This is a trial for patients with diagnosed advanced HER2-negative breast cancer and amutation in the genes BRCA1/2, ATM, BARD1, CHEK2, FANCC, PALB2,RAD51C, RAD51D, SLX4, XRCC2 or tumor tissue (homologousrecombination deficiency). The patients will be treated with a combinationof pembrolizumab and olaparib.
- Conditions
- patients with unresectable or metastatic HER2 negative breast cancer and a deleterious germlinemutation in BRCA 1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 or ahomologous recombination deficiencyMedDRA version: 21.1Level: PTClassification code 10057654Term: Breast cancer femaleSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: PTClassification code 10061020Term: Breast cancer maleSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10006187Term: Breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.1Level: PTClassification code 10055113Term: Breast cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-001940-25-DE
- Lead Sponsor
- Institut für Frauengesundheit GmbH
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 89
In order to be eligible for participation in this trial, participants must fulfill all of the following criteria:
1. The participant (or legally acceptable representative if applicable) must provide written informed consent.
2. Male/Female participants must be =18 years of age at the day of signing informed consent and must be willing to comply with the study specific procedures.
3. Histologically confirmed metastatic or advanced, unresectable HER2 negative (0, 1+ by IHC or ISH amplified < 2.0) breast cancer which is not eligible for curative treatment..
4. Cohort 1: Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious (known or predicted to be detrimental/lead to loss of function) irrespective of HRD status.
5. Cohort 2: Germline mutation in ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 that is predicted to be deleterious (known or predicted to be detrimental/lead to loss of function) irrespective of HRD status.
6. Cohort 3: High HRD status and no germline mutation in one of the above mentioned genes of cohort 1 or cohort 2.
7. Cohort 3: Availability of FFPE tumor material for further validation of HRD status (bridging tests).
8. Cohorts 2 and 3 Patients must have been treated with first line chemotherapy, if this chemotherapy is standard of care in this therapy situation
9. Prior platinum in the (neo)adjuvant setting is allowed as long as 12 months from last dose to study entry have elapsed.
10. Participants with hormone receptor positive breast cancer must have exhausted previous combination therapy of CDK4/6 inhibitors with endocrine treatment.
11. Measurable disease based on RECIST v1.1.
12. Provision of a recently obtained (within 12 months before study inclusion) core or excisional biopsy of a tumor lesion. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
13. ECOG performance status 0-1.
14. Female participants must have a negative urine or serum pregnancy test within 72 h prior to first dose of trial treatment, no breastfeeding.
15. Female participants of childbearing potential must agree to use sufficient methods of contraception as outlined in section 12.3.2 Contraception Requirements during treatment plus an additional 120 days after the last dose of study medication.
16. Male participants must agree to use sufficient methods of contraception as outlined in section 12.3.2 Contraception Requirements during treatment plus an additional 120 days after the last dose of study medication.
17. Adequate organ function defined as:
o Absolute neutrophile count =1500/µL
o Platelets =100 000/µL
o Hemoglobin =10.0 g/dL or =6.2 mmol/L
o Patients must have creatinine clearance estimated of =51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test
o Total bilirubin =1.5 ×ULN OR direct bilirubin =ULN for participants with total bilirubin levels >1.5 × ULN
o AST (SGOT) and ALT (SGPT) =2.5 × ULN (=5 × ULN for participants with liver metastases)
o International normalized ratio (INR) OR prothrombin time (PT) =1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 58
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 31
1. Has histologically confirmed HER2 positive (3+ by IHC or ISH amplified = 2.0) breast cancer.
2. Cohorts 1 and 2: germline mutations in BRCA1, BRCA2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 that are considered to be non-detrimental (e.g., variants of uncertain/unknown clinical significance” or benign polymorphism” etc.).
3. Cohort 3: no high tumor HRD.
4. Rapidly progressive disease which requires combination chemotherapy.
5. Current participation in another investigational trial within 4 weeks prior to the first dose of trial treatment
6. Known hypersensitivity to pembrolizumab or olaparib or any of its excipients.
7. Prior systemic anti-cancer therapy within 4 weeks prior to allocation or no recovery from all AEs due to previous therapies to = grade 1, excluding alopecia and = grade 2 peripheral neuropathy.
8. Prior treatment with a checkpoint inhibitor or a PARP inhibitor.
9. No complete recovery from prior surgery or radiotherapy. Starting study treatment is allowed not before 2 weeks after major surgery.
10. Prior malignancy unless curatively treated and disease-free for less than 3 years prior to study entry. Within this timeframe, prior adequately treated non-melanoma skin cancer, transitional cell carcinoma, carcinoma in situ of the prostate, of the cervix, of the breast or in situ or stage I grade 1 endometrial cancer is eligible.
11. Uncontrolled brain metastases (Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks (note that the assessment of the brain metastases should be performed during study screening for this purpose), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment).
12. Live vaccination within 30 days prior to study entry.
13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
14. Has an active infection requiring systemic therapy.
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
16. Known history of the following infections:
o Human Immunodeficiency Virus (HIV).
o Acute or chronic Hepatitis B or Hepatitis C
o Active Tuberculosis
17. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
18. Patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
19. Preexisting use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting trial treatment is 2 weeks.
20. Preexisting use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabuti
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method