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Olaparib and Radiotherapy in Inoperable Breast Cancer

Primary Purpose

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

Status
Completed
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
radiotherapy
olaparib
Sponsored by
The Netherlands Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Malignant Neoplasm focused on measuring radiotherapy, olaparib, breast cancer, locally advanced breast cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • The Netherlands Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

radiotherapy and olaparib

Arm Description

radiotherapy: 61.18 Gy olaparib: dose escalating

Outcomes

Primary Outcome Measures

The incidence of dose limiting toxicities.

Secondary Outcome Measures

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

Full Information

First Posted
August 26, 2014
Last Updated
August 3, 2021
Sponsor
The Netherlands Cancer Institute
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1. Study Identification

Unique Protocol Identification Number
NCT02227082
Brief Title
Olaparib and Radiotherapy in Inoperable Breast Cancer
Official Title
Olaparib Dose Escalation in Combination With High Dose Radiotherapy to the Breast Andregional Lymph Nodes in Patients With Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
October 21, 2013 (Actual)
Primary Completion Date
September 2019 (Actual)
Study Completion Date
August 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Malignant Neoplasm, Inflammatory Breast Carcinoma, Triple-Negative Invasive Breast Carcinoma
Keywords
radiotherapy, olaparib, breast cancer, locally advanced breast cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
radiotherapy and olaparib
Arm Type
Experimental
Arm Description
radiotherapy: 61.18 Gy olaparib: dose escalating
Intervention Type
Radiation
Intervention Name(s)
radiotherapy
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
olaparib
Other Intervention Name(s)
AZD2281, KU-0059436
Intervention Description
The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, 300 and 400 mg BID
Primary Outcome Measure Information:
Title
The incidence of dose limiting toxicities.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Acute toxicity
Description
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
Time Frame
3 months after treatment
Title
Late toxicity
Description
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
Time Frame
3 months until 2 years after end of treatment

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gabe Sonke, MD, PhD
Organizational Affiliation
The Netherlands Cancer Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marcel verheij, MD, PhD
Organizational Affiliation
The Netherlands Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Netherlands Cancer Institute
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
31500595
Citation
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.
Results Reference
derived

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Olaparib and Radiotherapy in Inoperable Breast Cancer

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