A Multicenter Phase II Trial to Evaluate the Efficacy and Safety of Pembrolizumab and Gemcitabine in Patients With HER2-negative Advanced Breast Cancer (ABC) "PANGEA-Breast"
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 9
- 主要终点
- Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle
研究概览
简要总结
Study Design and Treatment:
This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically contraindicated). In hormone receptor positive patients, previous treatment with 2 or more lines of hormone therapy will also be required. Patients must have at least one measurable lesion that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on the results of the run-in-phase) will be included in this trial.
详细描述
Study Design and Treatment (continuation):
The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with an approximate 1:1 distribution between both groups.
A safety dose testing or "run-in-phase", with a 6+6 design, in which toxicity will be evaluated within the first cycle, will be performed since pembrolizumab in combination with gemcitabine has not been previously tested. Initially 6 patients will be included in the study at dose level 0 (gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle):
- If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be included at the current dose level. If there is a confirmation of this dose to be safe (≤ 3 patients experiencing DLT), this will be considered the RP2D and it will be used for the following recruited patients.
- If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12 patients included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a dose of 1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) will be performed. In this case, a group of 12 additional patients will be included at dose level -1, if ≥ 4 experience DLT, this combination will be considered too toxic and the study will be stopped. If ≤ 3 experience DLT with this combination, this will be considered the RP2D and it will be used for the following recruited patients.
Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be followed closely during the first cycle to observe the occurrence of any DLT. At the times these 3 patients are completing the first cycle, the next 3 patients will be included one by one, until the first cohort is completed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
- •Female ≥ 18 years of age on day of signing informed consent.
- •Histological/cytological confirmation of breast cancer with evidence of advanced disease, not amenable to resection or radiation therapy with curative intent.
- •Documented luminal A, luminal B (HER2-negative) or triple negative disease by immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on local testing on the most recent tumour biopsy defined as follows:
- •Luminal A: tumour with positive oestrogen receptor (ER) status (≥1% of tumour cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio < 2 or for single probe assessment a HER2 copy number < 4) and high progesterone receptor (PgR) (≥ 20% of tumour cells with PgR expression) and low Ki67 (< 14%).
- •Luminal B (HER2-negative): tumour with positive ER status (≥1% of tumour cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a HER2 copy number < 4) and either low or negative PgR (< 20% of tumour cells with PgR expression) and/or high Ki67 (≥ 14%).
- •Triple negative: tumour with negative hormone receptor status (<1% of tumour cells with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a HER2 copy number < 4).
- •Have at least one unidimensionally measurable lesion by RECIST 1.
- •Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of inclusion and at progression (whenever possible).
- •Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- •Demonstrate adequate organ function as follows (all screening labs should be performed within 7 days of study treatment initiation):
- •Bone marrow:
- •Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) Platelets ≥ 100,000/mm3 (100x109/l) Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- •Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) Alkaline Phosphatase ≤ 2.5 x ULN Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastases Albumin ≥ 2.5 g/dl
- •Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for patients with creatinine levels > 1.5 x ULN
- •Coagulation:
- •International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- •Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- •Prior treatment with anthracyclines and taxanes (unless clinically contraindicated) and two or more prior lines of hormone therapy in hormone receptor positive disease.
- •At least 3 months life expectancy.
- •Patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study drug/medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Patients of childbearing potential (see section 4.
- •for definition) must be willing to use an adequate method of contraception as outlined in Section 4.
- •Contraception, for the course of the study through 120 days after the last dose of study medication.
- •Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- •Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
排除标准
- •HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-CISH).
- •Patient is currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug/medication.
- •Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent.
- •Note: Patients with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- •Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Has received prior therapy with an anti-Programmed death-1 (PD), anti-PD-L1, or anti-PD-L2 agent.
- •Has received a live vaccine within 30 days of planned start of study therapy.
- •o Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
- •Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and all neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug/medication.
- •Has an 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 a current or prior malignancy within the previous 5 years (other than breast cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
- •Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- •Has an active infection requiring systemic therapy.
- •Has a known history of active Tuberculosis Bacillus (TB) or Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the baseline visit through 120 days after the last dose of trial treatment.
研究组 & 干预措施
Single arm
Eligible patients will be enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) as a IV infusion on day 1 and 8 of each 21-day cycle.
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.
干预措施: Pembrolizumab (Drug)
Single arm
Eligible patients will be enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) as a IV infusion on day 1 and 8 of each 21-day cycle.
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.
干预措施: Gemcitabine (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle
时间窗: Up to cycle 1
DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting \> 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.
Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab
时间窗: Up to cycle 1
The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.
Objective Response Rate (ORR)
时间窗: Through study treatment, and average of 3 months
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions.
次要结局
- Immune Related Clinical Benefit Rate (irCBR)(Through study treatment, and average of 3 months)
- Immune-related Objective Response Rate (irORR)(Through study treatment, and average of 3 months)
- Progression-Free Survival (PFS)(Through study treatment, and average of 3 months)
- Clinical Benefit Rate (CBR)(Through study treatment, and average of 3 months)
- Clinical Benefit Rate (CBR) at Least 24 Weeks(24 weeks)
- Response Duration (RD)(Through study treatment, and average of 3 months)
- Overall Survival (OS)(Up to 2 years)
- The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment(Through study treatment, and average of 3 months)
- Immune-related Progression-Free Survival (irPFS)(Through study treatment, and average of 3 months)
- Immune Related Clinical Benefit Rate (irCBR) at Least 24 Weeks(Through study treatment, and average of 3 months)
- Immune Related Response Duration (irRD)(Through study treatment, and average of 3 months)