DESTINY-Biliary Tract Cancer-01: A Phase 3 Study of Trastuzumab Deruxtecan (T-DXd) and Rilvegostomig versus Standard-of-Care Gemcitabine, Cisplatin, and Durvalumab for First Line Locally Advanced or Metastatic HER2-expressing Biliary Tract Cancer
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 600
- 试验地点
- 8
- 主要终点
- To evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of OS in the FAS (HER2 IHC 3+) population
研究概览
简要总结
This is a global Phase 3, randomized, open label, multicenter, registrational intent study. It is designed to evaluate the efficacy and safety of T DXd with rilvegostomig or T DXd monotherapy vs gemcitabine, cisplatin and durvalumab as first line treatment in patients with advanced HER2 expressing BTC. Study details include
Patient Population:
Adult patients with previously untreated, unresectable, locally advanced or metastatic, HER2 expressing (IHC 3Plus or IHC 2Plus) BTC will be eligible. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is Greater Than 6 months between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease. Patients in the safety run-in are enrolled based on local HER2 IHC test results.
In the randomized portion of the study, patients will be enrolled based on a prospective HER2 test result. This HER2 result and the PD-L1 status used for stratification should come from a central test whenever possible, however patients who have locally-confirmed HER2 IHC 3Plus status may be enrolled onto the randomized portion of the trial without prospective central results. Patients with local HER2 IHC 3Plus result may also use a local PD-L1 result for stratification. In cases where local HER2 IHC and/or PD-L1 test results are used to enroll a patient, FFPE tissue samples must still be provided for retrospective central assessment of HER2 and/or PD-L1 expression status. The on-treatment visit frequency will be weekly to Q3W.
Study Arms and Duration
Patients will be randomized at a ratio of 1:1:1 between three treatment arms (T-DXd with rilvegostomig, T-DXd monotherapy, or gemcitabine, cisplatin and durvalumab, respectively). All randomized patients will receive the assigned treatment until disease progression per RECIST v1.1, or unacceptable toxicity, or withdrawal of consent, or other criteria for discontinuation are met. Crossover within the study will not be permitted.
This is an open-label study for the personnel at study sites; however, the study will be conducted as “Sponsor-blind” and the specific treatment to be taken by a patient will be assigned using an IRT. To maintain the integrity of the study, AstraZeneca personnel directly involved in the study conduct will not undertake or have access to efficacy data aggregated by the treatment arm prior to final data readout for the primary endpoint.
The purpose of this study is to measure the efficacy and safety of T-DXd with rilvegostomig or T-DXd monotherapy compared with gemcitabine plus cisplatin and durvalumab in patients with advanced treatment-naïve HER2-expressing BTC.
The visit frequency will be every 3 weeks in the experimental Arms A and B. In the control Arm C, this frequency will be twice every 3 weeks (on Day 1 and Day 8 of each cycle up to 8 cycles), and then once every 4 weeks thereafter.
Number of Patients:
The study plans to randomize a total of approximately 600 patients at a ratio of 1:1:1 to receive T DXd Plus rilvegostomig (N = 200), T-DXd monotherapy (N = 200), or SoC (N = 200) (Table 2). Of the 600 patients, the proportion of patients with HER2 IHC 2Plus will be capped globally at 40% to enrol approximately 360 patients with HER2 IHC 3Plus disease and 240 patients with HER2 IHC 2Plus disease will be randomized into the study. The number of patients with HER2 IHC 2Plus disease may be capped at site and/or country level
Randomization will be stratified based on the following factors:
HER2 status: IHC 3Plus vs IHC 2Plus,
PD L1 status: TAP Greater than or equal 1% vs TAP lass than 1%,
Primary tumor location: GBC vs IHCC vs EHCC.
Follow-up of Patients Post Discontinuation of Study Intervention:
After study intervention discontinuation, all patients will undergo an end-of-treatment visit (within 3 days of discontinuation) and will be followed up for safety assessments at 30 (Plus or minus 7) days, 60 (Plus or minus 7) days, and 90 (Plus or minus 7) days after their last dose of study intervention (ie, the safety follow-up visit).
