CTRI/2024/08/072371招募中3 期
An open-label randomized trial of the efficacy and safety of zanidatamab with standard-of-care therapy against standard-of-care therapy alone for advanced HER2-positive biliary tract cancer
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 286
- 试验地点
- 9
- 主要终点
- Progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) in the immunohistochemistry (IHC) 3+ subgroup
研究概览
简要总结
This is an open-label, randomized, multicenter, phase 3 study to investigate the efficacy and safety of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor (physician’s choice of either durvalumab or pembrolizumab, where approved under local regulations) as first-line treatment for participants with HER2-positive, locally advanced unresectable or metastatic BTC, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Participants are allowed to receive up to 2 cycles of systemic therapy consisting of gemcitabine with a platinum agent (eg, CisGem or gemcitabine in combination with oxaliplatin [GEMOX]) with or without a PD-1/L1 inhibitor (physician’s choice of either durvalumab or pembrolizumab, where approved under local regulations) prior to randomization for their advanced or metastatic disease.
Upon enrollment, participants will be randomized in a 1:1 ratio to 1 of 2 arms:
Arm A (experimental arm): Zanidatamab plus CisGem (for up to 8 cycles) with or without a PD-1/L1 inhibitor
Arm B (control arm): CisGem (for up to 8 cycles) with or without a PD-1/L1 inhibitor
Study treatment may continue beyond the up to 8 cycles total of CisGem until investigator-assessed disease progression (per RECIST 1.1), although maximum treatment durations for the selected PD-1/L1 inhibitor (if given) per the locally approved package insert will apply.
Primary Objective: Compare the efficacy of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor versus CisGem with or without a PD-1/L1 inhibitor in participants with advanced or metastatic HER2-positive BTC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Histologically- or cytologically confirmed BTC, including GBC, ICC, or ECC.
- •Locally advanced unresectable or metastatic BTC and not eligible for curative resection, transplantation, or ablative therapies.
- •Received no more than 2 cycles of systemic therapy with gemcitabine and a platinum agent (eg, CisGem or GEMOX) with or without a PD-1/L1 inhibitor (physician’s choice of durvalumab or pembrolizumab, where approved under local regulations) for advanced unresectable or metastatic disease.
- •Participants who have received prior adjuvant or neoadjuvant treatment (including investigational products) for earlier stage disease are permitted as long as therapy was completed more than 6 months prior to expected date of C1D1
- •HER2-positive disease (defined as IHC 3+; or IHC 2+/ ISH+) by IHC and ISH assay (in participants with IHC 2+ tumors) at a central laboratory on new biopsy tissue or archival tissue from the most recent biopsy.
- •Note that fine needle aspirates (FNAs; cytology samples) and biopsies from sites of bone metastases are not acceptable.
- •When the central laboratory is available, samples must be sent to the central laboratory prior to randomization for determination of HER2 status.
- •If it has been confirmed with the medical monitor that a central laboratory is not available, sites may use local testing for HER2 to enroll participants with IHC 3+ tumors.
- •In this case, samples still must be sent to the central laboratory for confirmatory analyses once the central laboratory becomes available.
- •Assessable (measurable or non-measurable) disease as defined by RECIST 1.1, per investigator assessment.
- •Male or female 18 years and above, or age (or the legal age of adulthood per country-specific regulations)
- •ECOG performance status of 0 or
- •Adequate hematologic function as follows: a.
- •Absolute neutrophil count (ANC) greater than or equal to 1.5 × 10 (to the power of 9)/L b.
- •Platelet count greater than or equal to 100 × 10 (to the power of 9)/L, not requiring transfusion support c.
- •Hemoglobin (Hgb) greater than or equal to 9 g/dL (participants with chronic anemia that is supported by intermittent red blood cell transfusions are eligible)
- •Adequate hepatic function, as defined by both: a.
- •Aspartate aminotransferase (AST) less than or equal to 3 × upper limit of normal (ULN), and alanine aminotransferase (ALT) less than or equal to 3 × ULN.
