A Randomized, Phase III Study of Rilvegostomig in Combination with Fluoropyrimidine and Trastuzumab Deruxtecan versus Trastuzumab, Chemotherapy, and Pembrolizumab for the First-line Treatment of HER2-positive Gastric Cancer (ARTEMIDE-Gastric01)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 880
- 试验地点
- 7
- 主要终点
- To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS.
研究概览
简要总结
This is a Phase III, 3 arm, randomized, open-label, multi-center, global study assessing the efficacy and safety of rilvegostomig in combination with fluoropyrimidine and T-DXd (Arm A) compared to trastuzumab, chemotherapy, and pembrolizumab (Arm B) in HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma participants whose tumors express PD-L1 CPS grater then equals to 1. Rilvegostomig in combination with trastuzumab and chemotherapy will be evaluated in a separate arm (Arm C) to assess the contribution of each component in the experimental arm.
Approximately 1680 participants with LA-HNSCC are planned to be screened in order to randomize approximately 880 participants in a 1:1:1 ratio to one of the following arms:
| Arm |
Study Intervention
Dose and Route of Administration
|Arm A
T-DXd + Rilvegostomig + Fluoropyrimidine: Capecitabine a OR 5-FU a
T-DXd: 5.4 mg/kg IV Q3W Rilvegostomig: 750 mg IV Q3W Capecitabine: 750 mg/m2 orally BID for 14 days, Q3W OR 5-FU: 600 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W
Arm B
Pembrolizumab + Trastuzumab + FP a OR CAPOX a
Pembrolizumab: 200 mg IV Q3W Trastuzumab: 8 mg/kg loading dose, followed by 6 mg/kg for subsequent cycles, IV Q3W FP: Cisplatin: 80 mg/m2 IV + 5-FU: 800 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W OR CAPOX: Capecitabine: 1000 mg/m2 orally BID for 14 days + oxaliplatin: 130 mg/m2 IV Q3W
| Arm C |
Rilvegostomig + Trastuzumab + FP a OR CAPOX a
Rilvegostomig: 750 mg IV Q3W Trastuzumab: 8 mg/kg loading dose, followed by 6 mg/kg for subsequent cycles, IV Q3W FP: Cisplatin: 80 mg/m2 IV + 5-FU: 800 mg/m2/day IV as a continuous infusion over 24 hours for the first 5 days of each cycle (120 hours or per local practice), Q3W OR CAPOX: Capecitabine: 1000 mg/m2 orally BID for 14 days + oxaliplatin: 130 mg/m2 IV Q3W
Randomization will be stratified by HER2 status (IHC 3plus versus IHC 2plus plus ISH-positive), geographic region (Japan/South Korea versus Rest of Asia [including China] versus North America/EU/ROW), and PD-L1 expression (CPS grater then equals 10 versus CPS less than 10).
Randomization of participants with CPS of 1 to less than10 (inclusive of 1 but less than 10) will be capped at approximately 60% of the planned total number of randomized participants to reflect the natural prevalence of PD-L1 expression.
All randomized participants will receive the assigned study interventions until RECIST v1.1defined PD or unacceptable toxicity, withdrawal of consent, or other criteria for discontinuation are met. Cisplatin and oxaliplatin will be administered for up to 6 cycles as tolerated and as per local guidelines. Oxaliplatin may be continued up to 8 cycles at the discretion of the Investigator.
Participants found to derive benefit from and tolerate treatment may continue study intervention after disease progression and separate informed consent needs to be provided.
Participants will receive study intervention for a maximum of 12 months or 18 cycles, or undergo observation for 12 months, or until RECIST 1.1 defined radiological PD confirmed by investigator assessment, unless there is evidence of unacceptable toxicity, or if a participant requests to stop the study intervention, as applicable to the arm participants are assigned to
Follow-up of Participants Post-discontinuation of Study Intervention:
After study intervention discontinuation, all participants will undergo an EoT Visit or early study intervention/discontinuation Visit (within 7 days of discontinuation) and will be followed up for safety assessments 30 (Plus 7), 60 (Plus 7), and 90 (Plus 7) days after their last dose of study intervention (ie, the safety follow up visit).