Patients who have discontinued study intervention in the absence of RECIST 1.1-defined radiological progression will be followed up with tumor assessments according to the SoA until RECIST 1.1-defined PD or death regardless of whether or not the patient started a subsequent anticancer therapy, unless they have withdrawn all consent to undergo study-related assessments.
In addition, all patients will be followed up for survival status after intervention discontinuation every 3 months (Plus or minus14 days) from the date of the 90-day safety follow-up until death, withdrawal of consent, or the end of the study (ie, progression/survival follow-up), as per the SoA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Outcome Assessor Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Inclusion criteria
- •Sign and date the written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
- •Male and female patients must be at least 18 years of age.
- •Male and female patients must be Greater than or equal 30 kg.
- •Unresectable, previously untreated, locally advanced or metastatic BTC.
- •Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is Greater than 6 months (180 days) between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease.
- •Has histologically confirmed HER2-expressing (IHC 3Plus or IHC 2Plus) BTC established by prospective central testing of tumor tissue or a histologically confirmed HER2-expressing (IHC 3Plus) BTC from an existing local result.
- •Patients must provide an FFPE tumor sample that is no older than 3 years for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 status, and other correlatives.
- •The mandatory FFPE tumor sample should be from the most recent biopsy but can be either from the primary tumor or metastatic biopsy.
- •Archival samples taken from a surgical or diagnostic biopsy confirming HER2 status can be accepted.
- •Specimens with limited tumor content and cytology samples are inadequate for defining tumor HER2 or PD-L1 status.
- •Additional details on sample requirements are defined in the Diagnostic Testing Manual and Central Laboratory Manual.
- •Note: This is a requirement for all patients including IHC 3Plus patients enrolled via local results.
- •Has at least one target lesion assessed by the Investigator based on RECIST v1.1 a.
- •Note: This is a requirement for the randomized portion of trial only.
- •8.Left ventricular ejection fraction Greater than or equal 50% within 28 days before study intervention.
- •9 WHO/ECOG performance status of 0 or
- •Adequate organ and bone marrow function within 14 days before randomization (Parameters for Adequate Organ and Bone Marrow Function).
- •Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to C1D
- •Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner.
- •For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of investigational product.
- •Women of childbearing potential are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.
- •Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, as presented in Table 12, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP.
- •Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP (Section 5.3).
- •Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study treatment administration.
- •Preservation of ova may be considered prior to enrollment in this study.
- •Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening for 6 months after the last dose of IMP.
- •It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception, as described in Table 12 (Section 5.3).
- •Patients with HBV infection (as characterized by positive HBsAg and/or anti-HBc with detectable HBV DNA Greater than or equal10 IU/mL or above the limit of detection per local laboratory) must receive antiviral therapy prior to randomization per institutional practice to ensure adequate viral suppression.
- •Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
- •Patients who test positive for anti-HBc with undetectable HBV DNA (Lass than10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy unless HBV DNA exceeds 10 IU/mL or reaches detectable limits per local laboratory during the course of treatment.
- •Patients with active co-infection of HBV and HCV as evidenced by positive anti-HCV antibody and actively co-infected with HBV and hepatitis D virus are not eligible.
- •Adequate treatment washout period before randomization,.
排除标准
- •Exclusion criteria Patients are eligible to be included only if none of the exclusion criteria apply:
- •Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors (eg, anti-PD-1/PD-L1 or CTLA-4) and therapeutic anticancer vaccines.
- •Has histologically confirmed ampullary carcinoma.
- •Has a history of substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the Investigator, interfere with the patient’s participation in the clinical study or evaluation of the clinical study results.
- •Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
- •Patients with clinically inactive brain metastases may be included in the study.
- •Patients with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy.
- •A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study randomization.
- •Patients with a medical history of myocardial infarction within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (Lass than 6 months) cardiovascular event including stroke.
- •Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
- •Serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease); active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.
