Trastuzumab Deruxtecan(T-DXd) and Afatinib Combination in HER2-low Advanced Gastric Cancer

NCT06085755 | Recruiting Phase 1

• 1 other identifier: 2023-09-015
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Stomach Neoplasm

Outcome Measures

Primary Outcomes (2)

• Adverse events by NCI-CTCAE v5.0

  Safety and tolerability

  through study completion, an average of 30 months

• ORR (Objective response rate)

  modified Recist v1.1

  through study completion, an average of 30 months

Secondary Outcomes (3)

• Disease Control rate (CR+PR+SD)

  through study completion, an average of 30 months

• Overall survival (OS)

  through study completion, an average of 30 months

• Progression free survival (PFS)

  through study completion, an average of 30 months

Study Arms (1)

Trastuzumab deruxtecan + Afatinib

EXPERIMENTAL

The first part (PART A) will be in combination with T-DXd the starting dose of 20 mg afatinib MWF will be escalated to reach a maximum tolerated dose in patients with advanced gastric cancer patients with HER2-low, as defined by dose-limiting toxicity. The second part (PART B) will be expansion cohort, in which Afatinib will be taken in combination with T-DXd according to the recommended Phase 2 dose(RP2D) confirmed through Part A from cycle 1.

Drug: Trastuzumab deruxtecan; Drug: Afatinib

Interventions

Trastuzumab deruxtecan DRUG

Trastuzumab deruxtecan will be administered 6.4mg/kg or 5.4mg/kg iv infusion q 3weeks as one cycle.

Also known as: T-DXd

Trastuzumab deruxtecan + Afatinib

Afatinib DRUG

Afatinib will be administered orally 20mg \~40mg once a day or three times a week(Monday, Wednesday, Friday \[MWF\]) or twice weekly (Monday, Thursday \[MT\]) for 3weeks as one cycle.

Also known as: Giotrif

Trastuzumab deruxtecan + Afatinib

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Medical history of myocardial infarction within 6 months before registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV, Section 17.4), troponin levels consistent with myocardial infarction as defined according to American College of Cardiology (ACC) guidelines, unstable angina, or serious cardiac arrhythmia requiring treatment.
• History of (non-infectious) ILD / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Has a pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
• Has uncontrolled infection requiring IV injection of antibiotics, antivirals, or antifungals.
• Active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Subjects with past or resolved hepatitis B virus (HBV) infection who are anti-HBc positive (+) are eligible only if they are HBsAg negative (-). Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and who do not require treatment with steroids for at least three weeks 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 enrollment/randomization.
• Has clinically significant corneal disease in the opinion of the investigator.
• Prior treatment with an ADC which consists of an exatecan derivative that is a topoisomerase I inhibitor.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than chronic toxicities per the discretion of the investigator, eg, alopecia, peripheral neuropathy, proteinuria, controllable hypertension, and controllable diabetes) not yet resolved to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, Grade ≤1 or baseline. Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to \>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:
• Chemotherapy-induced neuropathy
• Fatigue
• Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies which may include:
• Hypothyroidism/hyperthyroidism
• Type 1 diabetes
• Hyperglycaemia

Sponsors & Collaborators

• Jeeyun Lee: lead

Study Sites (1)

Samsung Medical Center

Seoul, South Korea

RECRUITING

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

trastuzumab deruxtecan; Afatinib

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Jeeyun Lee, Ph, MD

  Samsung Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jeeyun Lee, Ph, MD

CONTACT

+82-10-9933-1779; jyun.lee@samsung.com

Jeeyun Lee, Ph, MD

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 10, 2023
• First Posted: October 17, 2023
• Study Start: September 30, 2024
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: December 15, 2025

Record last verified: 2025-12

Locations

KR (1)