A phase 1b study of afatinib in combination with standard-dose cetuximab in patients with advanced solid tumours.

This phase 1b, open-label trial assessed the combination of afatinib, an ErbB family blocker, with cetuximab, an epidermal growth factor receptor (EGFR) monoclonal antibody, in heavily pretreated patients with unselected/EGFR wild-type, advanced solid tumours. In Part A, the maximum tolerated dose (MTD) of afatinib + cetuximab was evaluated using a 3 + 3 dose-escalation design; the starting dose was afatinib 30 mg/day plus cetuximab 250 mg/m2/week (after cetuximab 400 mg/m2 loading dose), escalating to afatinib 40 mg/day. Part B further evaluated safety and tolerability at the MTD and preliminary anti-tumour activity in three patient cohorts with squamous non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and other solid tumours. Nine patients were treated in Part A; the MTD and recommended dose was determined as afatinib 40 mg/day plus cetuximab 250 mg/m2/week. In Part B, 49 patients were treated at the recommended dose (12 with squamous NSCLC, 15 with HNSCC and 22 with other tumours). The most common treatment-related adverse events (AEs) across all 58 patients were diarrhoea (63.8%) and acneiform dermatitis (43.1%). Overall, the best confirmed response was stable disease (SD; 53.4%); mean duration of disease control was 4.5 months; median progression-free survival was 2.6 months. In Part B, 55.1% of patients had SD (squamous NSCLC, 75.0%; HNSCC, 66.7%; other tumours; 36.4%). In conclusion, the recommended phase 2 dose was determined as afatinib 40 mg/day plus cetuximab 250 mg/m2/week. AEs were predictable and manageable, and anti-tumour activity was observed in some patients, particularly in those with squamous NSCLC and HNSCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02020577.

Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study.

PURPOSE: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. PATIENTS AND METHODS: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. RESULTS: Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. CONCLUSION: Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.