計劃書編號CP-MGAH22-06
試驗已結束
2019-10-15 - 2024-05-28
Phase II/III
終止收納1
一項在未曾接受治療的轉移性或局部晚期 HER2 陽性胃或胃食道交接處癌症患者中，評估 Margetuximab 併用 INCMGA00012 加化學治療或 併用MGD013 加化學治療的第 2/3 期試驗
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試驗申請者
保瑞爾生技股份有限公司
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試驗委託 / 贊助單位名稱
MacroGenics, Inc.
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臨床試驗規模
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更新日期
2026/02/01
試驗主持人及試驗醫院
適應症
轉移性或局部晚期 HER2 陽性胃或胃食道交接處癌症
試驗目的
Primary objective
Cohort A:
• To evaluate the safety and tolerability of margetuximab + INCMGA00012 in patients with untreated locally advanced or metastatic GC or gastroesophageal junction (GEJ) cancer that is HER2 IHC 3+ and PD-L1+ by IHC staining.
• To evaluate the ORR of margetuximab plus INCMGA00012 for non-MSI-H patients in the response evaluable population (REP) using Investigatorassessed radiology reviews.
Cohort B, Part 1:
• To select the best margetuximab, chemotherapy and CPI-containing combination regimen for further evaluation in Part 2, based on evaluation of safety and ORR in the primary response evaluable population (PREP) of patients with GC or GEJ cancer, irrespective of PD-L1 status.
Secondary objective
Cohort A:
• To determine duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) using Investigator-assessed radiology
review, for non-MSI-H patients.
• To evaluate the number of patients with ADA to margetuximab or INCMGA00012, or both.
Cohort B, Part 1:
• To evaluate ORR and DCR of each treatment arm.
• To evaluate the number of patients with ADA to margetuximab, MGD013, or INCMGA00012.
藥品名稱
輸注液
輸注液
輸注液
輸注液
輸注液
主成份
Margetuximab (MGAH22)
MGA012 (INCMGA00012)
MGD013
MGA012 (INCMGA00012)
MGD013
劑型
27C
27C
27C
27C
27C
劑量
MG/ML
評估指標
A 群組的主要療效評估指標及分析
A 群組的主要療效評估指標是依 RECIST v1.1 判定的 ORR，其定義為反應可評估族群中，依照 RECIST v1.1 達到 CR 或 PR 之最佳整體反應 (best overall response，BOR) 的非 MSI-H 患者比例 (稱為反應者)。將計算 ORR 的雙尾 95% 精確二項信賴區間 (confidence interval，CI)。
在 RECIST v1.1 方面，BOR 將區分為 CR、PR、穩定疾病 (stable disease，SD)、PD 或無法評估 (not evaluable，NE)。若要符合 BOR 的資格，CR 和 PR 必須在首次觀察到反應的至少 4 週後進行確認。SD 必須在 6 週後至少觀察到一次。BOR 將從試驗治療的起點開始評估。
ORR 的分析將以試驗主持人審查判定的反應資料為依據。
B 群組第 1 部分的療效評估指標及分析
B 群組第 1 部分的療效評估指標為依照反應可評估族群的 ORR 和 DCR。分析方法與A 群組的分析方法相同。
A 群組的主要療效評估指標是依 RECIST v1.1 判定的 ORR，其定義為反應可評估族群中，依照 RECIST v1.1 達到 CR 或 PR 之最佳整體反應 (best overall response，BOR) 的非 MSI-H 患者比例 (稱為反應者)。將計算 ORR 的雙尾 95% 精確二項信賴區間 (confidence interval，CI)。
在 RECIST v1.1 方面，BOR 將區分為 CR、PR、穩定疾病 (stable disease，SD)、PD 或無法評估 (not evaluable，NE)。若要符合 BOR 的資格，CR 和 PR 必須在首次觀察到反應的至少 4 週後進行確認。SD 必須在 6 週後至少觀察到一次。BOR 將從試驗治療的起點開始評估。
ORR 的分析將以試驗主持人審查判定的反應資料為依據。
B 群組第 1 部分的療效評估指標及分析
B 群組第 1 部分的療效評估指標為依照反應可評估族群的 ORR 和 DCR。分析方法與A 群組的分析方法相同。
主要納入條件
Key Inclusion Criteria:
1. Patient must provide signed informed consent prior to initiation of any study-related tests or procedures that are not part of standard of care.
