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試驗計畫名稱
針對晚期HER2 陽性乳癌或胃/胃食道交接處腺癌患者，研究抗HER2之雙特異性抗體ZW25併用化學治療及有/無併用Tislelizumab下的安全性、耐受性、藥物動力學及初期抗腫瘤活性之第 1b/2 期試驗
| 試驗申請者： |
保瑞爾生技股份有限公司 |
| 試驗委託/贊助單位名稱： |
BeiGene, Ltd. |
| 試驗計畫書編號： |
BGB-A317-ZW25-101 |
| 核准執行文號： |
1086816192 |
| 登錄日期： |
2020-01-13 |
| 試驗預計執行期間： |
2020-01-01 至 2025-12-31 |
試驗目的
-To assess the safety and tolerability of ZW25 in combination with docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and ZW25 in combination with tislelizumab and chemotherapy in patients with HER2-positive gastric/gastroesophageal Junction (GEJ) adenocarcinoma
-To evaluate the preliminary antitumor activity of ZW25 in combination with docetaxel in
patients with HER2-positive breast cancer, and ZW25 in combination with tislelizumab and
chemotherap
試驗階段分級
Phase Ⅰ,Phase Ⅱ
藥品名稱
ZW25; Tislelizumab (BGB-A317)
主成分,劑型,劑量
Fulvestrant
GDC-0077
Palbociclib,錠劑
肌肉注射劑
膠囊,3毫克、9毫克
250mg/5ml
75mg; 100mg; 125mg
宣稱適應症
Breast Cancer or Gastric/Gastroesophageal Junction Adenocarcinoma
試驗醫院 / 受試者 召募狀態
| 試驗醫院 |
受試者召募狀態 |
| 國立成功大學醫學院附設醫院 |
N/A |
N/A |
評估指標(endpoint)
主要：
-不良事件 (Adverse event，AE) 及嚴重不良事件(serious adverse event，SAE)，視需要以類型、頻率、嚴重度(依美國國家癌症研究所常見不良事件評價標準[National Cancer Institute-Common Terminology Criteria for Adverse Events，NCI-CTCAE] 第5.0 版分級)、發生時間點、嚴重性及與試驗治療之關係、因毒性而停用試驗藥品，以及相較於基準期的實驗室檢驗、心電圖(electrocardiogram，ECG)、心臟超音波圖或多頻道心室功能攝影掃描(multiple gated acquisition scan，MUGA) 及生命徵象之變化描述特性
-試驗主持人依據實體腫瘤療效反應評估標準(Response Evaluation Criteria in Solid Tumors, RECIST) 第1.1 版評估的客觀療效反應率
次要：
-試驗主持人依據RECIST 第1.1 版評估的療效反應持續時間
-試驗主持人依據RECIST 第1.1 版評估的反應出現前所經時間
-試驗主持人依據RECIST 第1.1 版評估的無惡化存活期
-試驗主持人依據RECIST 第1.1 版評估的疾病控制率
-整體存活期
-ZW25 的PK 和免疫原性：
1.ZW25 的血清濃度，做為時間的函數
2.針對單一 (第一) 劑量和多重劑量的PK 參數(若資料允許)
3.抗 ZW25 抗體及中和抗體的頻率、持續時間及首次出現時間
探索性：
-腫瘤組織及周邊血液中的療效、抗藥性或疾病惡化的潛在生物標記，包括但不限於HER2 狀態、程序性死亡配體1 (programmed death ligand 1，PD-L1) 表現、出現腫瘤浸潤性淋巴球(tumor-infiltrating lymphocyte，TIL)、循環中核酸(circulating nucleic acid，CNA)、基因表現圖譜及/或腫瘤突變負荷
-Tislelizumab 及抗Tislelizumab 抗體的血清濃度(如適用)。
主要納入/排除條件
Inclusion Criteria:
1. Able to provide written informed consent and can understand and agree to comply with
the requirements of the study and the schedule of assessments
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of
consent in the jurisdiction in which the study is taking place)
3. Able to provide blood and tumor tissue (for archival tumor tissue: formalin-fixed
paraffin-embedded [FFPE] blocks or at least 12 unstained FFPE tumor specimen slides
for retrospective confirmation of HER2 status and/or other biomarker analysis). Note:
Patients may be permitted to be enrolled on a case-by-case basis after discussion with the
sponsor’s medical monitor if fewer than 12 unstained slides are provided.
a. Patients who have no archival tumor tissue available must consent to provide fresh
biopsy samples before receiving treatment, unless previously discussed with
sponsor’s medical monitor.
