A Phase Ib, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Ipatasertib in Combination With Atezolizumab and Paclitaxel or Nab-Paclitaxel in Patients With Locally Advanced or Metastatic Triple-Negative Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 139
- 试验地点
- 18
- 主要终点
- Cohort 1 and Cohort 4: Percentage of Participants With Objective Response (OR) as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version (v) 1.1
研究概览
简要总结
This is a study consisting of four cohorts in this setting. In Cohort 1, the safety and efficacy of ipatasertib (ipat) in combination with atezolizumab (atezo) and paclitaxel (pac) or nab-paclitaxel will be evaluated for participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not previously received chemotherapy. In Cohort 2, ipatasertib and atezolizumab (with no chemotherapy), will be administered to participants with locally advanced or metastatic TNBC. In Cohort 3, the safety and efficacy of neoadjuvant ipatasertib, atezolizumab, doxorubicin and cyclophosphamide (AC) (Ipat + Atezo + AC) followed by Ipat + Atezo + Pac will be evaluated in participants with locally advanced Type 2-4 (T2-4) TNBC. In Cohort 4, the safety and efficacy of Ipat + Atezo + Pac will be evaluated in participants with PD-L1 (Programmed Death-Ligand-1) positive locally advanced or metastatic TNBC that is not amenable to resection and who have not previously received chemotherapy in the advanced setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eastern Cooperative Oncology Group Performance Status of 0 or
- •Adequate hematologic and organ function.
- •For Cohorts 1, 2 and 4: Life expectancy of at least 6 months.
- •For men and women of child bearing potential: agreement to remain abstinent or use protocol defined contraceptive measures during the treatment period and for at least 28 days after the last dose of ipatasertib, 6 months after the last dose of paclitaxel, nab-paclitaxel, or doxorubicin, and 12 months after the last dose of cyclophosphamide, and 5 months after the last dose of atezolizumab, whichever occurs later along with refraining from donating sperm or eggs during this same period.
- •Disease-specific:
- •For Cohorts 1, 2 and 4: histologically documented TNBC that is locally advanced or metastatic and is not amenable to resection with curative intent.
- •For Cohort 2: disease progression following one or two lines of systemic therapy for inoperable locally advanced or metastatic TNBC.
- •For Cohorts 1, 2 and 4: measurable disease according to RECIST v1.1 criteria.
- •For Cohort 2: Treated brain or spinal cord metastases are allowed if participants have stable disease and are not on steroid treatment.
- •For Cohort 3: histologically documented TNBC with a primary breast tumour size of > 2 cm by at least one radiographic or clinical measurement and disease stage at presentation of cT2-4 cN0-3 cM
- •For Cohort 3: participant agreement to undergo appropriate surgical management, including axillary lymph node surgery and partial or total mastectomy, after completion of neoadjuvant treatment.
- •For Cohort 4: participants must have centrally confirmed PD-L1-positive tumour.
排除标准
- •History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills.
- •Active infection requiring antibiotics.
- •History of or current evidence of HIV infection.
- •Known clinically significant history of liver disease.
- •Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure (other than anticipated breast surgery for Cohort 3) during the course of the study.
- •Pregnant or breastfeeding.
- •New York Heart Association (NYHA) Class II, III, or IV heart failure; left ventricular ejection fraction < 50%; or active ventricular arrhythmia requiring medication.
- •Treatment with approved or investigational cancer therapy within 14 days prior to Day 1 of Cycle
- •Prior treatment with an Akt inhibitor.
- •Disease-specific:
- •For Cohorts 1 and 4: history of or known presence of brain or spinal cord metastases.
- •For Cohorts 1 and 4: participants who have received previous systemic therapy for inoperable locally advanced or metastatic TNBC, including chemotherapy, immune checkpoint inhibitors, or targeted agents.
- •Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy.
- •Participants who have received palliative radiation treatment to peripheral sites (e.g., bone metastases) for pain control and whose last treatment was completed 14 days prior to Day 1 of Cycle 1 and have recovered from all acute, reversible effects.
- •Uncontrolled pleural effusion, pericardial effusion, or ascites.
- •Uncontrolled tumor related complications.
- •Uncontrolled hypercalcaemia or symptomatic hypercalcaemia requiring continued use of bisphosphonate therapy.