2. Age ≥ 18 years old. (In Taiwan, only subjects with at least 20 years old will be enrolled.)
3. Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma. GEJ cancer is defined as any tumor that invades the GEJ.
a. Prior systemic perioperative treatment is allowed. The patient must have a disease-free interval of at least 6 months from complete surgical resection or initiation of adjuvant chemotherapy , whichever is later.
b. Patients receiving perioperative anti-HER2 therapy require repeat testing of HER2 status for eligibility.
c. Cohort A: HER2+ (by IHC 3+) and PD L1–positive (by IHC with 22C3 CPS ≥ 1%), per central review.
d. Cohort B: HER2+ (by IHC 3+ or IHC 2+ in combination with FISH+) by local review. HER2 local test must be conducted at a CAP or equivalent accreditation organization using HercepTestTM and HER2 FISH pharmaDxTM assays. PD-L1 status is not required for enrollment.
4. Patients enrolled on the study will be required to have an identified formalin-fixed, paraffin-embedded (FFPE) tumor specimen for HER2, PD-L1, LAG-3 and MSI testing. The specimen may be a formalin-fixed paraffin-embedded (FFPE) tumor specimen block, or a minimum of 10 unstained slides, with adequate tumor cells for analysis, or contemporaneous biopsy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, verified within 3 days of Day 1.
6. Life expectancy ≥ 6 months.
7. Has adequate organ function as determined by the site Investigator.
8. At least one radiographically measurable lesion (target lesion) as defined in RECIST v1.1 and documented by computed tomography (CT) or magnetic resonance imaging (MRI).
9. Acceptable laboratory parameters as follows:
a. Platelet count ≥ 100 × 103/μL without transfusion within 28 days prior to the initiation of study treatment.
b. Absolute neutrophil count ≥ 1.5 × 103/μL in the absence of any growth factor support within 28 days prior to the initiation of study treatment.
c. ALT/AST ≤ 3.0 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN.
d. Total bilirubin ≤ 1.5 × ULN, except patients with Gilbert’s syndrome, who may enroll if the conjugated bilirubin is within normal limits.
e. Creatinine < 2 mg/dL, or a calculated or measured creatinine clearance > 50 mL/min.
10. Women patients of child-bearing potential (WOCBP), defined as not surgically sterilized (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) and between menarche and 1-year post menopause, must have a negative serum pregnancy test performed within 72 hours prior to the initiation of study drug administration. Female patients must agree to abstain from egg donation during the course of the study.
11. WOCBP and male patients with partners of WOCBP must agree to use highly effective methods of contraception from the time of consent through 7 months after discontinuation of study drug administration. Male patients must agree to abstain from sperm donation during the course of the study.
12. WOCBP is not pregnant or breastfeeding or male patient is not expecting to father children within the projected duration of the study, starting with screening visit through 7 months after the last dose of study drug.
1. Patient must provide signed informed consent prior to initiation of any study-related tests or procedures that are not part of standard of care.
2. Age ≥ 18 years old. (In Taiwan, only subjects with at least 20 years old will be enrolled.)
3. Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma. GEJ cancer is defined as any tumor that invades the GEJ.
a. Prior systemic perioperative treatment is allowed. The patient must have a disease-free interval of at least 6 months from complete surgical resection or initiation of adjuvant chemotherapy , whichever is later.
b. Patients receiving perioperative anti-HER2 therapy require repeat testing of HER2 status for eligibility.
c. Cohort A: HER2+ (by IHC 3+) and PD L1–positive (by IHC with 22C3 CPS ≥ 1%), per central review.
d. Cohort B: HER2+ (by IHC 3+ or IHC 2+ in combination with FISH+) by local review. HER2 local test must be conducted at a CAP or equivalent accreditation organization using HercepTestTM and HER2 FISH pharmaDxTM assays. PD-L1 status is not required for enrollment.
4. Patients enrolled on the study will be required to have an identified formalin-fixed, paraffin-embedded (FFPE) tumor specimen for HER2, PD-L1, LAG-3 and MSI testing. The specimen may be a formalin-fixed paraffin-embedded (FFPE) tumor specimen block, or a minimum of 10 unstained slides, with adequate tumor cells for analysis, or contemporaneous biopsy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, verified within 3 days of Day 1.
6. Life expectancy ≥ 6 months.
7. Has adequate organ function as determined by the site Investigator.
8. At least one radiographically measurable lesion (target lesion) as defined in RECIST v1.1 and documented by computed tomography (CT) or magnetic resonance imaging (MRI).
9. Acceptable laboratory parameters as follows:
a. Platelet count ≥ 100 × 103/μL without transfusion within 28 days prior to the initiation of study treatment.
b. Absolute neutrophil count ≥ 1.5 × 103/μL in the absence of any growth factor support within 28 days prior to the initiation of study treatment.
c. ALT/AST ≤ 3.0 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN.
d. Total bilirubin ≤ 1.5 × ULN, except patients with Gilbert’s syndrome, who may enroll if the conjugated bilirubin is within normal limits.
e. Creatinine < 2 mg/dL, or a calculated or measured creatinine clearance > 50 mL/min.
