Olaparib Dose Escalating Trial in Patients Treated With Radiotherapy With or Without Daily Dose Cisplatin for Locally Advanced Non-small Cell Lung Carcinoma
Concurrent chemoradiotherapy (CCRT) is the treatment of choice for patients with locally
advanced NSCLC. The cure rates however need to be improved. The main mechanism by which both
radiation and Cisplatin kill tumor cells is by an accumulation of un- or misrepaired DNA
damage.PARP inhibitors increase radiation and chemotherapy (Cisplatin) response in
preclinical studies including lung cancer models.
This open label dose escalating trial consists of a screening phase, a treatment phase and a
follow up phase.
The screening phase: patients who can tolerate concurrent cisplatin will receive Olaparib,
RT and Cisplatin. Patients who can not tolerate concurrent cisplatin will receive Olaparib
and RT with or without prior sequential chemotherapy.
The treatment phase:dose escalation of Olaparib will be performed in cohorts of 3 subjects.
The decision to escalate to the next dose level will be based on the occurrence of DLTs
during the DLT evaluation period (i.e. 3 months following the last day of irradiation) and
will be made after all patients within the cohort have completed their third month of follow
Active follow-up phase: frequent follow up will take place during the first 3 months (acute
toxicity). Thereafter patients will be monitored for late toxicity and for disease activity
3-monthly throughout the first year and thereafter 6-monthly until 5 years, when patients
are deemed to be cured and follow up is no longer warranted.
Olaparib will be given orally BID for 36 consecutive days, administrated with a 12 hour
interval. Olaparib will start 2 days before start of RT and will continue for 2 days after
the last RT fraction. Olaparib is also given during the non-radiotherapy days but no
maintenance treatment is given after radiotherapy is finished.
Radiotherapy (for all patients): a total dose of 66Gy will be given in 24 fractions from
week 1 to 5.
Cisplatin (concurrent chemoradiotherapy): daily dose Cisplatin 6mg/m2 (5 days/week), 1-1.5
hr before the irradiation (week 1 to 5), given as a 5-minutes intravenous infusion.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The incidence of dose limiting toxicities (DLTs)
The incidence of dose limiting toxicities occuring during the DLT evaluation period (from start of study treatment until 3 months after the last radiation day). This endpoint will be used to determine the maximal tolerated dose of Olaparib in combination with radiotherapy with and without low dose Cisplatin.
from start until 3 months after the last RT day
Marcel Verheij, MD, PhD
Antoni van Leeuwenhoekziekenhuis (NKI-AVL)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)