Participants who have discontinued study intervention in the absence of RECIST v1.1 defined radiological progression confirmed by BICR assessment will be followed up with tumor assessments according to the SoA until RECIST v1.1 defined PD by BICR assessment or death regardless of whether or not the participant started a subsequent anti-cancer therapy, unless they have withdrawn all consent to study-related assessments.
In addition, all participants will be followed up for survival status after intervention discontinuation Q3M ( 2 weeks) from the date of randomization until death, withdra wal 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
- 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
- •Inclusion criteria Participant and Disease Characteristics
- •HER2-positive (IHC 3Plues or IHC 2Plues ISH-positive) on a tumor biopsy as detected by prospective central test on the primary or metastatic tumor tissue sample.
- •Provision of tumor tissue sample from recent biopsy adequate for HER2 and PD-L1 testing.
- •Additional details on sample requirements will be provided in the Laboratory Manual.
- •Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma.
- •Prior treatment in the neo-adjuvant and/or adjuvant setting is permissible provided there is a Grete then 6-month interval between the last administration of the prior regimen and the diagnosis of locally advanced or metastatic disease.
- •Prior use of approved immune CPIs (ie, anti-PD-1/PD-L1) in the neo-adjuvant and/or adjuvant setting is permissible provided there is Grete then 6 months between the last administration of immune CPIs and the diagnosis of locally advanced or metastatic disease.
- •However, patients with progression on neo-adjuvant or recurrence on adjuvant immune CPIs treatment should be excluded.
- •WHO or ECOG PS of 0 or 1 with no deterioration over the 2 weeks prior to the day of the first dosing.
- •Have measurable target disease assessed by the Investigator based on RECIST v1.
- •Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •Have adequate organ and bone marrow function within 14 days before randomization as described in Table
- •All parameters must be the most recent results available.
- •Have a life expectancy of at least 6 months.
- •LVEF Grete then equals to 55% within 28 days before randomization.
- •Participants with ejection fraction of 50% to 54% may still be eligible with discussion with Sponsor AND after consultation with cardiology AND after being medically optimized
- •Adequate treatment washout period before randomization, defined in Table
- •Participants must be Grete then equals to 30 kg Contraceptive/Barrier Requirements
- •Evidence of post-menopausal status or negative serum pregnancy test for FOCBP who are sexually active with a non-sterilized male partner.
- •For FOCBP, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU or mL) must be available at the Screening Visit and urine HCG pregnancy test prior to each administration of study intervention.
- •FOCBP are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (Appendix G).
- •Women will be considered post menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
- •FOCBP who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 27, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer.
- •Not all methods of contraception are highly effective.
- •It is strongly recommended that non-sterilized male partners of FOCBP use a male condom plus spermicide while on study and for 7 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer.
- •(Note: Male condoms are not reliable as a sole contraception method).
- •Female participants 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 last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 14 months), whichever is longer.
- •They should refrain from breastfeeding throughout this time.
- •Preservation of ova may be considered prior to enrollment in this study.
- •It is strongly recommended for the female partners of a male participant to also use at least one highly effective method of contraception throughout this period, as described in Table
- •In addition, male participants should refrain from fathering a child throughout the study treatment period and for 6 months after the last dose of study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer.
- •Male participants should refrain from freezing or donating sperm from the time of screening until 6 months after the last dose of the study intervention or as required by prescribing information for the Investigator’s choice of therapy received (following cisplatin USPI, this restriction period is 11 months), whichever is longer.
- •Informed Consent
- •Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
- •Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.
- •Optional Genetic Research
- •Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative.
排除标准
- •Exclusion Criteria Participants are excluded from the study if any of the following criteria apply: Medical Conditions
- •Lack of physiological integrity of the upper gastrointestinal tract.
- •Known partial or total DPD enzyme deficiency based on local or central laboratory testing, with testing required only in regions where it is SoC.
- •Central testing will be available for participants where testing is SoC and with unknown DPD status.
- •For regions where DPD testing is not SoC, local practice should be followed.
