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Novel Neoadjuvant and Adjuvant Strategy for Germline BRCA 1/2 Mutated Triple Negative Breast Cancer

Primary Purpose

Triple Negative Breast Neoplasms, Triple Negative Breast Cancer, Breast Neoplasms

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Pembrolizumab

Paclitaxel

Carboplatin

Olaparib

Definitive Surgery

About this trial

This is an interventional treatment trial for Triple Negative Breast Neoplasms focused on measuring BRCA1 protein, BRCA2 protein

Eligibility Criteria

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

Inclusion Criteria:

Male/female subjects who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of invasive breast cancer
Have histologically confirmed TNBC, as defined by the most recent ASCO/CAP guidelines.
Confirmed germline BRCA 1/2 mutated.
Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per AJCC for breast cancer staging criteria version 7 as assessed by the investigator based on radiological and/or clinical assessment:
1. T1c, N1-N2
2. T2, N0-N2
3. T3, N0-N2
4. T4a-d, N0-N2
It has been confirmed that there is no distant metastasis to each organ by the following tests. Chest: Contrast CT or FDG-PET/CT Abdominal: Contract CT* or FDG-PET/CT Bone: Bone scintigraphy or FDG-PET/CT Brain: In the case of no central nervous system symptoms, examination for brain metastasis is not required.
The subject (or legally acceptable representative if applicable) provides written informed consent for the trial.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment.

Exclusion Criteria:

Subjects who has a positive urine pregnancy test within 72 hours prior to registration
Has diagnosed as inflammatory breast cancer.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor .
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug.
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and investigational drugs used in this study and/or any of their excipients.
Has active autoimmune disease that has required systemic treatment in the past 2 years
Has a history of (non-infectious) pneumonitis/interstitial lung disease .
Has an active infection requiring systemic therapy.
Has a known history of Human Immunodeficiency Virus (HIV) infection.
Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HbsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Has a known history of active TB (Bacillus Tuberculosis).
Has a history or current evidence of any condition, therapy, or laboratory abnormality.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Is pregnant or breastfeeding, or expecting to conceive or father children.
Has had an allogenic tissue/solid organ transplant.
Has received pre-treatment with Olaparib or other PARP inhibitors.
Has significant cardiovascular disease
Has a resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions.
Subject has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
Subject received colony-stimulating factors within 28 days prior to the first dose of study intervention.
Subject is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption.
Is, in the judgement of the investigator, unlikely to comply with the study procedures, restrictions, and requirements of the study.
Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study.
Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Pembrolizumab+ Paclitaxel + Carboplatin Followed by Pembrolizumab + Olaparib

Arm Description

Neoadjuvant phase; Treatment 1: Pembrolizumab+ Paclitaxel + Carboplatin (Cycles 1-4) Treatment 2: Pembrolizumab + Olaparib (Cycles 1-4) Definitive Surgery Adjuvant phase; Pembrolizumab + Olaparib (1-9 cycles) Note: each cycle = 3 weeks (Neoadjuvant Treatment 1 and 2, and Adjuvant Treatment)

Outcomes

Primary Outcome Measures

Pathological Complete Response (pCR) Rate (ypT0/TisypN0)

Pathological complete response rate (ypT0/TisypN0) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

Secondary Outcome Measures

Residual Cancer Burden 0/1

Residual Cancer Burden (RCB) 0/1 rate is defined as the proportion of subjects on evaluation from routine pathologic sections of the primary breast tumor and the regional lymph nodes after the completion of neoadjuvant therapy assessed by the local pathologist at the time of definitive surgery. Six variables are included in a calculation formula. The calculated RCB index value can also be categorized as one of four RCB classes (0 - 3). The calculation formula and detailed description can be found at a dedicated Web site: http://www.mdanderson.org/breastcancer_RCB.

Pathological Complete Response (pCR) Rate (ypT0/is)

Pathological complete response rate (ypT0/is) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen regardless of regional lymph nodes status following completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of definitive surgery.

Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0)

Three-Year Overall Survival (3-year OS)

The Proportion of Three Year-Overall Survival (3y-OS) is defined as the proportion of survival subjects without death due to any cause at 3 years from registration. Subjects without documented death at the time of the analysis will be censored at the date of the last follow-up.

Three-Year Distant Metastatic Free Survival (3-year DMFS)

The Proportion of Three-Year Distant Metastatic Free Survival (3y-DMFS) is defined as the proportion of survival subjects without distant metastatic disease at 3 years from registration. Subjects without documented distant metastatic disease at the time of the analysis will be censored at the date of the last follow-up.

Three-Year Disease Free Survival (3-year DFS)

The Proportion of Three-Year Disease Free Survival (3y-DFS) is defined as the proportion of survival subjects without metastatic disease and secondary malignancy at 3 years from registration. Subjects without documented metastatic disease and secondary malignancy at the time of the analysis will be censored at the date of the last follow-up.

AEs/SAEs and treatment discontinuation due to AEs/SAEs

Safety measurements are the incidence of, causality of, and outcome of AEs/SAEs; and changes in vital sign measurements and laboratory values.

