Olaparib Plus Pembrolizumab Compared to Chemotherapy Plus Pembrolizumab After Initial Treatment With Chemotherapy Plus Pembrolizumab in Triple-Negative Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2020 → 26 Nov 2025

Decision date (initial)

2023-02-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-500418-24-00

EudraCT number

2019-001892-35

WHO UTN

U1111-1275-8575

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

1. To compare olaparib plus pembrolizumab to chemotherapy plus pembrolizumab with regards to progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).
2. To compare olaparib plus pembrolizumab to chemotherapy plus pembrolizumab with regards to overall survival (OS).

Secondary objectives 5

1. To evaluate OS, and PFS according to RECIST 1.1 by BICR, in participants with PD-L1 positive tumors (CPS ≥10) following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
2. To evaluate OS, and PFS according to RECIST 1.1 by BICR, in participants with BRCAm tumors following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
3. To evaluate health-related quality-of-life (HRQoL) and time to deterioration (TTD) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the breast cancer module (EORTC QLQ-BR23) in participants with BRCAm tumors and irrespective of BRCAm status following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
4. To evaluate visual analogue scale (VAS) using the EuroQoL 5-dimension, 5-level questionnaire (EQ-5D-5L) in participants with BRCAm tumors and irrespective of BRCAm status following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
5. To evaluate the safety and tolerability of olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.

Conditions and MedDRA coding

Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC)

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Has locally recurrent inoperable Triple Negative Breast Cancer (TNBC) that has not previously been treated with chemotherapy and that cannot be treated with curative intent OR has metastatic TNBC that has not been previously treated with chemotherapy
2. Has been treated with anthracycline and/or a taxane in the neoadjuvant/adjuvant setting, if they received systemic treatment in the neoadjuvant/adjuvant setting, unless anthracycline and/or taxane was contraindicated or not considered the best treatment option for the participant in the opinion of the treating physician
3. Has measurable disease based on RECIST 1.1
4. Has provided a recently obtained or archival (no more than 3 years old) core or excisional biopsy of a tumor lesion not previously irradiated
5. Be a male or female at least 18 years of age
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 as assessed within 7 days prior to the start of induction study treatment
7. Has a life expectancy ≥27 weeks from the day of first study treatment
8. Demonstrate adequate organ function within 10 days prior to the start of study treatment
9. A male participant must agree to be abstinent or use contraception and refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention (95 days for olaparib and chemotherapy; no requirement for pembrolizumab)
10. A female participant must not be pregnant or breastfeeding and must agree to the following if is a woman of childbearing potential (WOCBP): have a negative pregnancy test within 24 hours before the start of study treatment and agree to be abstinent or use contraception and refrain from donating eggs (ova, oocytes) during the intervention period and for at least the time needed to eliminate each study intervention (180 days for olaparib and chemotherapy; 120 days for pembrolizumab)
11. Has received up to 6 cycles but not less than 4 cycles of induction therapy without permanently discontinuing from pembrolizumab or both carboplatin and gemcitabine
12. Has achieved complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 by Blinded Independent Central Review (BICR) at the Week 18 evaluation
13. Is able to complete during post-induction at least the Cycle 1, Day 1 doses of olaparib and pembrolizumab or the Cycle 1, Day 1 doses of at least one of the chemotherapy agents being administered at the end of induction (carboplatin and/or gemcitabine) in addition to pembrolizumab
14. Has ECOG performance status of 0 or 1, as assessed within 7 days prior to the start of post-induction study treatment
15. Has no higher than Grade 1 toxicities related to induction therapy (excluding alopecia) prior to randomization

Exclusion criteria 39

1. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, cervical cancer in situ) that have undergone potentially curative therapy
2. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
3. Has an active autoimmune disease that has required systemic treatment in the past 2 years
4. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
5. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
6. Has a history of (non-infectious) pneumonitis\interstitial lung disease that required steroids or current pneumonitis\interstitial lung disease
7. Has active, or a history of, interstitial lung disease
8. Has a known history of active tuberculosis
9. Has an active infection requiring systemic therapy
10. Has a known history of human immunodeficiency virus (HIV) infection
11. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
12. Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months of first study treatment
13. Has neuropathy ≥Grade 2
14. Has not recovered (eg, to ≤Grade 1 or to baseline) from AEs due to a previously administered therapy
15. Has a known history of hypersensitivity or allergy to pembrolizumab, olaparib and any of its components, and/or to any of the study chemotherapies (eg, carboplatin or gemcitabine) and any of their components
16. Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients
17. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 180 days after the last dose of study treatment
19. Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization or treatment allocation
20. Has received prior therapy with either olaparib or any other poly adenosine diphosphate ribose polymerase (PARP) inhibitor
21. Has received prior radiotherapy within 2 weeks of start of study treatment
22. Has received colony-stimulating factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor [GM-CSF] or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment
23. Has had an allogenic tissue/solid organ transplant
24. Has received previous allogenic bone marrow transplant or double umbilical cord transplantation (dUCBT)
25. Has had major surgery within 2 weeks of starting study treatment or has not recovered from any effects of any major surgery
26. Has received a live or live-attenuated vaccine within 30 days prior to first study treatment
27. Is receiving any medication prohibited in combination with study chemotherapies unless medication was stopped within 7 days prior to first study treatment
28. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T cell receptor (such as cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137) or has previously participated in a study evaluating pembrolizumab regardless of treatment received
29. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
30. Has presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator
31. Has a history or current evidence of any condition (eg, cytopenia, transfusion-dependent anemia, or thrombocytopenia), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator
32. Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
33. Is unlikely to comply with the study procedures, restrictions, and requirements of the study; as judged by the investigator
34. Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their excipients
35. Has permanently discontinued from both carboplatin and gemcitabine during induction due to toxicity
36. Has permanently discontinued from pembrolizumab during induction due to toxicity
37. Has received less than 4 cycles of chemotherapy plus pembrolizumab during induction
38. Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
39. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Overall Survival (OS)

Secondary endpoints 15

1. Overall Survival (OS) in Participants with Programmed Cell Death Ligand 1 (PD-L1) Positive Tumors with a Combined Positive Score (CPS) ≥10
2. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Programmed Cell Death Ligand 1 (PD-L1) Positive Tumors with a Combined Positive Score (CPS) ≥10
3. Overall Survival (OS) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
4. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
5. Change From Baseline in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
6. Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score
7. Change From Baseline in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score
8. Change From Baseline in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality-of-Life (QoL) Questionnaire (EORTC QLQ-BR23) Items 1-4,6,7, and 8 Score
9. Time to Deterioration in Health-Related Quality-of-Life (QoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
10. Time to Deterioration in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1-5 Score
11. Time to Deterioration in Emotional Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 21-24 Score
12. Time to Deterioration in Systemic Therapy Side Effects Using the European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality-of-Life (QoL) Questionnaire (EORTC QLQ-BR23) Items 1-4,6,7, and 8 Score
13. Change From Baseline in Health Outcomes using the European Quality of Life 5-dimension, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score
14. Number of Participants Who Experienced At Least One Adverse Event (AE)
15. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme Corp.

Contact name

Jaime Mejia

Public contact point

Organisation

Merck Sharp & Dohme Corp.

Contact name

Jaime Mejia

Third parties 6

Locations

6 EU/EEA countries · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications