A phase Ib/II study of DMXAA combined with carboplatin and paclitaxel in non-small cell lung cancer (NSCLC)

Aims: DMXAA (AS1404) is a small-molecule vascular disrupting agent in trials for treatment of various tumours. This integrated phase Ib/II trial evaluated DMXAA in combination with carboplatin (C) and paclitaxel (P) in NSCLC. The phase Ib component confirmed 1200mg/m² as the principal dose of DMXAA for the phase II part of the trial.

Methods: Pat. had histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy. In the phase II part of the trial pats. were randomly assigned to receive up to 6 cycles of C (AUC 6mg/ml_*min) + P (175mg/m²) with or without 1200mg/m² DMXAA. Safety assessments included ECG, adverse events, laboratory screens, PK and ophthalmic exams. Efficacy endpoints were objective response rates, time to tumour progression, duration of response and stable disease, median and 1-year survival.

Results: 37 pats. were randomised to DMXAA 1200mg/m² with C and P (34 eligible for efficacy analysis) and 36 to C and P alone (all eligible for efficacy analysis). Overall safety profiles in the groups were similar (23 treatment-emergent SAEs with DMXAA and 24 with chemotherapy alone). Addition of DMXAA to C and P did not exacerbate chemotherapy-related adverse events. Pats. assigned to DMXAA showed a higher RECIST response rate (31.2 vs. 22.2% by independent assessment), longer time to tumour progression (5.0 vs. 4.3 months by investigators' assessment, hazard ratio (95% CI) 0.85 (0.52, 1.41)) and longer median survival (14.0 vs. 8.8 months, hazard ratio (95% CI) 0.73 (0.39, 1.38)) than pats. receiving C and P alone.

Conclusion: Addition of 1200mg/m² DMXAA to standard doses of C and P was well tolerated and increased median survival by 5.2 months. A phase III trial of DMXAA in NSCLC is planned.