| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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). |
|
| E.2.2 | Secondary objectives of the trial |
1. 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.
2.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 QLQBR23) in participants with BRCAm tumors and irrespective of BRCAm status following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
3. To evaluate visual analogue scale (VAS) using the European Quality of Life 5-dimension, 5-level questionnaire (EuroQoL EQ-5D-5L) in participants with BRCAm tumors and irrespective of BRCAm status following treatment with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab.
4.To evaluate the safety and tolerability of olaparib plus pembrolizumab or chemotherapy plus pembrolizumab. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (Blood, tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
1. Have locally recurrent inoperable centrally confirmed TNBC that has not previously been treated with chemotherapy in the metastatic setting and that cannot be treated with curative intent OR Have metastatic TNBC that has not been previously treated with chemotherapy
2. Have 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. Have measurable disease based on RECIST 1.1, as determined by local radiology review
4. Have provided a recently obtained or archival (no more than 3 years old) core or excisional biopsy of a tumor lesion not previously irradiated for central determination of TNBC, PD-L1, BRCA, and HRD status
5. Be a male or female at least 18 years of age on the day of signing the informed consent
6. Have an ECOG performance status of 0 or 1 as assessed within 7 days prior to the start of induction study treatment
7. Have a life expectancy ≥27 weeks from the day of first study treatment
8. Demonstrate adequate organ function
9. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
-Olaparib: 95 days
-Pembrolizumab: no contraception requirement
-Chemotherapy: 95 days
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
-Olaparib: 180 days
-Pembrolizumab: 120 days
-Chemotherapy: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie,noncompliance, recently initiated) in relationship to the first dose of study intervention.
◦ A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
11. The participant (or legally acceptable representative) has provided documented informed consent for the study. The participant may also provide consent for Future Biomedical Research (FBR). However, the participant may participate in the study without participating in FBR.
POST-INDUCTION PERIOD
Types of Participant and Disease Characteristics
12. Have received up to 6 cycles but not less than 4 cycles of induction therapy without permanently discontinuing from pembrolizumab or both carboplatin and gemcitabine
13. Have achieved CR, PR, or SD based on RECIST 1.1, as determined by BICR at the Week 18 evaluation. Radiographic eligibility will be determined solely based upon the Week 18 evaluation
14. Should be able to complete during post-induction at least the Cycle 1, Day 1 doses of olaparib and pembrolizumab (Arm 1) 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
15. Have an ECOG performance status of 0 or 1, as assessed within 7 days prior to the start of post-induction study treatment
16. Have no higher than Grade 1 toxicities related to induction therapy (excluding alopecia) prior to randomization |
|
| E.4 | Principal exclusion criteria |
INDUCTION PERIOD
1.Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
2.Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug
3.Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed
4.Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable
5.Has myelodysplastic syndrome/acute myeloid leukemia 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 HIV infection
11.Has a known history of Hepatitis B or known active Hepatitis C virus 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 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 and any of their components
16.Has severe hypersensitivity 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 PARP inhibitor
21.Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
22.Has received colony-stimulating factors 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
25.Had major surgery within 2 weeks of starting study intervention 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 as described in the respective product labels 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 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, or participant has congenital long QT syndrome.
31.Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study
32.Is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption
33.Is, in the judgement of the investigator, unlikely to comply with the study procedures, restrictions, and requirements of the study
POST-INDUCTION PERIOD
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. The required washout period prior to starting olaparib is 2 weeks
39.Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. 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. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 72 months
2. Up to approximately 72 months |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
2. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants with Breast Cancer Susceptibility Gene Mutation (BRCAm) Tumors
3. Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
4. 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
5. 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
6. 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
7. Time to Deterioration in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
8. 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
9. 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
10. 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
11. Change From Baseline in Health Outcomes using the European Quality of Life 5-dimension, 5-level Questionnaire (EuroQoL EQ-5D-5L) Visual Analogue Scale (VAS) Score
12. Number of Participants Who Experienced At Least One Adverse Event (AE)
13. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 72 months
2. Up to approximately 72 months
3. Baseline and up to approximately 72 months
4. Baseline and up to approximately 72 months
5. Baseline and up to approximately 72 months
6. Baseline and up to approximately 72 months
7. Up to approximately 72 months
8. Up to approximately 72 months
9. Up to approximately 72 months
10. Up to approximately 72 months
11. Baseline and up to approximately 72 months
12. Up to approximately 72 months
13. Up to approximately 72 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Chile |
| Colombia |
| Japan |
| Korea, Republic of |
| Taiwan |
| Ukraine |
| United States |
| France |
| Germany |
| Hungary |
| Ireland |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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