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About
Gastric cancer (GC) is the fifth most commonly diagnosed cancer, with over one million cases diagnosed annually worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression in GC (seen in 4.4% to 53.4% of patients in different reports) is predictive biomarker of response to HER2-targeting therapies.
Trastuzumab in combination with cisplatin or oxaliplatin, and a fluoropyrimidine (capecitabine or 5-fluorouracil [5-FU]), is approved anti-HER2 therapy for first-line treatment of HER2-positive gastric or gastroesophageal junction (GEJ) cancer.
Rilvegostomig 750 mg Q3W was selected as recommended Phase 2 dose based on all available ARTEMIDE-01 clinical safety, efficacy, PK, RO data as well as modeling analysis. The dose of 750 mg Q3W is predicted to achieve intra-tumoral RO of ≥ 90% in the majority of participants across a broad spectrum of conditions.
This is a phase II study to initially assess the efficacy of perioperative Trastuzumab Deruxtecan (T-DXd) and Capecitabine combination with or without Rilvegostomig in patients with HER2 positive locally advanced unresectable GC and potentially by subsequent protocol amendment in HER2 low locally advanced GC. Other agents may also subsequently be assessed in this protocol, by protocol amendments
Full description
Neoadjuvant therapy will begin following completion of the screening period, and patients will undergo resection surgery 4 to 8 weeks after the last dose of neoadjuvant therapy. Surgery >8 weeks after the last dose of neoadjuvant therapy may be permitted in consultation with the Sponsor. Adjuvant therapy will begin 4 to 12weeks post-surgery (based on the patient's recovery period).
Tumor evaluation using modified RECIST 1.1 will be conducted at screening (within 28 days prior to first dose) and ≤28 days after last dose of neoadjuvant therapy and after surgery.
Every 12 weeks (±1 week) relative to the Adjuvant Baseline scan for first years and then every 24 weeks (±2 week) until progression/recurrence
The imaging modalities used for modified RECIST 1.1 assessment will be CT or MRI scans of chest, abdomen and pelvis. Modified RECIST 1.1 scans will be analyzed by the investigator on site.
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Inclusion criteria
Has adequate organ and bone marrow, liver and renal function within 14 days before treatment (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 C1D1.)
Hemoglobin ≥ 9.0 g/dL (≥8.0 g/dL in GC Indications)
Platelet count ≥100 x 109/L
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Total bilirubin ≤ 1.5 ULN if no liver metastases < 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
AST (SGOT)/ALT (SGPT) ≤ 3.0 x ULN (< 5×ULN in participants with liver metastases)
Serum albumin ≥ 2.5 g/dL
CrCL(Ccr) ≥30mL/min (> 45ml/min in Rilvegostomig) as determined by Cockcroft Gault (using actual body weight)
International normalized ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN
Female patients must be using a highly effective method of contraception (refer to the restrictions on P45) during the clinical trial and for 7 months after permanent discontinuation of the study drug. There must be evidence that patients are not breastfeeding, have a negative pregnancy test, or not of childbearing potential by meeting one of the following criteria at screening:
Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatment.
Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.
Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution.
More detailed information is provided in Appendix G (Definition and accepted contraception for women of childbearing age). Also female participants must not breastfeed and must not donate/retrieve ova from screening to 60days post last dose.
Exclusion criteria
Active primary immunodeficiency/active infectious diseases. Active or prior documented autoimmune or inflammatory disorders (including IBD [e.g. Crohn's disease, ulcerative colitis or diverticulitis], SLE, sarcoidosis syndrome, tuberculosis, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, at screening, that requires use of immunosuppressives, glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis within the past 2 years prior to the start of treatment. The following are exceptions to this criterion:
Subjects with vitiligo or alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment; patients with coeliac disease controlled by diet alone and patients without active disease in the last 5 years may be included after consultation with Chief Investigator.
HBsAg carrier without active viral infection and under entecavir prophylaxis will be allowed.
Participants with past or resolved HBV infection are eligible only if they meet all of the following criteria*:
Anti-HBc (+) (IgG or total Ig),
HBV DNA undetectable,
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. Such participants should be closely monitored for HBV reactivation. Consideration should be given to exclusion of all participants with HBV infection if comparator or combination study treatments are associated with a high risk of HBV infection reactivation are incompatible with anti-viral medications.
Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). Active or prior documented history of primary immunodeficiency at screening. And HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled:
undetectable viral RNA,
CD4+ count ≥350 cells/μL,
no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV if acceptable by local regulations or an institutional IRB/IEC.
Patient with any of the following cardiac criteria:
Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from electrogram (ECG) using Fridericia's correction
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block, second degree heart block, PR Interval >250 msec.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, uncorrectable chronic hypokalemia, congenital long QT syndrome, family history (first-degree relatives) of long QT syndrome or unexplained sudden death under 40 years of age or concomitant medication known to prolong the QT interval
Uncontrolled hypotension: systolic BP < 90 mmHg and/or diastolic BP 60 mmHg or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mmHg
Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
Symptomatic congestive heart failure (NYHA grade II-IV)
Known reduced LVEF < 55%
Prior or current cardiomyopathy of any etiology
Prior or current acute myocardial infarction within the past 6 months
Severe valvular heart disease
Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)
Stroke or transient ischaemic attack in prior to screening
Acute coronary syndrome within 6 months prior to starting treatment
Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product is excluded. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection).
Systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or equivalent.
Steroids as premedication for hypersensitivity/infusion reactions and Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. (Note: Participants should not receive live vaccine while receiving study intervention and up to 30 days after the last dose of study intervention.)
Primary purpose
Allocation
Interventional model
Masking
50 participants in 2 patient groups
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Central trial contact
Jeeyun Lee, Ph, MD
Data sourced from clinicaltrials.gov
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