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

NCT05033756 | Active Not Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: IFG-05-2019AGO-B-0512020-001940-25
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 6

Brief 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, SLX4, XRCC2), and
• cohort 3: aBC patients with a HRD as assessed by whole genome sequencing.

Conditions

Malignant Neoplasm of Breast; Breast Cancer

Keywords

Germline mutation; Homologous Recombination Deficiency

Outcome Measures

Primary Outcomes (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.

  baseline up to 27 weeks

Secondary Outcomes (4)

• duration of response (DOR) time

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

• progression free survival (PFS) time

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

• overall survival (OS) time

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

• safety and tolerability of pembrolizumab in combination with olaparib

  study start until 90 days post last dose

Study Arms (1)

Pembrolizumab / Olaparib

EXPERIMENTAL

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).

Drug: Pembrolizumab Injection [Keytruda]; Drug: Olaparib Oral Tablet [Lynparza]

Interventions

Pembrolizumab Injection [Keytruda] DRUG

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.

Also known as: Keytruda

Pembrolizumab / Olaparib

Olaparib Oral Tablet [Lynparza] DRUG

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.

Also known as: Lynparza

Pembrolizumab / Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Institut fuer Frauengesundheit: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (6)

Department of Gynecology, Tübingen University Hospital

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

University Hospital Ulm

Ulm, Baden-Wurttemberg, 89075, Germany

Location

Department of Gynecology and Obstetrics, Erlangen University Hospital

Erlangen, Bavaria, 91054, Germany

Location

Marienhospital Bottrop

Bottrop, North Rhine-Westphalia, 46236, Germany

Location

University Hospital Düsseldorf

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Helios-Klinikum Berlin-Buch

Berlin, 13125, Germany

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

pembrolizumab; olaparib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Peter A. Fasching, MD, Prof.

  Department of Gynecology and Obstetrics, Erlangen University Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 3, 2021
• First Posted: September 5, 2021
• Study Start: July 30, 2022
• Primary Completion: January 1, 2025
• Study Completion: February 1, 2026
• Last Updated: May 7, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (6)