A Phase I/II Study of Bortezomib in Combination with Paclitaxel, Carboplatin and Concurrent Thoracic Radiation Therapy for Non-Small Cell Lung Cancer: NCCTG-N0321
Mené sur 27 patients atteints d'un cancer du poumon non à petites cellules de stade III, cet essai de phase I/II évalue, du point de vue du taux de survie à 1 an et du degré de toxicité, l'intérêt d'ajouter le bortézomib à une chimiothérapie par paclitaxel-carboplatine en combinaison avec une radiothérapie thoracique concomitante
Introduction : Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III NSCLC was evaluated in this phase I/ II study. Methods : Patients with histologic or cytologic confirmed stage III non-metastatic NSCLC who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A 1-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a .09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival (OS), progression-free survival (PFS), and the confirmed response rate (RR). Results : Thirty-one patients enrolled during the phase I portion of the trial, of which 4 cancelled prior to receiving treatment, leaving 27 evaluable patients. Of these 27 patients, 2 dose-limiting toxicities (DLTs) were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m2, paclitaxel at 150 mg/m2 and carboplatin at area under the curve (AUC) of 5) and one (grade 4 neutropenia lasting >=8 days) at dose level 6 (bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2, and carboplatin at AUC of 6). During the phase I portion, the most common grade 3/4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% CI: 70 to 98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6 - phase I RP2D; 21 - phase II). Of these 27 patients, the 12MS was 73% (95% CI: 58 - 92%), the median OS was 25.0 months (95% CI: 15.6 to 35.8), and the median PFS was 8.4 months (95% CI: 4.1 to 10.5). The confirmed RR was 26% (7/27; 95% CI: 11% to 46%), consisting of 4 partial responses and 3 complete responses. Grade 3+ and Grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. Conclusions : The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation appeared to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.