Olaparib and Radiotherapy in Inoperable Breast Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Locally Advanced Malignant Neoplasm; Triple-Negative Invasive Breast Carcinoma; Inflammatory Breast Carcinoma
• Intervention / Treatment: Radiation: radiotherapy; Drug: olaparib

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • The Netherlands Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: radiotherapy and olaparib; radiotherapy: 61.18 Gy olaparib: dose escalating	Radiation: radiotherapy; 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; Drug: olaparib; The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, 300 and 400 mg BID; Other Names: AZD2281; KU-0059436

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: Gabe Sonke, MD, PhD, The Netherlands Cancer Institute; Principal Investigator: Marcel Verheij, MD, PhD, The Netherlands Cancer Institute

Publications and helpful links

General Publications

• de Haan R, van Werkhoven E, van den Heuvel MM, Peulen HMU, Sonke GS, Elkhuizen P, van den Brekel MWM, Tesselaar MET, Vens C, Schellens JHM, van Triest B, Verheij M. Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib. BMC Cancer. 2019 Sep 10;19(1):901. doi: 10.1186/s12885-019-6121-3.

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2013
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): August 1, 2020

Study Registration Dates

• First Submitted: August 26, 2014
• First Submitted That Met QC Criteria: August 26, 2014
• First Posted (Estimate): August 27, 2014

Study Record Updates

• Last Update Posted (Actual): August 4, 2021
• Last Update Submitted That Met QC Criteria: August 3, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: olaparib; breast cancer; radiotherapy; locally advanced breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Breast Diseases; Neoplasms; Breast Neoplasms; Carcinoma; Inflammatory Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: N13ORB; 2011-001586-40 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No