Ph 1/2 Study of Trastuzumab Deruxtecan(T-DXd) and Afatinib Combination in HER2-low Advanced Gastric Cancer(VIKTORY-2)
Despite recent advances, the prognosis of patients with advanced gastric cancer remains poor. At present, regimens that combine a platinum and fluorouracil agent either alone or in combination with a third drug such as epirubicin or taxane constitute the most effective treatment option in the first-line metastatic setting, resulting in a median OS of approximately 10 months. In the second-line setting, ramucirumab (a vascular endothelial growth factor receptor 2 antagonist) was recently approved by the United States Food and Drug Administration, and has demonstrated modest activity in patients with advanced gastric or GEJ adenocarcinoma who progressed after first-line platinum- or fluoropyrimidine-containing chemotherapy. Median OS was 5.2 months in the ramucirumab group versus 3.8 months in the placebo group. At the updated DCO of 03 June 2020 in the DS8201-A-J202 (DESTINY-Gastric01) study in HER2-positive GC or GEJ adenocarcinoma subjects assigned to T-DXd 6.4 mg/kg, T-DXd further demonstrated clinically meaningful efficacy. The median OS was 12.5 months for the T-DXd group and 8.9 months for the physician's choice group (HR = 0.60, 95% CI: 0.42, 0.86). In a prespecified subgroup analysis, the percentages of patients with an objective response were analyzed in HER2-low group. The response rate in HER2 2+ was 29% (8 of 28) with T-DXd monotherapy. Refer to the figure below for the response rate in HER2-low group in previous DESTINY trials. This is a two part, phase I/Ⅱ, open-label, single center study of afatinib in combination with T-DXd, in 2L/3L gastric cancer patients with HER2-low. The study design allows an investigation of combination dose of afatinib with T-DXd, with intensive safety monitoring to ensure the safety of the patients.
• Provision of fully informed consent prior to any study specific procedures.
• Patients must be ≥ 19 years of age
• Has a pathologically documented advanced or metastatic adenocarcinoma of gastric or gastroesophageal junction with at least one measurable lesion according to the modified RECIST 1.1 are eligible
• HER2-low (HER2 1+, HER2 2+ (SISH negative))
• Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
• ECOG performance status 0-1 with no deterioration between screening and the first dose of study treatment.
• Patients must have a life expectancy ≥ 3 months from proposed first dose date.
• Patients must have had a washout period of 2 weeks for any prior therapy prior to the start of study drug. The following intervals between the end of the prior treatment and first dose of study drug must be observed:
‣ Major surgery ≥ 4 weeks
⁃ Radiation Therapy including palliative stereotactic radiation therapy to chest ≥ 4 weeks
⁃ Palliative stereotactic radiation therapy to other anatomic areas including whole brain radiation ≥ 2 weeks
⁃ Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\], retinoid therapy, hormonal therapy ≥ 3 weeks
⁃ Antibody based anti-cancer therapy ≥ 4 weeks
⁃ Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer
⁃ Nitrosoureas or mitomycin C ≥ 6 weeks
⁃ TKIs approved for treatment of NSCLC ≥1 week (baseline CT scan must be completed after discontinuation of TKI
⁃ Chloroquine/Hydroxychloroquine ≥ 14 days
⁃ Cell-free and CART, peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion ≥ 2 weeks prior to screening assessment
• Patients must have acceptable bone marrow, liver and renal function measured within 28 days prior to administration of study treatment as defined below:
‣ Hemoglobin ≥8.0 g/dL (Red blood cell transfusion is not allowed within 1 week prior to the day)
⁃ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (G-CSF administration is not allowed within 2 weeks prior to the day)
⁃ Platelet count ≥100 x 109/L (Platelet transfusion is not allowed within 1 week prior to the day)
⁃ Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or \< 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
⁃ AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN
⁃ Serum creatinine ≤1.5 x institutional ULN
⁃ CrCl 30≥mL/min as determined by Cockcroft Gault (using actual body weight)
⁃ Serum albumin ≥ 2.5 g/dL
⁃ International normalised 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 P37) 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 sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.
∙ Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), lutenizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution More detailed information is provided in Appendix F (Definition and accepted contraception for women of childbearing age).
⁃ Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of randomisation/enrolment, throughout the study and for 4 months after the last dose of IMP. Preservation of sperm should be considered prior to enrollment in this study.
⁃ Mandatory biopsy during the screening window prior to dosing and at progression