Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC
Phase I dose escalating trial. Primary objective of this study is to define the maximal tolerated dose (MTD)of Olaparib in combination with high dose radiotherapy with or without daily dose Cisplatin in locally advanced NSCLC. Secondary objectives include to define safety profile, determine PK/Pd variables and document preliminary evidence of objective tumor response.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Olaparib Dose Escalating Trial in Patients Treated With Radiotherapy With or Without Daily Dose Cisplatin for Locally Advanced Non-small Cell Lung Carcinoma|
- The incidence of dose limiting toxicities (DLTs) [ Time Frame: from start until 3 months after the last RT day ] [ Designated as safety issue: Yes ]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.
- Additional safety variables [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: Yes ](S)AE's, laboratory parameters, vital signs, lung function, long term toxicity: defined as grade ≥ 2 toxicity (with a special attention for pulmonary and esophageal toxicity) that is possibly, probably or definitely related to study treatment, occurring or persisting from 3 months after the last irradiation day until 5 years after treatment.
- Objective tumor response [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: No ]
- Locoregional control rate (LRCR) [ Time Frame: at one year ] [ Designated as safety issue: No ]
- Progression free survival [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: No ]
- Pharmacokinetic variables [ Time Frame: week -1 (baseline) until week 11 ] [ Designated as safety issue: No ]AUC, Cmax, Cmin
- Pharmacodynamic variables [ Time Frame: week -1 (baseline) until week 8 ] [ Designated as safety issue: No ]PARP inhibition, γH2AXfoci formation
- Surrogate biomarkers for antitumor response [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: No ]metabolic response determined by FDG-PET/CT-imaging, change in circulating tumor cells, molecular/biological parameters (tumor markers)
|Study Start Date:||April 2012|
|Estimated Study Completion Date:||March 2015|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Olaparib, radiation +/- Cisplatin
Olaparib and radiotherapy with or without Cisplatin
Olaparib will be given orally BID for 36 days, administrated with a 12 hour interval. Olaparib will start 2 days before 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.
The first cohort will receive Olaparib with a dose of 25mg BID combined with Cisplatin and RT. Thereafter in both with and without cisplatin arms dose escalation will follow to 50mg, 100mg, 200mg, 300mg and 400mg BID.
Other Name: AZD2281Drug: Cisplatin
6 mg/m2 (5 days/week), 1-1.5 hr before the irradiation (week 1 to 5), given as a 5-minutes intravenous infusion.
Other Name: L01XA03Radiation: Radiation
A total dose of 66 Gy will be given in 24 fractions from week 1 to 5, excluding the weekends.
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 up.
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.
|Contact: Marcel Verheij, MD, PhDfirstname.lastname@example.org|
|Contact: Michel M. van den Heuvel, MD, PhDemail@example.com|
|Netherlands Cancer Institute - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL)||Recruiting|
|Amsterdam, Noord-Holland, Netherlands, 1066 CX|
|Principal Investigator: M. M. van den Heuvel, MD, PhD|
|Principal Investigator: M. Verheij, MD, PhD|
|Principal Investigator:||Marcel Verheij, MD, PhD||Antoni van Leeuwenhoekziekenhuis (NKI-AVL)|
|Principal Investigator:||Michel M. van den Heuvel, MD, PhD||Antoni van Leeuwenhoekziekenhuis (NKI-AVL)|