Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC

• Status: Completed
• Trial end date: 2020-03-13
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: The Netherlands Cancer Institute
• Collaborator: AstraZeneca
• Treatments: Cisplatin; Olaparib

Criteria

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 predicted,

• 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 calculated

• 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 study

• 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