- •Has an active autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogrens, sarcoidosis etc) that has required systemic treatment in the past 2 years (eg, with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs), or where there is documented, or a suspicion of pulmonary involvement at the time of screening.
- •Replacement therapy (eg, thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
- •Corrected QT interval (QTcF) prolongation to Greater Than 470 msec (females) or Greater Than 450 msec (males) based on average of the screening triplicate 12-lead ECG.
- •Criteria related to lung disorders: History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- •Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion etc).
- •Prior pneumonectomy (complete).
- •Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
- •Active primary immunodeficiency, known uncontrolled active HIV infection or HCV.
- •Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- •Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board/ethics committee.
- •Acute hepatitis A.
- •Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade lass than or equal1 or baseline.
- •Chemotherapy-induced neuropathy a.
- •Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2 endocrinopathies which may include: o Hypothyroidism/hyperthyroidism c.
- •Type 1 diabetes d.
- •Hyperglycemia e.
- •Adrenal insufficiency f.
- •Adrenalitis g.
- •Skin hypopigmentation (vitiligo) Note: Patients may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Greater Than Grade 2 for at least 3 months prior to [randomization/enrollment/Cycle 1 Day 1 and managed with Standard-of-Care treatment) that the Investigator deems related to previous anticancer therapy, such as:
- •History of severe hypersensitivity reactions to other monoclonal antibodies.
- •Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.
- •History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence, adequately resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, lentigo maligna that has undergone potentially curative therapy or adequately treated in situ disease without evidence of disease.
- •A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Drainage and CART are not allowed within 2 weeks prior to screening assessment).
- •Current or prior use of immunosuppressive medication within 14 days before the first dose of study drugs.
- •The following are exceptions to this criterion: • Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
- •• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
- •• Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, CT scan premedication).
- •Any concurrent anticancer treatment.
- •Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
- •History of allogenic organ transplant.
- •Previous randomization in the present study or a previous T-DXd or rilvegostomig study regardless of treatment arm assignment.
- •Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 6 months prior to randomization, or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
结局指标
主要结局
To evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of OS in the FAS (HER2 IHC 3+) population
时间窗: study outcome will be evaluated at Baseline, q6w±1w for the first 24 weeks (relative to the date of randomization) and then q8w±1w thereafter (relative to the date of randomization) till the disease progression
次要结局
- To evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of OS in the FAS (HER2 IHC 3+/2+) population(• To evaluate the efficacy of T-DXd monotherapy vs SoC in terms of OS in the FAS (HER2 IHC 3+) population)
- To further evaluate efficacy of T DXd with rilvegostomig vs SoC in terms of PFS in FAS (HER2 IHC 3Plus) and FAS population(• To further evaluate efficacy of T DXd monotherapy vs SoC in terms of PFS in FAS (HER2 IHC 3Plus) and FAS populations)
- with rilvegostomig vs SoC in terms of ORR in the FAS (HER2 IHC 3Plus) and FAS populations(• To further evaluate the efficacy of T-DXd monotherapy vs SoC in terms of ORR in the FAS (HER2 IHC 3Plus) and FAS populations)
- rilvegostomig vs SoC in terms of DoR in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations(DoR (Investigator) in FAS (HER2 IHC 3Plus) and FAS populations)
- To further evaluate efficacy of T DXd monotherapy vs SoC in terms of DoR in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations(of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression.)
- To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of OS, PFS, DOR and ORR in FAS (HER2 IHC 3Plus) and FAS populations(OS, PFS, DOR and ORR definitions as detailed above.)
- To assess the safety and tolerability of T DXd with rilvegostomig vs SoC(• To assess the safety and tolerability of T DXd monotherapy vs SoC)
- To assess the safety and tolerability of T DXd with rilvegostomig vs T-DXd monotherapy(Assessed among all treated patients by the occurrence of AEs, SAEs, AESIs, and changes from baseline in laboratory parameters, vital signs, electrocardiogram and echocardiogram/MUGA results.)