- •For participants with liver involvement, AST and ALT less than or equal to 5 × ULN is acceptable.
- •Total bilirubin less than or equal 1.5 × ULN, or less than or equal to 3 × ULN for participants with Gilbert’s disease
- •Adequate renal function, as defined by estimated glomerular filtration rate (GFR) greater than 50 mL/min per local institutional standard method.
- •Left ventricular ejection fraction greater than or equal to 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA).
- •Females of childbearing potential must have a negative serum/plasma or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 3 days prior to expected date of C1D
- •Females with false positive results can be enrolled if subsequent serum/plasma testing is negative.
- •Females of childbearing potential and males with a partner of childbearing potential must be willing to use 2 methods of birth control with a failure rate of less than 1% per year during the study and for 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 5 months after the last dose of zanidatamab, 4 months after the last dose of pembrolizumab, and 3 months after the last dose of durvalumab.
- •Females must agree to not donate oocytes starting at screening and throughout the study period, and for at least 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 5 months after the last dose of zanidatamab, 4 months after the last dose of pembrolizumab, and 3 months after the last dose of durvalumab.
- •Males must agree to use condoms and not to donate sperm starting at screening and throughout the study period, and for at least 11 months after the last dose of cisplatin, 5 months after the last dose of zanidatamab, and 3 months after the last dose of gemcitabine.
- •Participant has life expectancy of greater than 3 months, in the opinion of the investigator.
- •The participant must provide written informed consent.
- •Participants who elect to be pre-screened for HER2 status must provide a separate written informed consent for collection, storage, and analysis of the tumor tissue.
排除标准
- •Prior treatment with a HER2-targeted agent, with the exception of participants who completed HER2-targeted treatment for breast cancer greater than 5 years prior to their diagnosis of BTC.
- •Prior treatment with check point inhibitors, other than durvalumab or pembrolizumab as part of the up to 2 cycles of systemic therapy allowed prior to expected date of C1D1 per Inclusion Criterion
- •Exclusionary checkpoint inhibitors include, but are not limited to anti-PD-1, anti-PD-L1, anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 antibodies.
- •The following BTC histologic subtypes are excluded: small cell cancer, neuroendocrine tumors, lymphoma, sarcoma, mixed tumor histology, and mucinous cystic neoplasms detected in the biliary tract region.
- •Received radiotherapy within 2 weeks of expected date of C1D
- •Had major surgery within 4 weeks of expected date of C1D
- •Total lifetime load of anthracycline exceeding 360 mg/m2 doxorubicin or equivalent.
- •Use of systemic corticosteroids administered at doses equivalent to greater than 10 mg per day of prednisone within 2 weeks of expected date of C1D
- •Topical, ocular, intra-articular, intranasal, and/or inhalation corticosteroids are permitted.
- •Brain metastases: Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of expected date of C1D
- •Stable, treated brain metastases are allowed (defined as participants who are off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks at the time of screening).
- •Known history of or ongoing leptomeningeal disease (LMD).
- •Participants will be eligible if LMD has been reported radiographically but is not suspected clinically by the investigator, and the participant does not have neurological symptoms of LMD.
- •Poorly controlled seizures in the judgment of the investigator.
- •Grade 2 or greater peripheral neuropathy.
- •Concurrent uncontrolled or active hepatobiliary disorders or untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, unresolved biliary obstruction, infected biloma, or abscess.
- •Any complications must be resolved at least 2 weeks prior to expected date of C1D
- •Severe chronic or active infections requiring systemic parenteral antibacterial, antifungal or antiviral therapy; or any other potentially life-threatening viral or bacterial infection (participants on oral antibiotics must complete the planned course of treatment prior to expected date of C1D1).
- •Active hepatitis, including the following: a.
- •Acute or chronic hepatitis B (Exception: Participants who are hepatitis B surface antigen [HBsAg] positive are eligible if they have hepatitis B virus (HBV) DNA less than 500 IU/mL or 2,500 copies/mL).
