breast cancer metastatic breast cancer
Conditions
Interventions
1)
Radiotherapy to the whole breast and regionale lymph nodes: 46.69 Gy in 23
fractions.
In the post-operatieve setting the dose is 42.56 Gy (noindication for boost)
and 46.20Gy (with the indicatio
arm B: 25 mg BID
Sponsors
Nederlands Kanker Instituut
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: For group A and B 1. *18 years of age 2. Patients should fulfill all inclusion criteria for patients with the tumor present in the breast (listed under point 3) OR all inclusion criteria for postoperative patients (listed under point 4) 3. For patients with the tumor present in the breast: a. Histological proven breast cancer or local recurrence of breast cancer which is inoperable or/and metastatic, including inflammatory breast cancer b. Tumor in breast accessible for biopsy 4. For postoperative patients: a. Histological proven BC b. Mastectomy or lumpectomy that is radical or focal irradical after (re-) excision c. High risk of locoregional recurrence defined as: - cN2-3 & (y)pN1-3 & non-operated pre-chemo, or pre-operative in case no neoadjuvant chemotherapy is given, PET-positive or PA-proven lymph nodes; - or as judged by both the principle investigator and the treating physician 5. WHO performance 0-2 6. Life expectancy of at least 6 months 7. Adequate hematological, renal and hepatic functions a. Hemoglobin * 6.2 mmol/l b. Leucocytes * 3.0 x 10E9/l c. Absolute neutrophil count * 1.5x10E9/l d. Platelet count * 100 x 10E9/l e. Total bilirubin * 1.5 x ULN f. ASAT/ALAT * 2.5 x ULN ; or in the presence of liver metastases * 5 x ULN g. Creatinine clearance * 50 ml/min; measured or calculated 8. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 21 days of study treatment. Non-childbearing potential or postmenopausal is defined as: * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments * LH and FSH levels in post menopausal range for women under 50 years of age * Radiation-induced oophorectomy with last menses > 1 year ago * Chemotherapy-induced menopause with > 1 year interval since last menses * Surgical sterilisation (bilateral oophorectomy or hysterectomy) 9 Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards 10. Signed written informed consent For arm A only: 11a Indication for breast irradiation without the use of skin bolus For arm B only: 11b Indication for breast irradiation with the use of skin bolus
Exclusion criteria
Exclusion criteria: 1. Anti-cancer therapy including chemotherapy, radiotherapy, immunotherapy or use of other investigational agents within 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 ornitrosourea). Patient may continue the use of tamoxifen, aromatase inhibitor and LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids. The use of denosumab for bone disease is not allowed. 2. Major surgery within two weeks of starting study treatment. 3. Participation in other trial with investigational drug or treatment modality 4. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. 5. Prior ipsilateral radiotherapy to the chest or breast. 6. Blood transfusion in the four weeks prior to study entry 7. Persistent toxicities (CTC * grade 2) with the exception of alopecia, caused by previous cancer therapy 8. QT-interval >470 msec 9. Significant cardiovascular disease as defined by a. History of congestive heart failure defined as NYHA class III b. History of unstable angina pectoris or myocardial infarction up to 3 months prior to trial entry; c. Presence of severe valvular heart disease d. Presence of a ventricular arrhythmia requiring treatment; e. Uncontrolled hypertension 10. Patients considered a poor medical risk due to: a. non-malignant systemic disease b. active, uncontrolled infection requiring parenteral antibiotics c. a serious, uncontrolled medical disorder; examples include, but are not limited to: i. uncontrolled major seizure disorder ii. unstable spinal cord compression iii. superior vena cava syndrome iv. extensive bilateral lung disease on HRCT scan v. any psychiatric disorder that prohibits obtaining informed consent. 11. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. 12. Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy. 13. Patients with known active hepatic disease (i.e. Hepatitis B or C) 14. Patients with myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear. 15. Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication 16. 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) i. Azole antifungals ii. Macrolide antibiotics iii. Protease inhibitors 17. Pregnant or breast-feeding women 18. Breast feeding women
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The incidence of dose limiting toxicities. | — |
Secondary
| Measure | Time frame |
|---|---|
| * Acute toxicity: severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03 occurring from start of treatment until 3 months after end of treatment * Late toxicity: severity, duration and relation with treatment of all adverse events that are possibly, probably or definitely related to the combination treatment according to CTCAE version 4.03 occurring from 3 months until 2 years after end of treatment * PK variables: steady state AUC, steady state C-max, steady state C-min * Pd variables: PARP inhibition in PBMCs and tumor biopsies; *H2AX foci formation upon ex vivo irradiation in PBMCs & circulating tumor cells * Objective response rate at 3 months after end of treatment assessed by RECIST version 1.1 using MRI-mamma ((only in patients with the tumor present in the breast) * Locoregional control in patients with the tumor present in the breast as assessed by physical examination and if clinically indicated supported by radiological and/or pathological investigations in postoperative patients as assessed by routine follow-up investigations (i.e. physical examination and radiological investigations), confirmed by pathology report(s) * Localisation of recurrences in relation to the planned radiotherapy fields: PTV & boost PTV | — |
Countries
Netherlands
Outcome results
None listed