- •Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle
- •For Cohort 3, participants with the following are excluded: [1] prior history of invasive breast cancer; [2] prior systemic therapy for treatment and/or prevention of invasive breast cancer; [3] previous therapy with anthracyclines or taxanes for any malignancy; [4] bilateral breast cancer; [5] undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes; [6] undergone axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy; [6] history of other malignancy within 5 years prior to screening; [7] history of cerebrovascular accident within 12 months prior to initiation of study treatment; [8] cardiopulmonary dysfunction; [9] known allergy or hypersensitivity to the components of cyclophosphamide/doxorubicin formulations and filgrastim or pegfilgrastim formulations; [10] severe infection within 4 weeks prior to initiation of study treatment; [11] treatment with therapeutic oral or IV (Intravenous) antibiotics within 2 weeks prior to initiation of study treatment and [12] prior treatment with CD137 agonists or immune checkpoint - blockade therapies.
- •Ipatasertib-specific:
- •History of Type I or Type II diabetes mellitus requiring insulin.
- •Grade >= 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.
- •History of or active inflammatory bowel disease or active bowel inflammation.
- •Clinically significant lung disease.
- •Treatment with strong CYP3A inhibitors or strong CYP3A inducers.
- •Atezolizumab-specific:
- •Active or history of autoimmune disease or immune deficiency.
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
- •Prior allogeneic stem cell or solid organ transplantation.
- •Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment with atezolizumab or within 5 months after the last dose of atezolizumab.
- •History of hypersensitivity reactions to study drug or any component of the study drug formulation.
- •Treatment with systemic immunostimulatory agents and immunosuppressive medication treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study.
- •Paclitaxel-specific:
- •Grade >= 2 peripheral neuropathy.
研究组 & 干预措施
Arm A1: Ipat + Atezo + Pacl
Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm A1: Ipat + Atezo + Pacl
Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm A1: Ipat + Atezo + Pacl
Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm A2: Ipat + Atezo + Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm A2: Ipat + Atezo + Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm A2: Ipat + Atezo + Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm A3: Ipat + Atezo + Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm A3: Ipat + Atezo + Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm A3: Ipat + Atezo + Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm B1: Ipat + Atezo + Nab-Pacl
Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm B1: Ipat + Atezo + Nab-Pacl
Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm B1: Ipat + Atezo + Nab-Pacl
Safety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Nab-Paclitaxel (Drug)
Arm B2: Ipat + Atezo + Nab-Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm B2: Ipat + Atezo + Nab-Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm B2: Ipat + Atezo + Nab-Pacl
Expansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Nab-Paclitaxel (Drug)
Arm C1: (Ipat + Pacl) (2 weeks) + Atezo
Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm C1: (Ipat + Pacl) (2 weeks) + Atezo
Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm C1: (Ipat + Pacl) (2 weeks) + Atezo
Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm C2 (Ipat + Pacl) (2 weeks) + Atezo
Expansion (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm C2 (Ipat + Pacl) (2 weeks) + Atezo
Expansion (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm C2 (Ipat + Pacl) (2 weeks) + Atezo
Expansion (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm D1: (Atezo + Pacl) (2 weeks) + Ipat
Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm D1: (Atezo + Pacl) (2 weeks) + Ipat
Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm D1: (Atezo + Pacl) (2 weeks) + Ipat
Safety Run-In (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm D2: (Atezo + Pacl) (2 weeks) + Ipat
Expansion (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm D2: (Atezo + Pacl) (2 weeks) + Ipat
Expansion (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm F1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Ipatasertib (Drug)
Arm D2: (Atezo + Pacl) (2 weeks) + Ipat
Expansion (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm E: Ipat + Atezo
Participants (Cohort 2) will receive Ipatasertib orally daily on Days 1-28 of Cycle 1 (35-day cycle) and on Days 1-21 of subsequent cycles (28-day cycles). Atezolizumab will be administered by IV infusion on Days 8 and 22 of Cycle 1 and on Days 1 and 15 of subsequent cycles. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm E: Ipat + Atezo
