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Olaparib & Radiation Therapy for Patients Triple Negative Breast Cancer (TNBC) (RadioPARP)

Primary Purpose

Breast Neoplasms, Triple-Negative, Breast Neoplasm Malignant Female, Radiotherapy Side Effect

Status
Unknown status
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Olaparib
Radiation therapy
Sponsored by
Institut Curie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Neoplasms, Triple-Negative

Eligibility Criteria

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

Inclusion Criteria:

  1. Woman aged >18 years.
  2. Histologically confirmed triple negative breast cancer with loco-regional radiotherapy indication :

    1. Non-operated with either:

      1. Inflammatory breast cancer in progression during neoadjuvant chemotherapy or inoperable after neoadjuvant chemotherapy.
      2. Loco-regional advanced breast cancer in progression during neoadjuvant chemotherapy or inoperable after neoadjuvant chemotherapy (T ≥ 3 and/or N ≥ 1; with evaluable disease according to RECIST 1.1 criteria).
      3. Non operable metastatic breast cancer (all T, all N, M1; with evaluable disease according to RECIST 1.1 criteria) needing local and regional treatment in case of good metastatic control after chemotherapy.
    2. Or patient operated after neoadjuvant treatment and surgery with residual disease (non-pCR and/or pN+ disease).
  3. Neoadjuvant chemotherapy (containing anthracyclines or taxanes or the combination of both or containing platinum-based chemotherapy) willingness to discontinue any cytotoxic chemotherapeutic agents, immunotherapy, and targeted therapies at least two weeks prior to start of Olaparib.
  4. ECOG performance status < 2.
  5. Life expectancy greater than 6 months.
  6. Adequate hematologic, renal and hepatic function (assessed within the two weeks prior to registration and within the month prior to the commencement of protocol treatment). For patients who have stopped chemotherapy two weeks prior to protocol treatment, hematologic function must be re-assessment 1 or 2 days before the first Olaparib intake:

    1. Haemoglobin ≥ 10.0 g/dL.
    2. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L.
    3. White Blood Cells (WBC) > 3 x 109/L.
    4. Platelet count ≥ 100 x 109/L.
    5. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (except in case of Gilbert syndrome).
    6. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5 x ULN.
    7. Patients must have Creatinine Clearance estimated using the Cockcroft-Gault equation of ≥ 51 mL/min
  7. Urine or serum negative pregnancy test within two weeks prior to registration for non-postmenopausal patients. Negative pregnancy test confirmed within 1 or 2 days prior to first Olaparib intake.
  8. For woman with child-bearing potential, an efficacious contraception following sponsor recommendations must be used during the whole treatment period and up to three months after the last Olaparib administration.
  9. Ability to swallow and retain oral medications without gastrointestinal disorders likely to interfere with absorption of the study medication.
  10. Affiliation to the French Social Security System.
  11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Radiation therapy: prior history of radiation therapy to the ipsilateral breast and/or regional nodes (except prior radiation therapy to other sites).
  2. Patient with unresolved or unstable, NCI-CTCAE v4.03 (National Cancer Institute Common Toxicity Criteria for Adverse Events) Grade 3 or greater toxicity from prior administration of prior anti-cancer treatment.
  3. Patient with clinically and uncontrolled significant comorbidity: major cardiac, respiratory, renal, hepatic, gastrointestinal, hematologic or neurological/psychiatric disease or disorder, including but not limited to: active uncontrolled infection; symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; any other illness condition(s) that could exacerbate potential toxicities, require excluded therapy for management, or limit compliance with study requirements.
  4. Patient with second primary cancer, except : adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
  5. Concomitant anti-cancer treatment during protocol treatment and/or not completed at least 2 weeks prior to Olaparib initiation, except bisphosphonates and RANK inhibitors without restriction even during protocol treatment as long as these where started at least 4 weeks prior to study treatment initiation.
  6. Any previous treatment with a PARP (Poly (Adenosine diphosphate [ADP]-Ribose) Polymerase) inhibitor, including Olaparib.
  7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Olaparib.
  8. Patient being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) within the last 7 days before first Olaparib intake.
  9. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
  10. Blood transfusions within 14 days prior to treatment start.
  11. Patient with myelodysplastic syndrome / acute myeloid leukaemia.
  12. Pregnant or breastfeeding woman.
  13. Patient already included in another clinical trial with an investigational drug.
  14. Patient individually deprived of liberty or placed under the authority of a tutor.
  15. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Sites / Locations

  • Institut Curie

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Olaparib + radiation therapy

Arm Description

One week of Olaparib alone followed by 5 weeks of Olaparib and concurrent loco-regional radiotherapy. Five levels of dose of Olaparib are expected.

