A Phase I dose-escalation study of two cycles carboplatinol-aparib followed by olaparib monotherapy in patients with advanced cancer

Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/ mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy. Primary objective was to assess the maximum tolerable dose (MTD). Twenty-four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%). Dose-level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL; n = 6) was defined as MTD. Fourteen out of 24 patients (56%) had a partial response as best response (RECIST 1.1). Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with olaparib tablet AUC0-12 of 16.3 mu g/mL*h at MTD. Polymers of ADP-ribose levels in peripheral blood mononuclear cells were reduced by 98.7% +/- 0.14% at Day 8 compared to Day 1 for dose-level 3. Olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/mL for two cycles preceding olaparib monotherapy 300 mg is a feasible and tolerable treatment schedule for patients with advanced cancer.

Automated summary

A dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin in advanced cancer patients showed that the combination treatment was feasible and tolerable, with dose-level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL) defined as the maximum tolerable dose (MTD). The study also indicated a comparable systemic exposure of the olaparib tablet formulation to the previous capsule formulation. Additionally, the treatment schedule resulted in a partial response in 56% of the patients with common adverse events including nausea and fatigue.