Comprehensive Analysis of Predictors of the Treatment With Pembrolizumab and Olaparib in Patients With Unresectable or Metastatic HER2 Negative Breast Cancer and a Deleterious Germline Mutation or a Homologous Recombination Deficiency (COMPRENDO

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT05033756

Studienbeginn:
Juli 2022

Letztes Update:
22.02.2023

Wirkstoff:
Pembrolizumab Injection [Keytruda], Olaparib Oral Tablet [Lynparza]

Indikation (Clinical Trials):
Breast Neoplasms, Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Institut fuer Frauengesundheit

Collaborator:
Merck Sharp & Dohme LLC

Studienleiter

Peter A. Fasching, MD, Prof.
Study Chair
Department of Gynecology and Obstetrics, Erlangen University Hospital

Kontakt

COMPRENDO Study manager
Kontakt:
Phone: +49 9131 927
Phone (ext.): 8967
E-Mail: comprendo@ifg-erlangen.de» Kontaktdaten anzeigen

Peter A. Fasching, MD, Prof.
Kontakt:
Phone: +49 9131 85
Phone (ext.): 43470
E-Mail: peter.fasching@uk-erlangen.de» Kontaktdaten anzeigen

Studienlocations
(3 von 6)

Department of Gynecology, Tübingen University Hospital
72076 Tübingen
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Andreas Hartkopf, MD, Prof.
Phone: +49 07071 29
Phone (ext.): 82211
E-Mail: andreas.hartkopf@med.uni-tuebingen.de» Ansprechpartner anzeigen

University Hospital Ulm
89075 Ulm
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Kristina Ernst, MD
Phone: +49 0731 50058
Phone (ext.): 520
E-Mail: kristina.ernst@uniklinik-ulm.de» Ansprechpartner anzeigen

Department of Gynecology and Obstetrics, Erlangen University Hospital
91054 Erlangen
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Peter A Fasching, Prof. Dr.
Phone: +49 9131 85
Phone (ext.): 43470
E-Mail: peter.fasching@uk-erlangen.de» Ansprechpartner anzeigen

Brustzentrum Marienhospital Bottrop
Josef-Albers-Straße 70
46236 Bottrop
DeutschlandNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Hans C Kolberg, PD
Phone: +49 02041 1061
Phone (ext.): 601
E-Mail: hans-christian.kolberg@mhb-bottrop.de» Ansprechpartner anzeigen

University Hospital Düsseldorf
40225 Düsseldorf
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Tanja Fehm, MD, Prof.
Phone: +49 211 81
Phone (ext.): 18483
E-Mail: tanja.fehm@med.uni-duesseldorf.de» Ansprechpartner anzeigen

Helios-Klinikum Berlin-Buch
13125 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Michael Untch, MD, Prof.
Phone: +49 30 94 01
Phone (ext.): 53300
E-Mail: michael.untch@helios-gesundheit.de» Ansprechpartner anzeigen

Alle anzeigen

Studien-Informationen

Detailed Description:

This is a multicenter, prospective, phase II, one-arm, three-cohort, open-label study of

pembrolizumab in combination with olaparib in patients with advanced HER2 negative breast

cancer who have either

- a deleterious germline mutation in BRCA1/2 irrespective of tumor HRD status (Cohort 1),

- or a deleterious germline mutation in ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D,

SLX4, XRCC2 irrespective of tumor HRD status (Cohort 2),

- or a centrally confirmed high tumor HRD status, but no deleterious germline mutation in

BRCA1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 (Cohort 3). HRD

assessment needs to be performed on a tumor biopsy not more than 12 months before study

entry.

All eligible participants according to the definition of cohorts 1-3 will receive

pembrolizumab i.v. 200 mg q3w in combination with olaparib tablets 300 mg twice daily (total

dose 600 mg per day).

Study medication will be withdrawn/ended in case of onset of unacceptable toxicities,

progression, withdrawal of consent, death, or end of study, whichever occurs first. Safety

follow-up is planned for 90 days after the last application of study medication. Participants

will be followed for survival for a maximum of 18 months after therapy start.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. The participant 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 ER/PR 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:

- Absolute neutrophile count ≥1500/µL

- Platelets ≥100 000/µL

- Hemoglobin ≥10.0 g/dL or ≥6.2 mmol/L

- Geschätzte Kreatinin-Clearance ≥51 mL/min berechnet mit der

Cockcroft-Gault-Gleichung oder basierend auf dem 24-Stunden-Sammelurin

- Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total

bilirubin levels >1.5 × ULN

- AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver

metastases)

- 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

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 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:

- Human Immunodeficiency Virus (HIV).

- Acute or chronic Hepatitis B or Hepatitis C

- 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, nevirapine and St John's Wort ) or

moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout

period prior to starting trial treatment is 5 weeks for enzalutamide or phenobarbital

and 3 weeks for other agents.

21. Previous allogenic bone marrow transplant or double umbilical cord blood

transplantation (dUCBT).

22. Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant

systemic disease or active, uncontrolled infection; any condition that interferes with

pembrolizumab or olaparib treatment.

23. Unability to swallow or gastrointestinal disorders with reduced absorption of

olaparib.

24. Psychiatric or substance abuse disorders.

25. A woman of childbearing potential who has a positive urine pregnancy test within 72

hours prior to inclusion. If the urine test is positive or cannot be confirmed as

negative, a serum pregnancy test will be required.

26. Participants being pregnant or breastfeeding, or expecting to conceive or father

children within the projected duration of the study, starting with the screening visit

through 120 days after the last dose of trial treatment.

27. Any other condition in opinion of the investigator that would interfere with applied

systemic treatment or other trial procedures

Studien-Rationale

Primary outcome:

1. Efficacy of the combination of pembrolizumab and olaparib via overall response rate (Time Frame - baseline up to 27 weeks):
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.

Secondary outcome:

1. duration of response (DOR) time (Time Frame - between the date of first response to the date of first tumor progression for up to 18 months after therapy start):
DOR is defined as the time between the date of first response (CR or PR) to the date of first tumor progression per RECIST v1.1.

2. progression free survival (PFS) time (Time Frame - between the date of study entry and the first date of progression or death for up to 18 months after therapy start):
PFS is defined as the time between the date of study entry and the first date of progression or death due to any cause, whichever occurs first

3. overall survival (OS) time (Time Frame - between the date of study entry and the date of death for up to 18 months after therapy start):
OS is defined as the time between the date of study entry and the date of death due to any cause

4. safety and tolerability of pembrolizumab in combination with olaparib (Time Frame - study start until 90 days post last dose):
Incidence of adverse events (AEs) and serious adverse events (SAEs), incidence of deaths, and incidence of abnormalities in the laboratory diagnostics

Geprüfte Regime

Pembrolizumab Injection [Keytruda] (Keytruda):
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.
Olaparib Oral Tablet [Lynparza] (Lynparza):
All patients will receive olaparib treatment as an addition to pembrolizumab. The dose of olaparib used in this study is 300 mg twice daily (total daily dose of 600 mg) which is the currently approved dose.

Quelle: ClinicalTrials.gov

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