Olaparib and Radiotherapy in Inoperable Breast Cancer

Study Overview
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Brief Summary
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The majority of breast cancer patients receive radiotherapy as part of their treatment. Radiotherapy improves both locoregional control and overall survival. In most patients with breast cancer the locoregional recurrence rate (LRR) is low, however still high LRRs are found in certain patient groups, especially in locally advanced, inflammatory and triple negative breast cancer. Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for homologous recombination (HR) defected tumors and as a dose intensifier for chemo- and radiotherapy. The combination of olaparib and radiotherapy is expected to improve locoregional control and thereby overall survival in both breast cancer patients with a high probability of locoregional recurrence and patients with HR deficient tumors. However, this combination treatment has never been tested in humans before. The purpose of this study is to determine the safety and tolerability of radiotherapy to the breast and regional lymph nodes with concurrent olaparib.

Official Title
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Olaparib Dose Escalation in Combination With High Dose Radiotherapy to the Breast Andregional Lymph Nodes in Patients With Breast Cancer

Conditions
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Locally Advanced Malignant Neoplasm, Inflammatory Breast Carcinoma, Triple-Negative Invasive Breast Carcinoma

Intervention / Treatment
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* Radiation: radiotherapy
* Drug: olaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Histological proven breast cancer or local recurrence of breast cancer which is inoperable or/and metastatic, including inflammatory breast cancer No participation in trial with neoadjuvant systemic treatment, except for previous contralateral breast cancer Tumor in breast accessible for biopsy WHO performance 0-2 Life expectancy of at least 6 months Adequate hematological, renal and hepatic functions Hemoglobin 6.2 mmol/l Leucocytes 3.0 x 10E9/l Absolute neutrophil count 1.5x10E9/l Platelet count 100 x 10E9/l Total bilirubin ≤ 1.5 x ULN ASAT/ALAT ≤ 2.5 x ULN; or in the presence of liver metastases ≤ 5 x ULN Creatinine clearance 50 ml/min; measured or calculated 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) 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: Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, 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. Major surgery within two weeks of starting study treatment. Participation in other trial with investigational drug or treatment modality Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Prior ipsilateral radiotherapy to the chest or breast. Blood transfusion in the four weeks prior to study entry Persistent toxicities (CTC ≥ grade 2) with the exception of alopecia, caused by previous cancer therapy QT-interval > 470 msec Significant cardiovascular disease as defined by History of congestive heart failure defined as NYHA class III History of unstable angina pectoris or myocardial infarction up to 3 months prior to trial entry; Presence of severe valvular heart disease Presence of a ventricular arrhythmia requiring treatment; Uncontrolled hypertension Patients considered a poor medical risk due to: non-malignant systemic disease active, uncontrolled infection requiring parenteral antibiotics a serious, uncontrolled medical disorder; examples include, but are not limited to: uncontrolled major seizure disorder unstable spinal cord compression superior vena cava syndrome extensive bilateral lung disease on HRCT scan any psychiatric disorder that prohibits obtaining informed consent. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy. Patients with known active hepatic disease (i.e. Hepatitis B or C) Patients with myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear. 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 6.4.2 for guidelines and wash out periods) Azole antifungals Macrolide antibiotics Protease inhibitors Patients with a known hypersensitivity to olaparib or any of the excipients of the product Breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: radiotherapy and olaparib<br>radiotherapy: 61.18 Gy olaparib: dose escalating | Radiation: radiotherapy<br>* The whole breast and regional lymph nodes will receive 23 x 2.03 Gy per fraction (total 46.69 Gy) At the macroscopic tumor a added SIB will be given of 23 x 0.63Gy . Total dose: 61.18 Gy<br>Drug: olaparib<br>* The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, 300 and 400 mg BID<br>* Other names: KU-0059436;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of dose limiting toxicities. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 3 months after 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 | 3 months until 2 years after end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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olaparib, radiotherapy, breast cancer, locally advanced breast cancer