10. Women patients of child-bearing potential (WOCBP), defined as not surgically sterilized (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) and between menarche and 1-year post menopause, must have a negative serum pregnancy test performed within 72 hours prior to the initiation of study drug administration. Female patients must agree to abstain from egg donation during the course of the study.
11. WOCBP and male patients with partners of WOCBP must agree to use highly effective methods of contraception from the time of consent through 7 months after discontinuation of study drug administration. Male patients must agree to abstain from sperm donation during the course of the study.
12. WOCBP is not pregnant or breastfeeding or male patient is not expecting to father children within the projected duration of the study, starting with screening visit through 7 months after the last dose of study drug.
主要排除條件
Exclusion Criteria:
1. Has a known additional malignancy that is progressing or has required treatment within the past 5 years. Patients who have been successfully treated for, and are disease free, non-melanomatous skin cancer, localized prostate cancer (Gleason Score < 6), or carcinoma in situ are eligible for participation in the study.
2. Patients with known MSI-H status.
3. Has poorly controlled diarrhea, despite optimal medical intervention.
4. Clinically significant accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs.
5. 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, in the opinion of the treating Investigator.
a. Known chronic hepatitis B virus (HBV) infection (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/ml).
• The patient with resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) is eligible.
b. Co-infection with hepatitis B (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/ml) and C (as evidenced by detectable hepatitis C virus [HCV] RNA); OR, hepatitis D infection in patients with hepatitis B.
• The patient with a history resolved hepatitis B and detectable HCV antibody is eligible.
c. Has a known history of human immunodeficiency virus 1 or 2 antibodies or has a diagnosis of immune-deficiency.
d. Has had an allogeneic stem cell or tissue/solid organ transplant.
e. Patients with central nervous system metastases.
f. Patients with a history of psoriatic arthritis.
g. Patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic treatment within the past 2 years and patients with a history of autoimmune disease who are now clinically stable with replacement therapy and by laboratory testing.
h. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study treatment. Patients requiring any systemic antiviral, antifungal, or antibacterial therapy for active infection must have completed treatment no less than 1 week prior to the initiation of study treatment.
i. Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient contained in the trastuzumab, margetuximab, INCMGA00012, or MGD013 drug formulation or contraindications to the specified chemotherapy regimens.
j. Any serious underlying medical or psychiatric condition (eg., known complete DPD deficiency) that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site.
k. History of uncontrolled seizures within 6 months registration.
l. Active or history of alcohol or other substance abuse within 1 year prior to registration.
6. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study treatment. Inactivated annual influenza vaccination is allowed.
7. Has received an investigational agent within 4 weeks prior to the initiation of study treatment. Prior neoadjuvant or adjuvant treatment with immunotherapy is excluded.
8. Major surgical procedure, including gastrectomy, or trauma within the 4 weeks prior to the initiation of study treatment.
9. Treatment with systemic corticosteroids (≥ 10 mg per day prednisone or equivalent) or other immune suppdrugs within the 14 days prior to the initiation of study treatment.
10. Clinically significant cardiovascular disease including but not limited to:
a. Myocardial infarction or unstable angina within the 6 months prior to the initiation of study treatment.
b. Stroke or transient ischemic attack within 6 months prior to the initiation of study treatment.
c. Clinically significant cardiac arrhythmias.
d. Uncontrolled hypertension: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥ 100 mmHg.
e. Congestive heart failure (New York Heart Association class III-IV).
f. Pericarditis or clinically significant pericardial effusion.
g. Myocarditis.
h. QTcF > 480 milliseconds as the average of 3 repeat examinations.
i. LVEF < 50%, or below the institutional lower limit of normal.
11. Clinically significant gastrointestinal disorders including:
a. Any history of gastrointestinal perforation unless the affected area has been deemed by the Investigator to no longer be a risk for perforation.
b. Clinically significant gastrointestinal bleeding in the opinion of the Investigator.
c. History of acute pancreatitis within 4 weeks prior to the initiation of study drug.
d. Diverticulitis that is clinically significant in the opinion of the Investigator based on the extent or severity of known disease and/or the occurrence of clinically significant disease flares within 4 weeks prior to the initiation of study drug administration.
12. A history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
13. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplemental oxygen therapy.
14. Clinically significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation.
15. The female patient who is pregnant or breastfeeding, or expecting to conceive, AND the male patient who is expecting to father children within the projected duration of the trial, starting with the screening visit through 7 months after the last dose of trial treatment.