4. Disease diagnosis and prior treatment:
a. Cohort 1 (the first-line breast cancer treatment cohort):
-Female patients with histologically or cytologically confirmed unresectable,
locally advanced, recurrent or metastatic adenocarcinoma of the breast and
candidate for chemotherapy. Locally recurrent disease must not be amenable to
resection with curative intent.
-HER2 IHC 3+ or in situ hybridization positive on the archival tumor tissue or
fresh biopsy sample. The most recently collected tissues are required if
applicable. For patients who had anti-HER2 therapy in neoadjuvant or adjuvant
setting, tumor tissue sample collected after completion of any prior anti-HER2
therapy is preferred. HER2 status determined (see details in Appendix 11) in the
investigational site is acceptable. If HER2 status cannot be acquired in the
investigational site, HER2 positivity must be confirmed in the sponsor designated
central laboratory as study entry eligibility.
-Have not received previous systemic anticancer therapy for locally advanced
unresectable or metastatic disease (with the exception of one prior hormonal
regimen for metastatic breast cancer which must be stopped with at least 14 days
of washout period), including any approved or investigational EGFR or anti-HER2
agents or vaccines, cytotoxic chemotherapy, antibody drug conjugate, checkpoint
inhibitors, or more than one prior hormonal regimen for metastatic breast cancer.
If a patient receives hormonal therapy for metastatic breast cancer and is switched
to a different hormonal therapy due to disease progression, this will be counted as
two “regimens” and the patient is not eligible.
Note: Prior systemic treatment in neoadjuvant or adjuvant setting is permitted if
the disease-free interval from completion of the systemic treatment (excluding
hormonal therapy) to diagnosis of locally advanced recurrent or metastatic disease
is ≥ 12 months. Prior trastuzumab with or without pertuzumab used in
neoadjuvant or adjuvant setting is permitted.
b. Cohort 2 (the first-line gastric/gastroesophageal junction adenocarcinoma
treatment cohort):
-Histologically or cytologically confirmed unresectable, locally advanced,
recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal
junction
-HER2 IHC 3+ or HER2 IHC 2+ together with in situ hybridization positive on the
archival tumor tissue or fresh biopsy sample. The most recently collected tissues
are required if applicable. HER2 status determined (see details in Appendix 11) in
the investigational site is acceptable. If HER2 status cannot be acquired in the
investigational site, HER2 positivity must be confirmed in the sponsor designated
central laboratory as study entry eligibility.
-Have not received previous systemic anticancer therapy for locally advanced
unresectable or metastatic disease, including any approved or investigational
EGFR or anti-HER2 agents or vaccines, cytotoxic chemotherapy or checkpoint
inhibitors
Note: Prior systemic treatment in neoadjuvant or adjuvant setting will be
permitted if the disease-free interval from completion of the systemic treatment to
diagnosis of locally advanced recurrent or metastatic disease is longer than 6
months. Prior use of trastuzumab and/or pertuzumab is not allowed.
5. At least 1 measurable lesion as defined per RECIST Version 1.1
Note: The target lesion(s) selected have not been previously treated with local therapy.
OR The target lesion(s) selected that are within the field of prior local therapy have
subsequently progressed as defined by RECIST Version 1.1.
6. ECOG Performance Status ≤ 1
7. Adequate organ function as indicated by the following laboratory values during
screening:
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days
before sample collection at screening for the following:
i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
ii. Platelets ≥ 90 x 109/L
iii. Hemoglobin ≥ 90 g/L or ≥ 5.6 mmol/L
b. Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or estimated Glomerular
Filtration Rate ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology
Collaboration Equation (Appendix 7)
c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 4 x ULN for patients
with documented Gilbert’s syndrome)
d. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN
e. Activated partial thromboplastin time ≤ 1.5 x ULN
f. AST and ALT ≤ 2.5 x ULN, or AST and ALT ≤ 5 x ULN for patients with liver
metastases
8. LVEF ≥ 50% at baseline as determined by either echocardiogram or MUGA
(echocardiogram is the preferred method) within 28 days before the first dose of study
drug
9. Females of childbearing potential must have a negative urine or serum pregnancy test
within 7 days of the first dose of study drug and must be willing to use a highly effective
method of birth control for the duration of the study, and ≥ 7 months after the last dose of
study drug(s). For Cohort 1 specifically, hormonal forms of contraception (oral,
injectable, or implantable) are not allowed. See Appendix 5.