- •Contraindication to pembrolizumab or trastuzumab, contraindications to fluoropyrimidine (5-FU and capecitabine) or platinum (cisplatin and oxaliplatin) treatment as per local label
- •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.
- •Exceptions also include adequately resected basal cell carcinoma 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.
- •Persistent toxicities caused by previous anti-cancer therapy excluding alopecia, not yet improved to Grade 1 or baseline.
- •Note: Participants may be enrolled with the following chronic, stable Grade 2 toxicities (defined as no worsening to Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the Investigator deems related to previous anti-cancer therapy: Chemotherapy-induced neuropathy Fatigue Vitiligo Endocrine disorders, that are controlled with replacement hormone therapy.
- •Residual Grade 1 or Grade 2 endocrinopathies from prior immune CPIs may be allowed (eg, hypothyroidism/hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis).
- •Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (eg, hearing loss).
- •Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring corticosteroid or anticonvulsant 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 or spinal cord compression and study randomization.
- •Uncontrolled infection including TB (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice) and active hepatitis A infection.
- •Uncontrolled infection requiring IV antibiotics, anti-virals, or antifungals.
- •Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study intervention.
- •Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.
- •Has a known history of active primary immunodeficiency, uncontrolled active HIV infection with serologic evidence of viral infection within 28 days of C1D
- •Participants should be tested for HIV prior to randomization if required by local regulations or IRB/IEC.
- •Has chronic or active hepatitis B; however, participants who have chronic hepatitis B are eligible only if they meet all of the following criteria Controlled HBV load: HBV DNA 100 UormL by PCR or undetectable ALT is normal.
- •Remain on anti-viral therapy, per institutional practice, during the study intervention and follow-up periods to ensure adequate viral suppression.
- •Absence of cirrhosis or fibrosis on prior imaging or biopsy.
- •Absence of HCV co-infection or history of HCV co-infection.
- •Access to a local hepatitis B expert during and after the study.
- •Has chronic or active hepatitis C; however, participants who have chronic hepatitis C are eligible if ALT is normal (NA for participants with liver metastases) and HCV RNA is undetectable by PCR, either spontaneously or in response to a successful prior course of anti-hepatitis C therapy.
- •Controlled hepatitis C viral load is defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy.
- •Has 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 participant’s participation in the clinical study or evaluation of the clinical study results
- •Participants with a medical history of MI within 6 months before enrollment, symptomatic CHF (NYHA Class II to IV), or clinically significant arrhythmia.
- •Participants 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 MI
- •QTcF prolongation to 470 ms (females) or 450 ms (males), based on average of the screening triplicate 12 lead ECG.
- •Participants with congenital long QT syndrome and those with a history of QT prolongation associated with other medications that required discontinuation of that medication.
- •As judged by the Investigator, any evidence of diseases (such as hearing loss, severe or uncontrolled systemic diseases, including ongoing or active infection, uncontrolled hypertension, and active bleeding diseases, serious chronic gastrointestinal conditions associated with diarrhea), which, in the Investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
- •Any active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.
- •A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART.
- •Previous severe toxicity, which is clinically significant as judged by the Investigator, observed during the participant’s previous exposure to any of the medications to be used in combination in the study.
- •History of any of the following: drug-induced severe cutaneous adverse reaction (including, but not limited to Stevens-Johnson syndrome/toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms).
- •Participants with a known allergy or hypersensitivity to any of the drugs used as study intervention, or any of the excipients of the product, or a history of severe hypersensitivity reactions to other monoclonal antibodies.
- •Prior/Concomitant Therapy
- •Prior exposure, without adequate treatment washout period before randomization, defined in Table
- •Prior exposure to other HER2 targeting therapies, ADCs, or therapeutic anti-cancer vaccines.
- •Any concurrent anti-cancer treatment with the exception of receptor activator of nuclear factor kappa-B ligand inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases).
- •Concurrent use of hormonal therapy for non-cancer-related conditions (eg, HRT therapy) is allowed.
- •Herbal and natural remedies which are used with immune-modulating intent.
- •EGFR TKIs must not be given concomitantly and should be used with caution in the 90 days after the last dose of rilvegostomig.
- •Have had major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks prior to the first dose of study intervention or an anticipated need for major surgery during the study.