16. Dementia or altered mental status that would preclude understanding and rendering of informed consent.
17. Employees of MacroGenics, Inc., and Zai Lab or its corporate business partners, including Incyte Corporation, unless approved by institutional review board (IRB) and principal Investigator.
18. Prisoners or other individuals who are involuntarily detained.
19. Any investigative site personnel directly affiliated with this study
1. Has a known additional malignancy that is progressing or has required treatment within the past 5 years. Patients who have been successfully treated for, and are disease free, non-melanomatous skin cancer, localized prostate cancer (Gleason Score < 6), or carcinoma in situ are eligible for participation in the study.
2. Patients with known MSI-H status.
3. Has poorly controlled diarrhea, despite optimal medical intervention.
4. Clinically significant accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs.
5. 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, in the opinion of the treating Investigator.
a. Known chronic hepatitis B virus (HBV) infection (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/ml).
• The patient with resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) is eligible.
b. Co-infection with hepatitis B (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/ml) and C (as evidenced by detectable hepatitis C virus [HCV] RNA); OR, hepatitis D infection in patients with hepatitis B.
• The patient with a history resolved hepatitis B and detectable HCV antibody is eligible.
c. Has a known history of human immunodeficiency virus 1 or 2 antibodies or has a diagnosis of immune-deficiency.
d. Has had an allogeneic stem cell or tissue/solid organ transplant.
e. Patients with central nervous system metastases.
f. Patients with a history of psoriatic arthritis.
g. Patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic treatment within the past 2 years and patients with a history of autoimmune disease who are now clinically stable with replacement therapy and by laboratory testing.
h. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study treatment. Patients requiring any systemic antiviral, antifungal, or antibacterial therapy for active infection must have completed treatment no less than 1 week prior to the initiation of study treatment.
i. Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient contained in the trastuzumab, margetuximab, INCMGA00012, or MGD013 drug formulation or contraindications to the specified chemotherapy regimens.
j. Any serious underlying medical or psychiatric condition (eg., known complete DPD deficiency) that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site.
k. History of uncontrolled seizures within 6 months registration.
l. Active or history of alcohol or other substance abuse within 1 year prior to registration.
6. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study treatment. Inactivated annual influenza vaccination is allowed.
7. Has received an investigational agent within 4 weeks prior to the initiation of study treatment. Prior neoadjuvant or adjuvant treatment with immunotherapy is excluded.
8. Major surgical procedure, including gastrectomy, or trauma within the 4 weeks prior to the initiation of study treatment.
9. Treatment with systemic corticosteroids (≥ 10 mg per day prednisone or equivalent) or other immune suppdrugs within the 14 days prior to the initiation of study treatment.
10. Clinically significant cardiovascular disease including but not limited to:
a. Myocardial infarction or unstable angina within the 6 months prior to the initiation of study treatment.
b. Stroke or transient ischemic attack within 6 months prior to the initiation of study treatment.
c. Clinically significant cardiac arrhythmias.
d. Uncontrolled hypertension: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥ 100 mmHg.
e. Congestive heart failure (New York Heart Association class III-IV).
f. Pericarditis or clinically significant pericardial effusion.
g. Myocarditis.
h. QTcF > 480 milliseconds as the average of 3 repeat examinations.
i. LVEF < 50%, or below the institutional lower limit of normal.
11. Clinically significant gastrointestinal disorders including:
a. Any history of gastrointestinal perforation unless the affected area has been deemed by the Investigator to no longer be a risk for perforation.
b. Clinically significant gastrointestinal bleeding in the opinion of the Investigator.
c. History of acute pancreatitis within 4 weeks prior to the initiation of study drug.
d. Diverticulitis that is clinically significant in the opinion of the Investigator based on the extent or severity of known disease and/or the occurrence of clinically significant disease flares within 4 weeks prior to the initiation of study drug administration.
12. A history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
13. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplemental oxygen therapy.
14. Clinically significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation.
15. The female patient who is pregnant or breastfeeding, or expecting to conceive, AND the male patient who is expecting to father children within the projected duration of the trial, starting with the screening visit through 7 months after the last dose of trial treatment.
16. Dementia or altered mental status that would preclude understanding and rendering of informed consent.
17. Employees of MacroGenics, Inc., and Zai Lab or its corporate business partners, including Incyte Corporation, unless approved by institutional review board (IRB) and principal Investigator.
18. Prisoners or other individuals who are involuntarily detained.
19. Any investigative site personnel directly affiliated with this study
試驗計畫預計收納受試者人數
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台灣人數
5 人
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全球人數
82 人