- •Note: Participants with detectable HBsAg or detectable HBV DNA should be managed per institutional or local standards.
- •Participants beginning antiviral agents at screening should be treated for greater than 2 weeks prior to expected date of C1D
- •Infection with hepatitis C (Exceptions: [i] Participants who have no history of curative viral treatment and are documented to be viral load negative are eligible; [ii] Participants who have completed curative viral therapy greater than or equal to 12 weeks prior to expected date of C1D1, and viral load is negative are eligible.)
- •Infection with human immunodeficiency virus (HIV)-1 or HIV-
- •(Exception: Participants with well-controlled HIV [ie, CD4 greater than 350/mm3 and undetectable viral load] are eligible.)
- •Active tuberculosis.
- •History of allogeneic organ transplantation.
- •Active or prior autoimmune inflammatory conditions with the exception of: a.
- •Vitiligo or alopecia b.
- •Hypothyroidism stable on thyroid replacement c.
- •Celiac disease controlled by diet alone e.
- •Without active disease in the last 5 years after consultation with the treating physician
- •History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of any of the agents in the trial (cisplatin, gemcitabine, the selected PD-1/L1 inhibitor, or zanidatamab).
- •Known hypersensitivity to any components of the combination therapy.
- •Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer therapies, with the exception of alopecia.
- •QTc Fridericia (QTcF) greater than 470 ms.
- •Note: For participants with longer QTcF on initial electrocardiogram (ECG), follow-up ECG may be performed in triplicate to determine eligibility.
- •Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF).
- •Participants with known myocardial infarction or unstable angina within 6 months prior to expected date of C1D1 are also excluded.
- •Previous anticancer therapy-related CHF must have been less than or equal to Grade 1 at the time of occurrence and must have completely resolved.
- •History of interstitial lung disease or non-infectious pneumonitis.
- •Participation in another clinical trial with an investigational medicinal product within the last 3 months.
结局指标
主要结局
Progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) in the immunohistochemistry (IHC) 3+ subgroup
时间窗: The time from the date of randomization to the date of documented disease progression (per RECIST 1.1) per investigator, or death from any cause
次要结局
- a) Overall survival (OS) in the IHC 3+ subgroup(b) PFS per RECIST 1.1 in the overall population)
- Confirmed objective response rate (cORR) per RECIST 1.1(The time from the date of randomization to the date of documented disease progression (per RECIST 1.1) per investigator, or death from any cause.)
- Duration of response (DOR) per RECIST 1.1(The time from the first objective response (CR or PR) that is subsequently confirmed to documented PD per RECIST 1.1 or death from any cause.)
- Frequency, severity, seriousness, and relatedness of treatment-emergent adverse events (AEs)(From the start of dosing of study drug to 30 days after the last dose of study drug.)
- Serum concentrations of zanidatamab as a function of time post-dosing(The time from the date of randomization pre dose to the End of Treatment date.)
- Frequency, duration, and time of onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable, to zanidatamab(The time from the date of randomization pre dose to the End of Treatment date. If positive at EOT, retests to be performed approximately 3-month intervals until the ADA levels return to baseline or stabilize at a level acceptable to the investigator and sponsor.)
- Time to definitive deterioration (TDD) from baseline in the IHC 3+ subgroup in patient-reported PF domain score as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30)(Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death)
- TDD from baseline in the overall population in patient-reported PF domain score as measured by the EORTC QLQ-C30(Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death.)
- TDD from baseline in IHC 3+ subgroup in patient-reported symptoms scores as measured by EORTC Quality of Life Questionnaire – Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21) (Pain, Jaundice, Abdominal Pain, and Pruritis)(Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death.)
- TDD from baseline in the overall population in patient-reported symptoms scores as measured by the EORTC QLQ-BIL21 (Pain, Jaundice, Abdominal Pain, and Pruritis)(Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death.)
研究者
研究点 (9)
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