A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma

The CD40-CD40L pathway is an important potential immunotherapy target. This trial demonstrates a safe, tolerable, and active combination dose and schedule of cisplatin, pemetrexed, and the CD40-activating antibody CP-870,893 in mesothelioma. Immunological monitoring demonstrates a cyclical effect of chemotherapy and evidence of an immunopharmacological effect of the study drug. Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Patients and methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Results: Fifteen patients were treated at three dose levels. The MTD of CP- 870,893 was 0.15 mg/ kg, and was exceeded at 0.2 mg/ kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome ( CRS) occurred in most patients ( 80%) following CP- 870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses ( 40%) and 9 stable disease ( 53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy ( P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells ( P < 0.001) and activated CD86+ CD27+ memory B cells ( P< 0.001), as an immunopharmacodynamic marker of CD40 activation. Conclusions: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. Australia New Zealand Clinical Trials Registry number: ACTRN12609000294257.