10. Non-sterile males in Cohort 2 must be willing to use a highly effective method of birth
control for the duration of the study, and for ≥ 7 months after the last dose of study
drug(s).
Exclusion Criteria:
1. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
2. History of approved or investigative tyrosine kinase/HER inhibitors in any treatment
setting
a. except trastuzumab with or without pertuzumab used in neoadjuvant or adjuvant
setting for Cohort 1
3. Active leptomeningeal disease or uncontrolled brain metastasis. Patients with equivocal findings or with confirmed brain metastases are eligible for enrollment provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment for ≥ 4 weeks before the first dose of study drug
4. Any active malignancy ≤ 2 years before the first dose of study drug, except for the
specific cancer under investigation in this trial and any localized cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast)
5. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study drug
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal
systemic absorption
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen)
6. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc.
7. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy.
8. A known history of HIV infection
9. Currently active infection with hepatitis B virus or hepatitis C virus
10. Any major surgical procedure ≤ 28 days before the first dose of study drug, except if the procedure is minimally invasive (for example, introduction of peripherally inserted central catheter)
11. Any of the following cardiovascular risk factors:
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of
daily living, ≤ 28 days before the first dose of study drug
b. Symptomatic pulmonary embolism ≤ 28 days before the first dose of study drug
c. Any history of acute myocardial infarction ≤ 6 months before the first dose of study
drug
d. Any history of congestive heart failure meeting any New York Heart Association
(NYHA) Classification II-IV (Appendix 6) ≤ 6 months before the first dose of study
drug
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study drug
f. Any history of cerebrovascular accident ≤ 6 months before the first dose of study
drug
g. Inadequately controlled hypertension (ie, systolic blood pressure > 180 mmHg or
diastolic blood pressure > 100 mmHg)
h. Any history of LVEF decline to below 50% during or after previous trastuzumab/pertuzumab neoadjuvant or adjuvant therapy
i. Has a QTc prolongation to > 450 millisecond (ms) in males and > 470 ms in females
based on 12-lead ECG in triplicate.
12. A history of severe hypersensitivity reactions to other monoclonal antibodies
13. Has received any radiotherapy, hormonal therapy, immunotherapy (eg, interleukin,
interferon, thymosin) or any investigational therapies within 28 days or 5 half-lives
(whichever is shorter) of the first study drug administration. Exceptions may be considered for palliative radiotherapy to a limited field following consultation with the sponsor medical monitor.
14. Has received any herbal medicine or patent medicines used to control cancer within
14 days of the first study drug administration
15. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or stabilized. The following are exceptions: neuropathy (which must have resolved to ≤ Grade 2); congestive heart failure (which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely); and specific laboratory abnormalities which are not considered a likely safety risk
16. Underlying medical conditions or alcohol or drug abuse or dependence that, in the
investigator’s opinion, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs; or insufficient compliance during the study according to investigator’s judgement
17. Concurrent participation in another therapeutic clinical trial, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
18. History of exposure to the following cumulative doses of anthracyclines in
adjuvant/neoadjuvant setting (for Cohort 1 only), meeting any one of the following
criteria:
a. doxorubicin or liposomal doxorubicin > 360 mg/m2
b. epirubicin > 720 mg/m2
c. mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2
d. Other anthracycline > the equivalent of 360 mg/m2 of doxorubicin
e. If more than 1 anthracycline has been used, then the cumulative dose must not exceed
the equivalent of 360 mg/m2 of doxorubicin.
19. Prior allogeneic stem cell transplantation or organ transplantation (for Cohort 2 only)
20. Active autoimmune diseases or history of autoimmune diseases that may relapse (for
Cohort 2 only).
Note: Patients with the following diseases are not excluded and may proceed to further
screening:
a. Controlled Type I diabetes
b. Hypothyroidism (provided it is managed with hormone replacement therapy only)
c. Controlled celiac disease
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia)
e. Any other disease that is not expected to recur in the absence of external triggering factors
21. Was administered a live vaccine ≤ 4 weeks before the first dose of study drug (for
Cohort 2 only)
試驗計畫聯絡資訊
林佩儀 (02)7725-6669
試驗計畫受試者收納人數
本計畫預計收納受試者人數：台灣人數20 人，全球人數50 人
本計畫資料最近更新日期：2020-02-13
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