Outcomes

Primary Outcome Measures

Determination of the Maximal Tolerated Dose of Olaparib administered with concurrent loco regional radiotherapy
Incidence of early Dose Limited Toxicity (DLTs: early adverse effects related to Olaparib administered with concurrent radiotherapy) to determinate the Maximal Tolerated Dose (MTD) of Olaparib administered with concurrent loco regional radiotherapy in patients who have triple negative inflammatory, loco-regional advanced or metastatic breast cancer either inoperable after neoadjuvant chemotherapy or operated patient with residual disease (after neoadjuvant chemotherapy).

Secondary Outcome Measures

Incidence of Serious Adverse Events (SAEs), graded according to NCI-CTCAE version 4.03 criteria to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Incidence of Serious Adverse Events (SAEs), graded according to NCI-CTCAE version 4.03 criteria
Incidence and severity of Adverse Events (AEs), graded according to NCI-CTCAE version 4.03 criteria to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Incidence and severity of Adverse Events (AEs), graded according to NCI-CTCAE version 4.03 criteria
Incidence and severity of laboratory abnormalities, graded according to NCI-CTCAE version 4.03 criteria to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Incidence and severity of laboratory abnormalities, graded according to NCI-CTCAE version 4.03 criteria
Incidence of acute toxicity 2 weeks and 6 weeks after the end of radiotherapy to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Incidence of acute toxicity 2 weeks and 6 weeks after the end of radiotherapy
Incidence of late toxicity at 1 year and at 2 years as of initiation of radiation therapy to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Incidence of late toxicity at 1 year and at 2 years as of initiation of radiation therapy
Incidence of treatment discontinuations and treatment modifications due to AEs to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Incidence of treatment discontinuations and treatment modifications due to AEs
Evaluation of the Objective Response Rate (ORR) to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Evaluation of the Objective Response Rate (ORR) to treatment
Evaluation of the Complete Response Rate to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Evaluation of the Complete Response Rate to treatment
Evaluation of Pathological Response Rate (pRR) after salvage surgery to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Evaluation of Pathological Response Rate (pRR) after salvage surgery
Evaluation of the loco-regional Progression Free Survival (l-PFS) to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Evaluation of the loco-regional Progression Free Survival (l-PFS)
Evaluation of the Progression Free Survival (PFS) or Disease Free survival (DFS) according to stage of disease to evaluate patient outcome
Evaluation of the Progression Free Survival (PFS) or Disease Free survival (DFS)
Evaluation of the distant relapse rate to evaluate patient outcome
Evaluation of the distant relapse rate
Evaluation of patient outcome by evaluation of the Overall Survival (OS).
Evaluation Overall Survival (OS).
Evaluation of patient outcome by evaluate disease specific survival rate.
Evaluation of the disease specific survival rate.
Explore biomarkers of Olaparib activity in combination with concurrent radiotherapy.
Exploration of biomarkers of Olaparib associated with radiotherapy on biopsies.

Full Information

First Posted
March 2, 2017
Last Updated
October 23, 2020
Sponsor
Institut Curie
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03109080
Brief Title
Olaparib & Radiation Therapy for Patients Triple Negative Breast Cancer (TNBC)
Acronym
RadioPARP
Official Title
A Phase I of Olaparib With Radiation Therapy in Patients With Inflammatory, Loco-regionally Advanced or Metastatic TNBC (Triple Negative Breast Cancer) or Patient With Operated TNBC With Residual Disease
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Unknown status
Study Start Date
July 24, 2017 (Actual)
Primary Completion Date
February 17, 2020 (Actual)
Study Completion Date
April 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut Curie
Collaborators
AstraZeneca

4. Oversight

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

5. Study Description

Brief Summary
A Phase I of Olaparib with Radiation Therapy in Patients With Inflammatory, Loco-regionally Advanced or Metastatic TNBC (triple negative breast cancer) or Patient With Operated TNBC with Residual Disease.
Detailed Description
Open label phase I, dose escalation trial for patients with triple negative inflammatory, loco-regional advanced or metastatic breast cancer either inoperable after neoadjuvant chemotherapy or operated with residual disease (after neoadjuvant chemotherapy).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Neoplasms, Triple-Negative, Breast Neoplasm Malignant Female, Radiotherapy Side Effect

