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Olaparib Dose Escalating Trial in Patients Treated With Radiotherapy With or Without Daily Dose Cisplatin for Locally Advanced Non-small Cell Lung Carcinoma

Phase 1
18 Years
Open (Enrolling)

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Trial Information

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.

Inclusion Criteria:

- ≥18 years of age

- Histologically or cytologically confirmed diagnosis of NSCLC

- Stage II/III non-operable disease, without malignant pleural effusion

- Presence of at least one measurable target lesion

- Acceptable pulmonary function as defined by a Fev1 of ≥30% and a DLCO of ≥ 40% of

- NYHA I-II functional status

- Expected risk of radiation-induced pulmonary toxicity is modest: MLD ≤ 20 and maximum
cord dose 50 Gy

- WHO performance 0-1

- Life expectancy of at least 6 months

- Adequate hematological, renal and hepatic functions

- Hemoglobin ≥ 5.5 mmol/l

- Leucocytes > 3.0 x 109/l

- Absolute neutrophil count > 1.5x109/l

- Platelet count > 100 x 109/l

- Total bilirubin < 1.5 x UNL

- ASAT/ALAT < 2.5 x UNL

- Alkaline phosphatase < 5 x UNL

- Creatinine < 130 mmol/l or creatinine clearance > 50 ml/min; measured or

- Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2, 24 hour urine
must demonstrate < 500 mg of protein in 24 hours

- No pre-existing sensory neurotoxicity grade ≥ 1 (CTCAE)

- Patients of reproductive potential must agree to practice two effective medically
approved contraceptive method during the trial and 3 months afterwards

- Signed written informed consent.

Exclusion Criteria:

- Concurrent active malignancy other than localized, non-melanoma skin cancer or
carcinoma-in-situ of the cervix (unless definitive treatment was completed 5 years or
more before study entry and the patient has remained disease free)

- Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy,
immunotherapy or use of other investigational agents within the 3 weeks prior to
start of therapy (or a longer period depending on the defined characteristics of the
agents used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use
of LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids.

- Patients, selected for sequential chemoradiotherapy, are excluded if no disease
control (all responses except progression) is obtained after induction chemotherapy.

- Prior:

- Ipsilateral radiotherapy to the chest;

- Chemotherapy for other indications than NSCLC within the last 5 years

- History of interstitial pneumonitis (to include diffuse alveolar damage,
non-malignant causes of pneumonitis, ARDS, alveolitis, cryptogenic organising
pneumonia, obliterative bronchiolitis, non-malignant causes of pulmonary fibrosis,
eligibility based on the judgement of the primary investigator), active infection on
day of enrolment

- Significant cardiovascular disease as defined by:

- History of congestive heart failure requiring therapy;

- History of unstable angina pectoris or myocardial infarction up to 6 months
prior to trial entry;

- Presence of severe valvular heart disease;

- Presence of a ventricular arrhythmia requiring treatment;

- Uncontrolled hypertension

- Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule; those conditions
should be assessed with the patient before registration in the trial.

- Participation in other trial with investigational drug or treatment modality

- Co-existing serious active infection requiring parenteral antibiotics

- Patients with hepatic disease e.g. patients with known serologically positive
Hepatitis B or Hepatitis C as they may be more at risk of toxicity from Olaparib

- Immunocompromised patients e.g. human immunodeficiency virus (HIV)

- Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on
peripheral blood smear.

- Any co-existing medical condition that in the investigator's judgement will
substantially increase the risk associated with the patient's participation in the

- Gastrointestinal disorders that may interfere with absorption of the study drug or
patients who are not able to take oral medication

- Concomitant medications:

- Any previous treatment with a PARP inhibitor, including Olaparib

- Patients receiving the following classes of inhibitors of CYP3A4 (see Section
7.4 for guidelines and wash out periods)

- Azole antifungals

- Macrolide antibiotics

- Protease inhibitors

- Persistent grade 2 or greater toxicities, from any cause

- Pregnant or breast-feeding women

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The incidence of dose limiting toxicities (DLTs)

Outcome Description:

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.

Outcome Time Frame:

from start until 3 months after the last RT day

Safety Issue:


Principal Investigator

Marcel Verheij, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Antoni van Leeuwenhoekziekenhuis (NKI-AVL)


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

April 2012

Completion Date:

March 2015

Related Keywords:

  • Olaparib
  • CCRT
  • Carcinoma, Non-Small-Cell Lung