- To describe patient-reported tolerability of T DXd with rilvegostomig in comparison to SoC based on a summary of symptomatic AEs and overall side-effect bother(• To describe patient-reported tolerability of T DXd monotherapy in comparison to SoC based on a summary of symptomatic AEs and overall side-effect bother)
- To describe patient-reported tolerability of T DXd with rilvegostomig in comparison to T-DXd monotherapy based on a summary of symptomatic AEs and overall side-effect bother(Symptomatic AEs and overall side-effect bother definitions as above)
- To assess TTD in physical functioning in patients treated with T-DXd with rilvegostomig vs SoC(• To assess TTD in physical functioning in patients treated with T-DXd monotherapy vs SoC)
- To assess TTD in physical functioning in patients treated with T-DXd with rilvegostomig vs T-DXd monotherapy(TTD in physical function as measured by the PROMIS Short Form v2.0 – Physical Function 8c)
- To assess the PK of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig in serum(Descriptive analysis of serum concentration of T DXd, total anti-HER2 antibody, DXd and rilvegostomig in all applicable arms.)
- To investigate the immunogenicity of T-DXd and of rilvegostomig(Descriptive summary of presence of ADAs for T DXd and rilvegostomig in all applicable arms.)
- To further evaluate the efficacy of T-DXd with rilvegostomig vs SoC in terms of PFS2 in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations.(• To further evaluate the efficacy of T-DXd monotherapy vs SoC in terms of PFS2 in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations.)
- To further evaluate the efficacy of T-DXd with rilvegostomig vs T-DXd monotherapy terms of PFS2 in patients with HER2 expressing BTC in the FAS (HER2 IHC 3Plus) and FAS populations.(PFS2 definition as above)
- To explore the impact of treatment on symptoms associated with BTC among patients receiving T-DXd with rilvegostomig relative to patients receiving SoC.(The analysis will include all randomized patients as randomized.)
- To explore the impact of treatment on symptoms associated with BTC among patients receiving T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy(The analysis will include all randomized patients as randomized.)
- To explore the impact of treatment and disease on select functioning and health related QoL/GHS outcomes in patients receiving T-DXd with rilvegostomig relative to patients receiving SoC.(• To explore the impact of treatment and disease on select functioning and health related QoL/GHS outcomes in patients receiving T-DXd monotherapy relative to patients receiving SoC.)
- To explore the impact of treatment and disease on select functioning and health related QoL/GHS outcomes in patients receiving T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy.(Change from baseline and time to worsening in on select functioning (role, emotional, cognitive, social) and health related QoL/GHS outcomes as measured by the EORTC IL172.)
- To explore the impact of treatment and disease on health state in patients receiving T-DXd with rilvegostomig relative to patients receiving SoC.(• To explore the impact of treatment and disease on health state in patients receiving T-DXd monotherapy relative to patients receiving SoC)
- To explore the impact of treatment and disease on health state in patients in patients receiving T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy.(VAS mean score and change from baseline and 5-dimension response as measured by the EQ-5D-5L.)
- To evaluate pulmonary symptom tolerability of:(• T-DXd with rilvegostomig relative to patients receiving SoC)
- To evaluate pulmonary symptom tolerability of T-DXd with rilvegostomig relative to patients receiving T-DXd monotherapy(Pulmonary symptoms definition as above)
- To further evaluate the efficacy of T-DXd with rilvegostomig vs SoC in patients with centrally confirmed HER2-positive status(Efficacy (OS, PFS, DOR and ORR)/safety (occurrence of AEs, SAEs, AESIs) endpoints in patients confirmed as HER2-positive by central testing)
- To collect blood and tissue samples for defining biological responses to T-DXd with rilvegostomig and T-DXd monotherapy and identifying candidate markers that may correlate with clinical benefit and/or intrinsic or acquired resistance, and participant safety and tolerability.(•Biomarkers include but are not limited to:)
研究者
Mr Sandeep AV
AstraZeneca Pharma India Ltd