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Olaparib + radiation therapy
Arm Type
Experimental
Arm Description
One week of Olaparib alone followed by 5 weeks of Olaparib and concurrent loco-regional radiotherapy. Five levels of dose of Olaparib are expected.
Intervention Type
Drug
Intervention Name(s)
Olaparib
Other Intervention Name(s)
PARP (Poly (Adenosine diphosphate [ADP]-Ribose) Polymerase) inhibitor, Lynparza, AZD-2281
Intervention Description
five levels of dose, per os administration, twice daily each day
Intervention Type
Radiation
Intervention Name(s)
Radiation therapy
Other Intervention Name(s)
Radiotherapy
Intervention Description
3D conformal radiotherapy or intensity-modulated radiotherapy (IMRT), Simultaneous Integrated Boost (SIB), postoperative radiotherapy
Primary Outcome Measure Information:
Title
Determination of the Maximal Tolerated Dose of Olaparib administered with concurrent loco regional radiotherapy
Description
Incidence of early Dose Limited Toxicity (DLTs: early adverse effects related to Olaparib administered with concurrent radiotherapy) to determinate the Maximal Tolerated Dose (MTD) of Olaparib administered with concurrent loco regional radiotherapy in patients who have triple negative inflammatory, loco-regional advanced or metastatic breast cancer either inoperable after neoadjuvant chemotherapy or operated patient with residual disease (after neoadjuvant chemotherapy).
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Incidence of Serious Adverse Events (SAEs), graded according to NCI-CTCAE version 4.03 criteria to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Description
Incidence of Serious Adverse Events (SAEs), graded according to NCI-CTCAE version 4.03 criteria
Time Frame
2 years
Title
Incidence and severity of Adverse Events (AEs), graded according to NCI-CTCAE version 4.03 criteria to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Description
Incidence and severity of Adverse Events (AEs), graded according to NCI-CTCAE version 4.03 criteria
Time Frame
2 years
Title
Incidence and severity of laboratory abnormalities, graded according to NCI-CTCAE version 4.03 criteria to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Description
Incidence and severity of laboratory abnormalities, graded according to NCI-CTCAE version 4.03 criteria
Time Frame
2 years
Title
Incidence of acute toxicity 2 weeks and 6 weeks after the end of radiotherapy to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Description
Incidence of acute toxicity 2 weeks and 6 weeks after the end of radiotherapy
Time Frame
2 years
Title
Incidence of late toxicity at 1 year and at 2 years as of initiation of radiation therapy to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Description
Incidence of late toxicity at 1 year and at 2 years as of initiation of radiation therapy
Time Frame
2 years
Title
Incidence of treatment discontinuations and treatment modifications due to AEs to assess the safety profile of Olaparib administered with concurrent loco-regional radiotherapy.
Description
Incidence of treatment discontinuations and treatment modifications due to AEs
Time Frame
2 years
Title
Evaluation of the Objective Response Rate (ORR) to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Description
Evaluation of the Objective Response Rate (ORR) to treatment
Time Frame
2 years
Title
Evaluation of the Complete Response Rate to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Description
Evaluation of the Complete Response Rate to treatment
Time Frame
2 years
Title
Evaluation of Pathological Response Rate (pRR) after salvage surgery to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Description
Evaluation of Pathological Response Rate (pRR) after salvage surgery
Time Frame
2 years
Title
Evaluation of the loco-regional Progression Free Survival (l-PFS) to evaluate Olaparib administered with concurrent loco regional radiotherapy efficacy profile
Description
Evaluation of the loco-regional Progression Free Survival (l-PFS)
Time Frame
2 years
Title
Evaluation of the Progression Free Survival (PFS) or Disease Free survival (DFS) according to stage of disease to evaluate patient outcome
Description
Evaluation of the Progression Free Survival (PFS) or Disease Free survival (DFS)
Time Frame
2 years
Title
Evaluation of the distant relapse rate to evaluate patient outcome
Description
Evaluation of the distant relapse rate
Time Frame
2 years
Title
Evaluation of patient outcome by evaluation of the Overall Survival (OS).
Description
Evaluation Overall Survival (OS).
Time Frame
2 years
Title
Evaluation of patient outcome by evaluate disease specific survival rate.
Description
Evaluation of the disease specific survival rate.
Time Frame
2 years
Title
Explore biomarkers of Olaparib activity in combination with concurrent radiotherapy.
Description
Exploration of biomarkers of Olaparib associated with radiotherapy on biopsies.
Time Frame
2 years