Full Information

NCT ID

NCT05485766

First Posted

August 1, 2022

Last Updated

August 1, 2022

Sponsor

Okayama University

Collaborators

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT05485766

Brief Title

Novel Neoadjuvant and Adjuvant Strategy for Germline BRCA 1/2 Mutated Triple Negative Breast Cancer

Official Title

Neoadjuvant and Adjuvant Olaparib Plus Pembrolizumab Following Platinum Based Chemotherapy Plus Pembrolizumab for Germline BRCA Mutated Triple Negative Breast Cancer (WJOG14020B)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

October 1, 2022 (Anticipated)

Primary Completion Date

September 30, 2025 (Anticipated)

Study Completion Date

September 30, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Okayama University

Collaborators

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a Phase II, single-arm, open label study to evaluate Olaparib plus Pembrolizumab following platinum-based chemotherapy plus Pembrolizumab as neoadjuvant therapy for germline BRCA (gBRCA) 1/2 mutated triple negative breast cancer (TNBC). Pembrolizumab in combination with weekly paclitaxel and carboplatin (treatment 1) is followed by Pembrolizumab in combination with Olaparib (treatment 2) in neoadjuvant setting and Pembrolizumab in combination with Olaparib in adjuvant setting will be studied

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Triple Negative Breast Neoplasms, Triple Negative Breast Cancer, Breast Neoplasms, Breast Cancer, BRCA1 Mutation, BRCA2 Mutation, BRCA Mutation, BRCA-Associated Breast Carcinoma

Keywords

BRCA1 protein, BRCA2 protein

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

23 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Pembrolizumab+ Paclitaxel + Carboplatin Followed by Pembrolizumab + Olaparib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pembrolizumab

Other Intervention Name(s)

Keytruda, MK-3475

Intervention Description

200 mg fixed dose, IV, every 3 weeks (Q3W), on Days 1 of Cycles 1-4

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Intervention Description

80 mg/m2, IV, weekly, on Days 1, 8, 15 of Cycles 1-4

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Intervention Description

Area under the curve (AUC 1.5), intravenously (IV), weekly, on Days 1, 8, 15 of Cycles 1-4

Intervention Type

Drug

Intervention Name(s)

Olaparib

Other Intervention Name(s)

Lynparza

Intervention Description

300 mg BID (twice daily) orally

Intervention Type

Procedure

Intervention Name(s)

Definitive Surgery

Intervention Description

Each subject will undergo definitive surgery 3-6 weeks after conclusion of the last cycle of the neoadjuvant treatment.

Primary Outcome Measure Information:

Title

Pathological Complete Response (pCR) Rate (ypT0/TisypN0)

Description

Time Frame

From 27 weeks up to 30 weeks

Secondary Outcome Measure Information:

Title

Residual Cancer Burden 0/1

Description

Time Frame

From 27 weeks up to 30 weeks

Title

Pathological Complete Response (pCR) Rate (ypT0/is)

Description

Time Frame

From 27 weeks up to 30 weeks

Title

Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0)

Description

Time Frame

From 27 weeks Up to 30 weeks

Title

Three-Year Overall Survival (3-year OS)

Description

Time Frame

Up to 3 years

Title

Three-Year Distant Metastatic Free Survival (3-year DMFS)

Description

Time Frame

Up to 3 years

Title

Three-Year Disease Free Survival (3-year DFS)

Description

Time Frame

Up to 3 years

Title

AEs/SAEs and treatment discontinuation due to AEs/SAEs

Description

Safety measurements are the incidence of, causality of, and outcome of AEs/SAEs; and changes in vital sign measurements and laboratory values.

Time Frame

Up to 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male/female subjects who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of invasive breast cancer Have histologically confirmed TNBC, as defined by the most recent ASCO/CAP guidelines. Confirmed germline BRCA 1/2 mutated. Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per AJCC for breast cancer staging criteria version 7 as assessed by the investigator based on radiological and/or clinical assessment: T1c, N1-N2 T2, N0-N2 T3, N0-N2 T4a-d, N0-N2 It has been confirmed that there is no distant metastasis to each organ by the following tests. Chest: Contrast CT or FDG-PET/CT Abdominal: Contract CT* or FDG-PET/CT Bone: Bone scintigraphy or FDG-PET/CT Brain: In the case of no central nervous system symptoms, examination for brain metastasis is not required. The subject (or legally acceptable representative if applicable) provides written informed consent for the trial. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment. Exclusion Criteria: Subjects who has a positive urine pregnancy test within 72 hours prior to registration Has diagnosed as inflammatory breast cancer. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor . Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and investigational drugs used in this study and/or any of their excipients. Has active autoimmune disease that has required systemic treatment in the past 2 years Has a history of (non-infectious) pneumonitis/interstitial lung disease . Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV) infection. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HbsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Has a known history of active TB (Bacillus Tuberculosis). Has a history or current evidence of any condition, therapy, or laboratory abnormality. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children. Has had an allogenic tissue/solid organ transplant. Has received pre-treatment with Olaparib or other PARP inhibitors. Has significant cardiovascular disease Has a resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions. Subject has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML. Subject received colony-stimulating factors within 28 days prior to the first dose of study intervention. Subject is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption. Is, in the judgement of the investigator, unlikely to comply with the study procedures, restrictions, and requirements of the study. Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Yuko Takahashi, MD., PhD.

Phone

+81-086-223-7151

yukotaka@okayama-u.ac.jp

First Name & Middle Initial & Last Name or Official Title & Degree

Hironobu TAN, PhD.

Phone

+81-086-235-7994

hironobu_tan@okayama-u.ac.jp

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yuko Takahashi, MD., PhD.

Organizational Affiliation

Assistant Professor, Endocrinological Center, Okayama University Hospital

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Novel Neoadjuvant and Adjuvant Strategy for Germline BRCA 1/2 Mutated Triple Negative Breast Cancer

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