- •Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention.
- •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).
- •History of allogenic tissue/solid organ transplant Prior/Concurrent Clinical Study Experience
- 另有 4 项未显示
结局指标
主要结局
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS.
时间窗: To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS. | OS is defined as time from randomization until the date of death due to any cause. | The analysis will include all randomized participants, regardless of whether the participant withdraws from study interventions or receives another anti-cancer therapy. | The measure of interest is the HR of OS.
To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by OS.
时间窗: To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS. | OS is defined as time from randomization until the date of death due to any cause. | The analysis will include all randomized participants, regardless of whether the participant withdraws from study interventions or receives another anti-cancer therapy. | The measure of interest is the HR of OS.
次要结局
- To evaluate the efficacy of rilvegostomig in combination with trastuzumab and chemotherapy compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by PFS.(PFS per RECIST v1.1 as assessed by BICR as defined above.)
- To evaluate the efficacy of rilvegostomig in combination with trastuzumab and chemotherapy compared to trastuzumab, chemotherapy, and pembrolizumab, as measured by OS.(OS as defined above.)
- To further evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.(Investigator assessments, based on RECIST v1.1, to allow the calculation of:)
- To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd compared to rilvegostomig in combination with trastuzumab and chemotherapy(PFS per RECIST v1.1 as assessed by BICR and OS endpoints will be repeated for rilvegostomig in combination with fluoropyrimidine and T-DXd versus rilvegostomig in combination with trastuzumab and chemotherapy.)
- To assess the safety and tolerability of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.(Assessed among all treated participants by the occurrence of AEs, SAEs, AESIs, changes from baseline in laboratory parameters, vital signs, ECG, and ECHO/MUGA results)
- To assess the PK of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd in serum, 5-FU and capecitabine in plasma.(Descriptive analysis of serum concentration of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd, plasma concentration of 5-FU and capecitabine.)
- To investigate the immunogenicity of rilvegostomig and T-DXd.(Descriptive summary of presence of ADAs for rilvegostomig and T-DXd.)
- To evaluate the efficacy of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination(with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab, based on an increase in enteral feeding assistance and eating difficulties.)
- To assess the tolerability of rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab by assessment of the proportion of time on study intervention with high side-effect bother.(Proportion of time on study intervention with high side-effect bother relative to low side-effect burden as measured by the PGI-TT. The analysis will include all dosed participants, as treated, during the acute intervention phase defined as the first 24 weeks.)
- To assess participant-reported PF in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.(Participant-reported PF will be evaluated by describing the proportion of participants who maintain their baseline level of PF while on treatment, based on the PF subscale of the EORTC QLQ-C30 (in EORTC IL334 PF items).)
- To collect and assess blood and tumor(samples for biomarker analysis in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.)
- To assess participant-reported treatment tolerability in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with(trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.)
- To assess participant-reported cancer symptoms and functioning in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.(Participant-reported symptoms and functioning will be described as the proportion of participants experiencing each symptom and functional impact as measured by symptom subscales and items from EORTC QLQ-C30, and the EORTC QLQ-OG25 (C30 and OG25 subscales found in EORTC IL333, 334, and 335). Proportion of participants in each PGIS cancer symptom severity category.)
- To explore the impact of the study intervention and disease on participant-reported health status in participants treated with rilvegostomig in combination with fluoropyrimidine and T-DXd, and rilvegostomig in combination with trastuzumab and chemotherapy, compared to trastuzumab, chemotherapy, and pembrolizumab.(VAS mean score and change from baseline and 5-dimension scores as measured by the EQ-5D-5L.)
- To explore how multi-omics variations, including genetics, may affect clinical parameters, risk and prognosis of diseases and the response to medications as detailed in Appendix D Optional Genomics Initiative Sample. Note: The samples are taken from consented participants for DNA isolation, RNA, blood derivatives and storage. Results will not be reported in the CSR.(Exploratory endpoints are related to the data generated from multi-omics analysis, including genetics which may be part or all of the participant’s genetic information)
研究者
Sandeep AV
AstraZeneca Pharma India Ltd