Phase 3 Randomized Study of Trastuzumab Deruxtecan vs. Ramucirumab and Paclitaxel in HER2-Positive Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
- Trial ID
- 2023-507963-20-00
- Protocol
- DS8201-A-U306
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **overall survival (OS)** in subjects with **HER2-positive** gastric cancer (GC) and gastroesophageal junction (GEJ) adenocarcinoma who are treated with Trastuzumab Deruxtecan (TDXd) versus Ramucirumab plus Paclitaxel (Ram + PTX). This is clinically relevant as it aims to determine the efficacy of TDXd in improving survival outcomes in patients who have progressed on or after a trastuzumab-containing regimen, which is a critical factor in the management of metastatic gastric adenocarcinoma.
Secondary objectives include:
- Comparing progression-free survival (PFS) in HER2-positive GC and GEJ adenocarcinoma subjects treated with TDXd or Ram + PTX.
- Comparing the clinical efficacy of TDXd and Ram + PTX by objective response rate (ORR) based on investigator assessment.
- Comparing the clinical efficacy of TDXd and Ram + PTX by duration of response (DoR).
- Comparing the clinical efficacy of TDXd and Ram + PTX by disease control rate (DCR).
- Evaluating the safety of TDXd compared to Ram + PTX.
- Evaluating the pharmacokinetics (PK) of TDXd.
- Evaluating the immunogenicity of TDXd.
Participants
The clinical trial involves a total of **277 participants** diagnosed with **metastatic gastric adenocarcinoma**. The study population includes both male and female adults, as defined by local regulations, who are capable of providing informed consent. Participants are required to have a pathologically documented gastric or gastroesophageal junction adenocarcinoma that has been previously treated in the metastatic setting. The age range of the participants falls within categories 3 and 4, which typically correspond to adult age groups. The trial population was selected based on specific inclusion criteria, including progression on or after first-line therapy with a trastuzumab or approved trastuzumab biosimilar-containing regimen. Participants must have a confirmed HER2-positive status, as determined by immunohistochemistry (IHC) and in situ hybridization (ISH). The study also considers lifestyle factors such as the ability to comply with scheduled visits and study procedures. Both male and female subjects of reproductive potential are required to use highly effective contraception during and after the study period. The trial includes a vulnerable population, ensuring that all participants meet the necessary health and laboratory parameters to safely participate in the study.
Plans and Procedures
The clinical trial is a Phase 3, multicenter, two-arm randomized, open-label study designed to evaluate the efficacy of **trastuzumab deruxtecan** in subjects with HER2-positive metastatic and/or unresectable gastric or gastroesophageal junction adenocarcinoma who have progressed on or after a trastuzumab-containing regimen. The primary objective is to compare overall survival in these subjects when treated with trastuzumab deruxtecan versus a combination of **ramucirumab** and **paclitaxel**. The trial is expected to run from November 25, 2021, to October 27, 2025, with participants involved for a maximum treatment period of 8 cycles, each cycle lasting 21 days.
The trial design includes an initial screening visit to confirm eligibility, where participants must provide informed consent and meet specific inclusion criteria, such as having a documented diagnosis of HER2-positive gastric or gastroesophageal junction adenocarcinoma and having progressed after prior treatment. Following the screening, eligible participants will be randomized into one of the two treatment arms. The study involves regular follow-up visits to monitor the participants' health, assess the efficacy of the treatment, and record any adverse events. These visits will include physical examinations, laboratory tests, and imaging studies as required by the protocol.
The end-of-study visit will occur after the completion of the treatment cycles or upon early termination. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The primary endpoint of the study is overall survival, while secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate, and safety parameters such as treatment-emergent adverse events and pharmacokinetic profile. The study also aims to assess the immunogenicity of the treatment by evaluating the incidence of anti-drug antibodies and neutralizing antibodies.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Trastuzumab deruxtecan**, marketed under the name DS-8201a, is the primary experimental medication. It is provided as a **solution for infusion** and is administered intravenously. The dosage is set at a maximum of 6.4 mg/kg, with a treatment period extending up to 8 weeks. This medication is developed by Daiichi Sankyo, Inc. and is classified as a protein-based therapeutic agent.
