Olaparib dose escalating trial in patients treated with radiotherapy with of without daily dose Cisplatin for locally advanced non-small cell lung carcinoma.

Recruiting

Conditions: lung cancer
10038666

Registration Number: NL-OMON39751

Lead Sponsor: Antoni van Leeuwenhoek Ziekenhuis

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 72

Inclusion Criteria

1. >=18 years of age
2. Histologically or cytologically confirmed diagnosis of NSCLC
3. For chemoradiotherapy patients only: stage II/III non-operable disease, without malignant pleural effusion
4. For (sequential chemo-)radiotherapy patients only: indication for radical locoregional radiotherapie
5. Acceptable pulmonary function as defined by a Fev1 of >=30% and a DLCO of >= 40% of predicted,
6. NYHA I-II functional status
7. Expected risk of radiation-induced pulmonary toxicity is modest: MLD <= 20 and maximum cord dose 50 Gy
8. WHO performance 0-1
9. Life expectancy of at least 6 months
10. Adequate hematological, renal and hepatic functions
a. Hemoglobin >= 6.2 mmol/l
b. Leucocytes > 3.0 x 109/l
c. Absolute neutrophil count > 1.5x109/l
d. Platelet count > 100 x 109/l
e. Total bilirubin < 1.5 x UNL
f. ASAT/ALAT < 2.5 x UNL
g. Alkaline phosphatase < 5 x UNL
h. Creatinine clearance >= 70 ml/min; creatinine clearance >= 50 ml/min in patients not receiving concurrent cisplatin; measured using a 24-hours urine sample or calculated using the Cockcroft-Gault formula
i. Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2, 24 hour urine must demonstrate < 500 mg of protein in 24 hours
11. No pre-existing sensory neurotoxicity grade >= 2 (CTCAE)
12. Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards
13. Signed written informed consent.

Exclusion Criteria

1. Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 1 year or more before study entry and the patient has remained disease free)
2. 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.
3. Patients, selected for sequential chemoradiotherapy, are excluded if no disease control (all responses except progression) is obtained after induction chemotherapy.
4. Prior:
o Ipsilateral radiotherapy to the chest;
o Chemotherapy within the last year
5. 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 enrollment
6. Significant cardiovascular disease as defined by:
o History of congestive heart failure requiring therapy;
o History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry;
o Presence of severe valvular heart disease;
o Presence of a ventricular arrhythmia requiring treatment;
o Uncontrolled hypertension
7. 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.
8. Participation in other trial with investigational drug or treatment modality
9. Co-existing serious active infection requiring parenteral antibiotics
10. 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
11. Immunocompromised patients e.g. human immunodeficiency virus (HIV)
12. Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear
13. Any co-existing medical condition that in the investigator*s judgement will substantially increase the risk associated with the patient*s participation in the study
14. Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication
15. Concomitant medications:
a. Any previous treatment with a PARP inhibitor, including Olaparib
b. 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
16. Persistent grade 2 or greater toxicities, from any cause
17. Pregnant or breast-feeding women

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The incidence of dose limiting toxicities (DLTs) including severe late<br /><br>esophageal toxicity (sLET).</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>o Additional safety variables: (S)AE*s, Laboratory parameters, Vital signs,<br /><br>Lung function, Long term toxicity (toxicity related to treatment, occurring or<br /><br>persisting from 3 months after the last irradiation day until 5 years after<br /><br>treatment)<br /><br>o PK variables (AUC, Cmax, Cmin)<br /><br>o Pd variables (PARP inhibition; γH2AXfoci formation)<br /><br>o Objective tumor response<br /><br>o Surrogate biomarkers for antitumor response: metabolic response determined by<br /><br>FDG-PET/CT-imaging), change in circulating tumor cells, molecular/biological<br /><br>parameters (tumor markers)<br /><br>o Locoregional control rate (LRCR) at one year<br /><br>o Localisation of recurrences with respect to different dose levels<br /><br>administered (inside or outside Planning Target Volume)<br /><br>o Progression free survival </p><br>