed patients (safety population).
Statistical analyses of biomarkers are detailed in the Online Supplementary Appendix.
Results
Overall, 61 patients were enrolled (January 20, 2012 to July 23, 2013) and received at least one dose of study drug (safety population). Twenty patients were excluded from the PP population (Figure 1), of whom 16 were wrongly enrolled in the study due to misclassification of their prior treatment history. Of these 16 patients, primary refracto-
ry disease was the sole important deviation at study entry in 14. The primary end point (ORR) was analyzed sepa- rately in this subgroup.
Baseline characteristics of the safety population are summarized in Table 1. Most patients (50 of 61 patients; 82.0%) presented with DLBCL at initial diagnosis. Of those patients with transformed lymphoma (n=11), 7 were initially diagnosed with follicular lymphoma, and 9 had received prior anticancer therapy for non-DLBCL lymphoma (6 patients received ≥1 prior anti-CD20-con- taining regimen). Almost half of the patients (45.9%) had bulky disease (defined as longest diameter of the lesion >5 cm for at least one location). Patients had received a median of 2.0 (range 0-9) prior treatment regimens for DLBCL, with 18 patients (29.5%) having received 3 or more prior regimens.
Patients received a median of 3 (range 1-10) cycles of therapy [median duration of treatment 13.3 (range 5-41) weeks]. Thirty-nine of 61 treated patients (63.9%) received 3 or more treatment cycles, including 16 patients who received 6 cycles or more. Overall, 56 patients discontin- ued treatment due to: PD (n=47), AEs (n=6), or investiga- tor’s decision (n=3). At the time of analysis (May 6, 2014), 5 patients were continuing on therapy.
The ORR (primary end point), analyzed in the PP popu- lation (n=41), was 43.9% (18 of 41; 90%CI: 30.6-57.9%); therefore, the null hypothesis was rejected (P<0.0001). Among the 18 responders, 6 achieved CR (PET negative) and 12 achieved PR [PET positive (n=8) or not examined
Figure 1. Inclusion of patients in the per protocol (PP) efficacy analysis. Patients were recruited at 28 sites in the USA, Belgium, Czech Republic, Israel, Italy, Poland, Spain, Turkey, and UK. The PP population consisted of all treated patients who had an evaluable response assessment during or at the end of the treatment protocol or who died due to progressive disease before response assessment, without any important protocol deviations affecting efficacy at study entry. CT: computed tomography; DLBCL: diffuse large B-cell lymphoma. *Some patients met multi- ple exclusion criteria. †Fourteen patients had primary refractory disease as their only protocol deviation.
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