patients with unresectable or metastatic HER2 negative breast cancer and a deleterious germline mutation in BRCA 1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 or a homologous recombination deficiency MedDRA version: 21.1 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10061020 Term: Breast cancer male System
Conditions
Interventions
Trade Name: KEYTRUDA
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Pembrolizumab
CAS Number: 1374853-91-4
Other descriptive name: MK-3475
Concentration unit: mg/ml mi
Sponsors
Institut für Frauengesundheit GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 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 3
Exclusion criteria
Exclusion criteria: 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 allowed. 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, rifabutin, rifapentine, carbamazepine, nevir
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the efficacy of the combination of pembrolizumab and olaparib, as determined by overall response rate (ORR) using RECIST v1.1 criteria (time frame: baseline up to 27 weeks).;Secondary Objective: (1) To investigate the duration of response (DOR) time for the three cohorts. (2) To investigate the progression free survival (PFS) time for the three cohorts. (3) To investigate the overall survival (OS) time for the three cohorts. (4) To investigate the safety and tolerability of pembrolizumab in combination with olaparib.;Primary end point(s): • Overall response rate (ORR) is defined as the number of participants with a confirmed best response of complete response (CR) or partial response (PR) per RECIST v1.1.;Timepoint(s) of evaluation of this end point: Baseline up to 27 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • DOR (median duration of response) • PFS (median progression free survival) • OS (median overall survival) • Incidence of AEs, SAEs, fatal events; ratio of AEs/SAEs ;Timepoint(s) of evaluation of this end point: • first response to the date of first tumor progression • until date of progression (after approximately 10 months) • time to the date of death due to any cause. • screening until 120 days post last dose Participants will be followed for survival for a maximum of 18 months. | — |
Countries
Germany
Contacts
Public ContactComprendo Study Management
Institut für Frauengesundheit GmbH
Outcome results
None listed