Exploiting drug targets for development of rational combinations of classical and novel anticancer agents

Abstract

Chapter 1 describes treatment with poly ADP-ribose polymerase (PARP) inhibitors in patients with advanced cancer. In chapter 1.1 several treatment options for patients with triple negative breast cancer are discussed, with a focus on treatment with PARP inhibitors. We discuss the patient selection, biomarkers, use of combination therapy and pharmacodynamics (PD) assays. In chapter 1.2 the results of a phase I dose escalation study with olaparib and carboplatin are discussed. In total, 24 patients were included. The maximum tolerable dose was olaparib 75 mg bidaily (BID) in combination with carboplatin target area under the curve (AUC) 5. The toxicity profile showed mainly hematological toxicity and gastro-intestinal side effects. In this study, one patient was included with advanced breast cancer who was treated successfully with olaparib and carboplatin. Despite an ongoing systemic response, she developed brain metastases during the maintenance treatment with olaparib. In chapter 1.3 this case has been described, followed by a review of the literature. In chapter 2 the Wee1 protein and the inhibition of Wee1 as anticancer treatment has been discussed. In a review in chapter 2.1 the cell cycle, the role of Wee1 and Wee1 inhibition as target for anti-cancer therapy are being discussed. AZD1775 is a small molecule inhibitor of Wee1 kinase. In chapter 2.2 an interim analysis with the Wee1 inhibitor AZD1775 in combination with carboplatin is discussed. Patients with advanced ovarian cancer who are refractory or resistant to platinum containing therapy are being treated with carboplatin and AZD1775. Patients received carboplatin with a target AUC 5 mg/ml.min in combination with AZD1775 225 mg bidaily during 2.5 days in a 21 day cycle. The interim analysis showed comparable toxicity with mainly hematological toxicity,nausea, vomiting and fatigue. In chapter 2.3 the results are presented of a phase II study combining the Wee1 inhibitor adavosertib with chemotherapy in patients with advanced ovarian, fallopian and peritoneal cancer. The study had four treatment arms where patients were treated with adavosertib in combination with gemcitabine, paclitaxel, Pegylated liposomal doxorubicin (PDL) of a combination of these, in different dosing schedules. The responses observed were highest in the carboplatin with weekly adavosertib group. Chapter 3 shows the results of this Ib study in patients with advanced ovarian, fallopian, endometrial, cervical and breast-cancer. Patients received the combination of cyclophosphamide, carboplatin and atezolizumab. In total, 6 patients were included. The safe dose was carboplatin target AUC 5 mg/ml.min, cyclophosphamide 600mg/m2 on day 1 and atezolizumab 840 mg on day 1 and day 15. Most common toxicities were hematological. In chapter 4 the results of a dose escalation study are discussed, in which patients received trastuzumab-duocarmazine, an antibody drug conjugate. The dose escalation part of the study, included patients with advanced cancer with variable Her2 status, who were refractory for standard therapy. In the expansion part, patients with breast, gastric, urothelial or endometrial cancer with at least a Her2 score of 1+ were treated. The recommended phase II dose was 1.2 mg/kg. Finally, conclusions, future perspectives and challenges were discussed in chapter 5.