臨床研究等提出・公開システム

多施設共同、無作為化、並行群間、非盲検

Multicenter clinical study,randomized controlled trial,parallel assignment,open(masking not used)

導入療法期
1)転移性病変に対する化学療法の治療歴がなく、根治的治療が行えない切除不能の局所再発TNBC患者。又は、化学療法の治療歴がない転移性TNBC患者。
2)術前／術後補助療法で全身治療を受けた患者の場合、アントラサイクリン系薬剤及び／又はタキサン系薬剤による術前／術後補助療法の治療歴を有する患者。ただし、アントラサイクリン系薬剤及び／又はタキサン系薬剤の使用が禁忌、又は主治医判断で最良の治療選択肢ではないと判断された場合はこの限りではない。
3)RECIST 1.1の評価に基づき、測定可能病変を有する患者
4)以前に放射線照射を受けていない腫瘍病変から直近に採取した検体、保存した（3年以内）コア生検又は切開生検検体を提出可能な患者
5)導入療法期の治験薬初回投与前7日以内の評価でECOG Performance Statusが0又は1の患者
6)治験薬初回投与日から27週間以上の生存が見込まれる患者
7)治験薬初回投与前10日以内に適切な臓器機能が保持された患者
8)男性患者の場合、投与期間中及び治験薬の最終投与後少なくとも各治験薬が消失するのに必要な期間（オラパリブ及び化学療法剤：95日、ペムブロリズマブ：避妊要件なし）、以下の項目に同意した男性患者。精子を提供しない。避妊法を遵守する、又は異性間性交渉をしない。
9)女性患者の場合、妊娠しておらず、授乳中でない女性患者。妊娠可能な女性の場合、以下の項目に同意した女性患者：治験薬初回投与前24時間以内に妊娠検査で陰性が確認されている。投与期間中及び治験薬の最終投与後少なくとも各治験薬が消失するのに必要な期間（オラパリブ及び化学療法剤：180日、ペムブロリズマブ：120日）、避妊法を遵守する、又は異性間性交渉をしない。卵子（卵子、卵母細胞）提供をしない。

導入後療法期
10)ペムブロリズマブ又はカルボプラチン及びゲムシタビンを中止することなく、導入療法を最大6コース（ただし、4コース以上）受けた患者。
11)18週の評価時に RECIST 1.1に基づく盲検下独立中央画像判定機関の評価で、CR、PR又は SDと判定された患者。
12)オラパリブ＋ペムブロリズマブ、又はカルボプラチン及び／又はゲムシタビン＋ペムブロリズマブ、のいずれかの群で導入後療法期に少なくとも1コース1日目の投与を完了できる患者。導入療法期終了時に少なくともいずれかの化学療法が投与されていること。
13)導入後療法期の治験薬初回投与前7日以内の評価で ECOG Performance Statusが0又は1の患者
14)無作為割付け前に導入療法に関連したGrade 2以上の毒性（脱毛症は除く）のない患者

Induction Period:
1. Has locally recurrent inoperable 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. 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
6. Has a life expectancy >=27 weeks from the day of first study treatment
7. Demonstrate adequate organ function within 10 days prior to the start of study treatment
8. 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)
9. 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)

Post-induction Period:
10. 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
11. 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
12. 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
13. Has ECOG performance status of 0 or 1, as assessed within 7 days prior to the start of post-induction study treatment
14. Has no higher than Grade 1 toxicities related to induction therapy (excluding alopecia) prior to randomization

