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Malignant Neoplasm of BreastPhase 2COMPRENDONCT05033756

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

A Phase 2 study testing Pembrolizumab Injection [Keytruda] and Olaparib Oral Tablet [Lynparza] in people with Malignant Neoplasm of Breast and Breast Cancer, run by Institut fuer Frauengesundheit at 6 sites in Germany.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This study will examine the combination of pembrolizumab and olaparib in three populations. Cohort 1: aBC patients with a germline mutation in BRCA1 or BRCA2, cohort 2: aBC patients with a germline mutation in one of the moderate penetrance homologous repair genes (ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Neoplasm of Breast, Breast Cancer
What is being tested?
Pembrolizumab Injection [Keytruda] and Olaparib Oral Tablet [Lynparza]
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
6 sitesGermany
Study dates
30 Jul 2022to Feb 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The participant must provide written informed consent.
  • 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.
  • 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.
  • 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.
  • 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.
  • Cohort 3: High HRD status and no germline mutation in one of the above mentioned genes of cohort 1 or cohort 2.
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  • Cohort 3: Availability of FFPE tumor material for further validation of HRD status (bridging tests).
  • Cohorts 2 and 3: Patients must have been treated with first line chemotherapy, if this chemotherapy is standard of care in this therapy situation.
  • Prior platinum in the (neo)adjuvant setting is allowed as long as 12 months from last dose to study entry have elapsed.
  • Participants with ER/PR positive breast cancer must have exhausted previous combination therapy of CDK4/6 inhibitors with endocrine treatment.
  • Measurable disease based on RECIST v1.1.
  • 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.
  • ECOG performance status 0-1.
  • Female participants must have a negative urine or serum pregnancy test within 72 h prior to first dose of trial treatment, no breastfeeding.
  • 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.
  • 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.
  • 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

Who cannot join

  • Has histologically confirmed HER2 positive (3+ by IHC or ISH amplified ≥ 2.0) breast cancer.
  • 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.).
  • Cohort 3: no high tumor HRD.
  • Rapidly progressive disease which requires combination chemotherapy.
  • Current participation in another investigational trial within 4 weeks prior to the first dose of trial treatment
  • Known hypersensitivity to pembrolizumab or olaparib or any of its excipients.
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  • 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.
  • Prior treatment with a checkpoint inhibitor or a PARP inhibitor.
  • No complete recovery from prior surgery or radiotherapy. Starting study treatment is allowed not before 2 weeks after major surgery.
  • 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.
  • 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).
  • Live vaccination within 30 days prior to study entry.
  • 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.
  • Has an active infection requiring systemic therapy.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • Known history of the following infections:
  • Human Immunodeficiency Virus (HIV).
  • Acute or chronic Hepatitis B or Hepatitis C
  • Active Tuberculosis
  • 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.
  • Patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
  • 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.
  • 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.
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
  • 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.
  • Unability to swallow or gastrointestinal disorders with reduced absorption of olaparib.
  • Psychiatric or substance abuse disorders.
  • 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.
  • 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.
  • Any other condition in opinion of the investigator that would interfere with applied systemic treatment or other trial procedures

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

Germany6 sites

  • Helios-Klinikum Berlin-Buch

    Berlin, 13125

  • Marienhospital Bottrop

    Bottrop, North Rhine-Westphalia, 46236

  • University Hospital Düsseldorf

    Düsseldorf, North Rhine-Westphalia, 40225

  • Department of Gynecology and Obstetrics, Erlangen University Hospital

    Erlangen, Bavaria, 91054

  • Department of Gynecology, Tübingen University Hospital

    Tübingen, Baden-Wurttemberg, 72076

  • University Hospital Ulm

    Ulm, Baden-Wurttemberg, 89075

Other trials in Germany

About this study

Official title: A Phase II Open-Label Study for the 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 in BRCA1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 or a Homologous Recombination Deficiency

This study will examine the combination of pembrolizumab and olaparib in three populations.

  • Cohort 1: aBC patients with a germline mutation in BRCA1 or BRCA2,
  • cohort 2: aBC patients with a germline mutation in one of the moderate penetrance homologous repair genes (ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2), and
  • cohort 3: aBC patients with a HRD as assessed by whole genome sequencing.
Read the 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.

Being tested
Pembrolizumab Injection [Keytruda], Olaparib Oral Tablet [Lynparza]
Keywords
Germline mutation, Homologous Recombination Deficiency
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pembrolizumab Injection [Keytruda]Drug

    Also called 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]Drug

    Also called 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.

Study groups in NCT05033756
Study groupRoleWhat they receive
Pembrolizumab / OlaparibExperimentalAll 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).
Receives: Drug: Pembrolizumab Injection [Keytruda]; Drug: Olaparib Oral Tablet [Lynparza]

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Efficacy of the combination of pembrolizumab and olaparib via overall response rate

    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.

    Measured: baseline up to 27 weeks

Secondary outcomes (4)

  1. duration of response (DOR) time

    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.

    Measured: between the date of first response to the date of first tumor progression for up to 18 months after therapy start

  2. progression free survival (PFS) time

    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

    Measured: between the date of study entry and the first date of progression or death for up to 18 months after therapy start

  3. overall survival (OS) time

    OS is defined as the time between the date of study entry and the date of death due to any cause

    Measured: between the date of study entry and the date of death for up to 18 months after therapy start

  4. safety and tolerability of pembrolizumab in combination with olaparib

    Incidence of adverse events (AEs) and serious adverse events (SAEs), incidence of deaths, and incidence of abnormalities in the laboratory diagnostics

    Measured: study start until 90 days post last dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Sep 2021
  2. Study start30 Jul 2022
  3. Primary completionJan 2025 (estimated)
  4. Study completionFeb 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05033756
Sponsor's protocol ID
IFG-05-2019
Other IDs
AGO-B-051, 2020-001940-25
Acronym
COMPRENDO
Status last verified
May 2024
First submitted
3 Apr 2021
Last updated
7 May 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab Injection [Keytruda] and Olaparib Oral Tablet [Lynparza] in people with Malignant Neoplasm of Breast and Breast Cancer, run by Institut fuer Frauengesundheit at 6 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 7 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy of the combination of pembrolizumab and olaparib via overall response rate (time frame: baseline up to 27 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05033756.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 May 2024.

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