Participants (Cohort 2) will receive Ipatasertib orally daily on Days 1-28 of Cycle 1 (35-day cycle) and on Days 1-21 of subsequent cycles (28-day cycles). Atezolizumab will be administered by IV infusion on Days 8 and 22 of Cycle 1 and on Days 1 and 15 of subsequent cycles. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
Arm F1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Paclitaxel (Drug)
Arm F1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Atezolizumab (Drug)
Arm F1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: AC (Drug)
Arm F2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Ipatasertib (Drug)
Arm F2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Paclitaxel (Drug)
Arm F2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Atezolizumab (Drug)
Arm F2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: AC (Drug)
Arm G1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Ipatasertib (Drug)
Arm G1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Paclitaxel (Drug)
Arm G1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Atezolizumab (Drug)
Arm G1: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Safety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: AC (Drug)
Arm G2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Ipatasertib (Drug)
Arm G2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Paclitaxel (Drug)
Arm G2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: Atezolizumab (Drug)
Arm G2: Ipat + Atezol + AC / Ipat + Atezo + Pacl
Expansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
干预措施: AC (Drug)
Arm H: Ipat + Atezo + Pacl
Participants (Cohort 4) will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Ipatasertib (Drug)
Arm H: Ipat + Atezo + Pacl
Participants (Cohort 4) will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Paclitaxel (Drug)
Arm H: Ipat + Atezo + Pacl
Participants (Cohort 4) will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Cohort 1 and Cohort 4: Percentage of Participants With Objective Response (OR) as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version (v) 1.1
时间窗: From screening up to approximately 43.6 months
Objective Response Rate: percentage participants with confirmed complete response (CR) or partial response (PR) on 2 consecutive occasions \>or= 4 weeks apart, as determined by investigator according to RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Percentages have been rounded off. No participants were enrolled in cohort 4, hence no data reported.
Cohort 3: Pathological Complete Response (pCR) Rate
时间窗: 2-6 weeks following last dose of study treatment (up to 69 weeks)
pCR rate was defined as the percentage of participants who had no residual invasive disease in the breast and no residual disease in the lymph nodes (ypT0/Tis ypN0 in the current American Joint Committee on Cancer (AJCC )staging system) based on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant therapy.
Cohort 1, Cohort 2, Cohort 3 and Cohort 4: Number of Participants With Adverse Events (AEs)
时间窗: Up until 90 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to 4 years 1 month)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any new disease or worsening of an existing disease are also considered as AEs. AEs were reported based on the National Cancer Institute Common Terminology Criteria for AEs, version 4.0 (NCI-CTCAE, v4.0). No participants were enrolled in cohort 3 Arm G and 4, and hence no data was reported.
次要结局
- Cohort 1 and Cohort 4: Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1(From the date of first documented confirmed response (CR or PR) to disease progression or death due to any cause (up to approximately 43.6 months))
- Cohort 1 and Cohort 4: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1(From enrollment up to disease progression or death due to any cause whichever occurs first (up to approximately 43.6 months))
- Cohort 1 and Cohort 4: Overall Survival (OS)(From enrollment up to death due to any cause (up to approximately 43.6 months).)
- Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib(Day 15 Cycle 1: pre-dose and 1, 2, 4 and 6 hours post-dose, Day 15 Cycle2: predose and 1, 2, 4 and 6 hours post-dose and Day 15 Cycle 3 - post dose up to - 3 hours (each cycle is of 28 days))
- Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib Metabolite M1 (G-037720)(Day 15 Cycle 1 - pre-dose and 1 hour, 2 hours, 4 hours and 6 hours post-dose, Day 15 Cycle2: predose and 1 hour, 2 hours, 4 hours and 6 hours post-dose and Day 15 Cycle 3 - post dose up to - 3 hours (each cycle is of 28 days))
- Cohort 1 and Cohort 4: Number of Participants With Anti-Drug Antibodies (ADAs) for Atezolizumab During Study Treatment(From baseline up to 30 days from the last dose of atezolizumab (to approximately 4 years 1.1 month))
- Cohort 1 and Cohort 4: Plasma Concentration of Atezolizumab(Cycle 1 Day 1 and 15: predose and 30 mins post dose; Cycle 2: Day 1 and 15 predose, Cycle 3, 4, 8, 12, and 16 Day 1: predose; treatment discontinuation visit)
- Cohort 1 and Cohort 4: Clinical Benefit Rate (CBR) as Assessed by Investigator Based on RECIST v1.1(From screening up to confirmed SD or CR or PR (up to approximately 43.6 months))