導入療法期
1)過去5年以内に進行又は治療が必要な他の悪性腫瘍を有する患者。根治的治療を受けた皮膚の基底細胞癌、皮膚の扁平上皮癌、又は上皮内がん（例：子宮頸 部上皮内癌）の患者は組入れ可能である
2)免疫不全状態と診断された患者、又は治験薬初回投与前7日以内に長期全身性ステロイド療 法（プレドニゾロン換算で10 mg／日超）や他の免疫抑制療法による治療を受けた患者
3)過去2年以内に全身性の治療を要した 活動性の自己免疫疾患を有する患者
4)活動性の中枢神経系（CNS）への転移又は癌性髄膜炎を有する患者
5)骨髄異形成症候群（MDS）又は急性骨髄性白血病（AML）、又は MDS／AMLを疑う所見 を有する患者
6)肺臓炎を合併、若しくはステロイド投与が必要な（非感染性の）肺臓炎の既往を有する患者。
7)活動性の間質性肺疾患を現在有する、又は既往を有する患者
8)活動性の結核の既往を有する患者（結核菌、Bacillus tuberculosis）
9)全身性の治療を必要とする活動性の感染症を有する患者
10)HIV感染の既往を有する患者
11)B型肝炎（HBs抗原陽性）又は活動性の C型肝炎［HCV RNA（定性）陽性］を有する患者
12)治験薬初回投与前6ヵ月以内にクラスII～IVのうっ血性心不全又は心筋梗塞の既往を有する患者
13)Grade 2以上のニューロパチーを有する患者
14)前治療による毒性から回復（例：Grade 1以下又はベースラインまで）していない患者
15)ペムブロリズマブ、オラパリブ及びその成分、本治験の化学療法（カルボプラチン又はゲ ムシタビン）及びそれらの成分に対する過敏症又はアレルギーの既往を有する患者
16)治験薬又は治験薬の添加剤に対する重度（Grade 3以上）の過敏症を有する患者
17)治験の実施に影響を与える可能性があると判断された精神疾患又は薬物乱用障害を有する 患者
18)妊娠中又は授乳中、若しくはスクリーニング時から治験薬最終投与後180日間に妊娠を希望する女性 患者又はパートナーの妊娠を希望する男性患者
19)割付け／無作為化前24時間以内の尿妊娠検査の結果が陽性であった妊娠可能な女性。
20)オラパリブ又はその他の PARP 阻害薬の投与を過去に受けたことがある患者
21)治験薬初回投与前2週間以内に放射線療法を受けた患者
22)治験薬初回投与前2週間以内にコロニー刺激因子［例：顆粒球コロニー刺激因子（G-CSF）、 顆粒球マクロファージコロニー刺激因子（GM-CSF）又は遺伝子組換えエリスロポイエチ ン］の投与を受けた患者
23)同種組織／臓器の移植歴を有する患者
24)同種骨髄移植又はダブルユニット臍帯血移植（dUCBT）の既往がある患者
25)治験薬初回投与前2週間以内に大手術を受けた又は大手術による影響から回復していない患者
26)治験薬初回投与前30日以内に生ワクチンの接種を受けた患者
27)治験薬初回投与前7日以内に本治験で用いる化学療法の各添付文書に記載されている併用 禁止薬が投与された患者
28)抗 PD-1、抗 PD-L1、抗 PD-L2の薬剤又は他の共抑制性 T細胞受容体（CTLA-4、OX-40、 CD137等）を標的とした薬剤の治療歴を有する患者、又は（受けた治療にかかわらず）過去にペムブロリズマブを評価する臨床試験に参加したことのある患者
29)現在他の治験薬の治験に参加している、又は治験薬初回投与前4週間以内に他の治験薬の治 験に参加した若しくは治験用の医療機器を用いた患者
30)安静時心電図において、管理不能な潜在的な可逆性の心疾患と治験担当医師によって判断された患者
31)治験担当医師の判断により、治験結果に影響を与える、患者の治験の完遂を妨げる、又は、患者の治験の参加が患者の利益とならないと考えられるあらゆる疾患（例：血球減少症、輸血依存性貧血又は血小板減少症）、治療歴又は臨床検査値異常の既往又は合併を有する患者
32)経口投与が難しい又は吸収に影響を与える消化器疾患（例：胃切除術、部分的な腸閉塞症 又は吸収不良）を有する患者
33)治験担当医師の判断により、本治験の処置、制限及び要件を遵守できない可能性が高い患者

導入後療法期
34)治験薬及び／又は添加剤に対する重度の過敏症（Grade 3以上）を有する患者
35)導入療法期に毒性発現のためにカルボプラチン及びゲムシタビンの投与を中止した患者
36)導入療法期に毒性発現のためにペムブロリズマブの投与を中止した患者
37)導入療法期の化学療法＋ペムブロリズマブの併用投与が4コース未満の患者
38)現在、強力なチトクローム P450（CYP）3A4阻害剤を使用しており、治験期間中に投与を中止できない患者
39)現在、強力な又は中等度の CYP3A4誘導剤を使用しており、治験期間中に投与を中止できない患者

Induction Period:
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

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
39. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study

18歳以上

18age old over

上限なし

No limit

男性・女性

Both

実施中

progressing