**Ramucirumab**, marketed as Cyramza, is used as a comparator treatment in the study. It is also a **solution for infusion** and is administered intravenously. The dosage for ramucirumab is 8 mg/kg, with a maximum treatment period of 8 weeks. This medication is produced by Eli Lilly Nederland B.V. and is similarly classified as a protein-based therapeutic agent. The study utilizes multiple batches of Cyramza, each with the same pharmaceutical form and administration route.
**Paclitaxel** is another comparator treatment used in the trial. It is provided as a concentrate for solution for infusion and is administered intravenously. The dosage is set at 80 mg/m², with a treatment period of up to 8 weeks. Paclitaxel is classified as a chemical-based therapeutic agent. This medication serves as a standard-of-care therapy in the study, complementing the experimental and other comparator treatments.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured to determine the length of time from randomization until death from any cause. Secondary endpoints include **Progression-Free Survival (PFS)**, **Objective Response Rate (ORR)**, **Duration of Response (DoR)**, and **Disease Control Rate (DCR)**. These endpoints will provide additional insights into the treatment's effectiveness in controlling the disease and improving patient outcomes.
The trial will also evaluate safety parameters, including the incidence of Treatment-Emergent Adverse Events (TEAEs), and will assess the pharmacokinetic (PK) profile and immunogenicity, specifically the incidence of Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (NAb). These assessments will be conducted throughout the study to ensure a comprehensive evaluation of the treatment's efficacy and safety.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Sign and date the Tissue Screening and Main ICFs, prior to the start of any study-specific qualification procedures.
- Adults (according to local regulation) and able to provide informed consent for study participation.
- Pathologically documented gastric and GEJ adenocarcinoma that has been previously treated in the metastatic setting (unresectable, locally advanced, or metastatic disease).
- Progression on or after first-line therapy with a trastuzumab or approved trastuzumab biosimilar-containing regimen. Note: Prior neoadjuvant or adjuvant therapy with a trastuzumab containing regimen can be counted as a line of therapy if the subject progressed on or within 6 months of completing therapy neoadjuvant or adjuvant therapy. Prior neoadjuvant or adjuvant therapy that does not of the progression status of the subject
- Is willing and able to provide an adequate tumor sample for tissue screening to confirm HER2 status by local or central laboratory. See Section 8.1.2.
- Locally or centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) as classified by ASCO-CAP on a tumor biopsy obtained after progression on or after a first-line trastuzumab or approved trastuzumab biosimilar-containing regimen.
- Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening.
- Adequate laboratory parameters as evidenced by all blood counts (refer protocol for details) within 14 days of randomization.
- Has adequate treatment washout period before randomization/enrollment, as described in the protocol.
- LVEF ≥50% within 28 days before randomization per echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
- Recovered from the effects of any prior surgery or radiotherapy.
- Males and females of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for female subjects and 4 months for male subjects after the last dose of study drug. For subjects receiving Ram + PTX, sites should follow the locally approved label. - If the subject is a female of childbearing potential, she must have a negative serum or urine pregnancy test at Screening before the first dose of study drug and must be willing to use highly effective birth control, as detailed in Section 10.3.4 , upon randomization, during the Treatment Period, and for 7 months following the last dose of study drug. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). - If male, the subject must be surgically sterile or willing to use highly effective birth control upon enrollment, during the treatment period, and for 4 months following the last dose of study drug.
- Male subjects must not freeze or donate sperm starting from randomization and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to randomization/enrollment in this study. For Ram + PTX, sites should follow local label or institutional guidelines.
- Female subjects must not donate, or retrieve for their own use, ova from the time of randomization and throughout the study Treatment Period, and for at least 7 months after the final study drug administration. Preservation of ova may be considered prior to randomization in this study. For Ram + PTX, sites should follow local label or institutional guidelines.
- Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
Exclusion Criteria
- Use of anticancer therapy after trastuzumab-containing treatment.
- Medical history of myocardial infarction (MI) within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation before enrollment to rule out MI.
- Has a QT interval corrected by Fridericia’s formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate 12-lead electrocardiogram.
- Criterion removed.
- Has a history of (non-infectious) interstitial lung disease (ILD/pneumonitis) that required steroids, 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 disease (eg, pulmonary emboli within the previous 3 months of the study randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.).
- Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented (or a suspicion of) pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the electronic case report form for patients who are included in the study.
- Prior complete pneumonectomy.
- 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. a. Subjects with clinically inactive brain metastases may be included in the study. b. Subjects with brain metastases who were treated and are no longer symptomatic, and subjects 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 (WBRT) and randomization/study enrollment.
- Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.
- History of severe hypersensitivity reactions to either the T-DXd or inactive ingredients in T-DXd.
- History of severe hypersensitivity reactions to other monoclonal antibodies, including ramucirumab or any of its excipients.
- Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy.
- Current uncontrolled infection requiring antibiotics, antivirals, or antifungals or an unexplained fever >38.0°C during Screening visits or on the first scheduled day of dosing (at the discretion of the investigator, subjects with tumor fever may be enrolled), which in the investigator’s opinion might compromise the subject’s participation in the study or affect the study outcome
- Substance abuse or any other medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results
- Social, familial, or geographical factors that would interfere with study participation or follow-up
- Known human immunodeficiency virus (HIV) infection or 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 infection are eligible if hepatitis B virus surface antigen(-) and anti- hepatitis B core(+). Subjects positive for hepatitis C virus (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 (IRB)/independent ethics committee (IEC).
- Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Note: Subjects may be enrolled with chronic, stable, Grade 2 toxicities (defined as not worsening to >Grade 2 for at least 3 months prior to randomization and managed with standard-of-care treatment) that the investigator deems related to previous anticancer therapy, such as the following: · Chemotherapy-induced neuropathy · Fatigue · Residual toxicities from prior immuno-oncology treatment: Grade 1 or Grade 2 endocrinopathies, which may include the following: - Hypothyroidism/hyperthyroidism - Type I diabetes - Hyperglycemia - Adrenal insufficiency - Adrenalitis - Skin hypopigmentation (vitiligo)
- Prior treatment with an antibody-drug conjugate (ADC) consisting of an exatecan derivative that is a topoisomerase I inhibitor
- Pregnant, breastfeeding, or planning to become pregnant. In addition, for subjects enrolled in the study, breastfeeding should not commence until at least 7 months after the last dose of study drug.
- Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of Screening or otherwise considered inappropriate for the study by the investigator
- Clinically significant gastrointestinal disorder (eg, including hepatic disorders, bleeding, inflammation, occlusion, ileus, diarrhea Grade >1, jaundice, intestinal paralysis, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or partial bowel obstruction) in the opinion of investigator
- Has history of receiving live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 25 Nov 2021 | 20 |
 France | Not Recruiting | 25 Nov 2021 | 57 |
 Germany | Not Recruiting | 25 Nov 2021 | 4 |
 Hungary | Not Recruiting | 25 Nov 2021 | 1 |
 Ireland | Not Recruiting | 25 Nov 2021 | 6 |
 Italy | Not Recruiting | 25 Nov 2021 | 55 |
 Poland | Not Recruiting | 25 Nov 2021 | 9 |
 Portugal | Not Recruiting | 25 Nov 2021 | 12 |
 Romania | Not Recruiting | 25 Nov 2021 | 8 |
 Spain | Not Recruiting | 25 Nov 2021 | 41 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cyramza 10 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 8 | 8 | PRD1961195 |
PACLITAXEL | Comparator | — | INTRAVENOUS USE | 80 | 8 | SUB09583MIG |
Cyramza 10 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 8 | 8 | PRD1970752 |
DS-8201a | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 6.4 | 8 | PRD5308994 |
Cyramza 10 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 8 | 8 | PRD1970734 |