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Woman aged >18 years. Histologically confirmed triple negative breast cancer with loco-regional radiotherapy indication : Non-operated with either: Inflammatory breast cancer in progression during neoadjuvant chemotherapy or inoperable after neoadjuvant chemotherapy. Loco-regional advanced breast cancer in progression during neoadjuvant chemotherapy or inoperable after neoadjuvant chemotherapy (T ≥ 3 and/or N ≥ 1; with evaluable disease according to RECIST 1.1 criteria). Non operable metastatic breast cancer (all T, all N, M1; with evaluable disease according to RECIST 1.1 criteria) needing local and regional treatment in case of good metastatic control after chemotherapy. Or patient operated after neoadjuvant treatment and surgery with residual disease (non-pCR and/or pN+ disease). Neoadjuvant chemotherapy (containing anthracyclines or taxanes or the combination of both or containing platinum-based chemotherapy) willingness to discontinue any cytotoxic chemotherapeutic agents, immunotherapy, and targeted therapies at least two weeks prior to start of Olaparib. ECOG performance status < 2. Life expectancy greater than 6 months. Adequate hematologic, renal and hepatic function (assessed within the two weeks prior to registration and within the month prior to the commencement of protocol treatment). For patients who have stopped chemotherapy two weeks prior to protocol treatment, hematologic function must be re-assessment 1 or 2 days before the first Olaparib intake: Haemoglobin ≥ 10.0 g/dL. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L. White Blood Cells (WBC) > 3 x 109/L. Platelet count ≥ 100 x 109/L. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (except in case of Gilbert syndrome). AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5 x ULN. Patients must have Creatinine Clearance estimated using the Cockcroft-Gault equation of ≥ 51 mL/min Urine or serum negative pregnancy test within two weeks prior to registration for non-postmenopausal patients. Negative pregnancy test confirmed within 1 or 2 days prior to first Olaparib intake. For woman with child-bearing potential, an efficacious contraception following sponsor recommendations must be used during the whole treatment period and up to three months after the last Olaparib administration. Ability to swallow and retain oral medications without gastrointestinal disorders likely to interfere with absorption of the study medication. Affiliation to the French Social Security System. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Radiation therapy: prior history of radiation therapy to the ipsilateral breast and/or regional nodes (except prior radiation therapy to other sites). Patient with unresolved or unstable, NCI-CTCAE v4.03 (National Cancer Institute Common Toxicity Criteria for Adverse Events) Grade 3 or greater toxicity from prior administration of prior anti-cancer treatment. Patient with clinically and uncontrolled significant comorbidity: major cardiac, respiratory, renal, hepatic, gastrointestinal, hematologic or neurological/psychiatric disease or disorder, including but not limited to: active uncontrolled infection; symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; any other illness condition(s) that could exacerbate potential toxicities, require excluded therapy for management, or limit compliance with study requirements. Patient with second primary cancer, except : adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years. Concomitant anti-cancer treatment during protocol treatment and/or not completed at least 2 weeks prior to Olaparib initiation, except bisphosphonates and RANK inhibitors without restriction even during protocol treatment as long as these where started at least 4 weeks prior to study treatment initiation. Any previous treatment with a PARP (Poly (Adenosine diphosphate [ADP]-Ribose) Polymerase) inhibitor, including Olaparib. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Olaparib. Patient being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) within the last 7 days before first Olaparib intake. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. Blood transfusions within 14 days prior to treatment start. Patient with myelodysplastic syndrome / acute myeloid leukaemia. Pregnant or breastfeeding woman. Patient already included in another clinical trial with an investigational drug. Patient individually deprived of liberty or placed under the authority of a tutor. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Youlia KIROVA, MD
Organizational Affiliation
Institut Curie
Official's Role
Study Director
Facility Information:
Facility Name
Institut Curie
City
Paris
ZIP/Postal Code
75005
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36301572
Citation
Loap P, Loirat D, Berger F, Rodrigues M, Bazire L, Pierga JY, Vincent-Salomon A, Laki F, Boudali L, Raizonville L, Mosseri V, Jochem A, Eeckhoutte A, Diallo M, Stern MH, Fourquet A, Kirova Y. Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer: The Phase 1 Olaparib and Radiation Therapy for Triple-Negative Breast Cancer Trial. JAMA Oncol. 2022 Dec 1;8(12):1802-1808. doi: 10.1001/jamaoncol.2022.5074.
Results Reference
derived
PubMed Identifier
32971187
Citation
Loap P, Loirat D, Berger F, Ricci F, Vincent-Salomon A, Ezzili C, Mosseri V, Fourquet A, Ezzalfani M, Kirova Y. Combination of Olaparib and Radiation Therapy for Triple Negative Breast Cancer: Preliminary Results of the RADIOPARP Phase 1 Trial. Int J Radiat Oncol Biol Phys. 2021 Feb 1;109(2):436-440. doi: 10.1016/j.ijrobp.2020.09.032. Epub 2020 Sep 21.
Results Reference
derived

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Olaparib & Radiation Therapy for Patients Triple Negative Breast Cancer (TNBC)

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