T-DXd Combinations for Stomach Cancer

(DG-03 Trial)

Recruiting at 65 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

413 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called trastuzumab deruxtecan (T-DXd), either alone or combined with other drugs, for certain types of stomach and esophageal cancer. The goal is to determine if these combinations are safe, tolerable, and effective against the cancer. The trial seeks participants with advanced or metastatic stomach or esophageal cancer that shows specific markers (HER2-positive or HER2-low). Participants should have measurable disease and either have progressed after prior treatment or not received treatment for advanced cancer. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that trastuzumab deruxtecan (T-DXd) is generally well-tolerated in people with gastric cancer, but important safety considerations exist. Common side effects include nausea and low counts of white and red blood cells, with a risk of serious lung inflammation.

When combined with drugs like capecitabine, 5-FU, or pembrolizumab, side effects can increase, necessitating careful monitoring.

For T-DXd combined with durvalumab, studies suggest that over two-thirds of patients survived three years with this treatment. While promising, it is crucial to closely examine safety data, as combining drugs can sometimes increase risks.

In newer combinations with T-DXd, such as with rilvegostomig, safety information is still being gathered. These combinations are under testing to assess their tolerance.

Overall, T-DXd is approved for use in other cancers, providing some reassurance about its safety. However, each combination can have different effects, so ongoing trials are crucial to fully understand the safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Trastuzumab deruxtecan (T-DXd) for treating stomach cancer because it offers a novel approach by combining a targeted therapy with a chemotherapy agent. Unlike traditional chemotherapy that attacks all rapidly-dividing cells, T-DXd specifically targets cancer cells by linking trastuzumab, a monoclonal antibody, to deruxtecan, a potent chemotherapy drug. This targeted delivery can lead to fewer side effects and potentially more effective cancer cell destruction. Additionally, combining T-DXd with drugs like durvalumab or pembrolizumab, which are immune checkpoint inhibitors, might enhance the immune system's ability to fight cancer, offering a promising new direction beyond standard chemotherapy regimens.

What evidence suggests that this trial's treatments could be effective for stomach cancer?

This trial will evaluate various combinations of trastuzumab deruxtecan (T-DXd) for treating stomach cancer. Studies have shown that T-DXd is effective in treating certain stomach cancers, specifically HER2-positive gastric and gastroesophageal junction cancers. Earlier research demonstrated that T-DXd helped patients live longer compared to standard treatments. In this trial, some participants will receive T-DXd with 5-FU or capecitabine, both of which have shown strong cancer-fighting effects. Other participants will receive T-DXd combined with durvalumab or pembrolizumab, immunotherapy drugs that have slowed cancer growth in previous studies. While T-DXd alone or in combination appears promising, ongoing studies continue to assess the effectiveness of these combinations. ^{3 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced HER2-expressing stomach, GEJ, or esophageal cancer. Participants must have progressed after a trastuzumab regimen (Part 1) or be untreated for metastatic disease (Part 2), and have measurable disease. They need proper organ function and agree to contraception if of reproductive potential. Exclusions include active infections like HIV/HBV/HCV, uncontrolled illnesses, CNS metastases, lung issues like ILD/pneumonitis, and problematic fluid accumulation.

Inclusion Criteria

My cancer has spread and cannot be removed with surgery.

My heart, kidneys, and liver are functioning well.

For Part 1: Must have progression on or after at least one prior trastuzumab-containing regimen. For Part 2, Part 3, and Part 4: Must be previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/esophagus with HER2-positive (Part 2 and Part 3 [Arm 3A] and Part 4 [Arm 4A]) or HER2-low (Part 3 [Arm 3B] and Part 4 [Arm 4B]) status

Exclusion Criteria

I do not have a history of significant immune system diseases or known HIV, hepatitis B, or C.

I have or might have a lung condition not caused by infection.

I do not have any severe lung-related illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive T-DXd alone or in combination with chemotherapy and/or immunotherapy

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Cisplatin
• Durvalumab
• Fluorouracil (5-FU)
• Oxaliplatin
• Pembrolizumab
• Trastuzumab
• Trastuzumab deruxtecan

Trial Overview DESTINY-Gastric03 tests the safety and effectiveness of T-DXd alone or combined with chemotherapy/immunotherapy in advanced gastric cancers expressing HER2. The study aims to find tolerable doses that show anti-tumor activity as a potential new treatment option for patients who haven't received prior therapy for their metastatic disease.

How Is the Trial Designed?

Group I: Part 5 Main Cohort Experimental Treatment 4 Interventions

T-DXd, Volrustomig and 5-FU or capecitabine

Group II: Part 5 Cohort 2 Experimental Treatment 4 Interventions

T-DXd, Volrustomig and 5-FU or capecitabine

Group III: Arm 4B Experimental Treatment 4 Interventions

T-DXd, Rilvegostomig and 5-FU or capecitabine

Group IV: Arm 4A Experimental Treatment 4 Interventions

T-DXd, Rilvegostomig and 5-FU or capecitabine

Group V: Arm 3B Experimental Treatment 4 Interventions

T-DXd, Volrustomig and 5-FU or capecitabine

Group VI: Arm 3A Experimental Treatment 4 Interventions

T-DXd, Volrustomig and 5-FU or capecitabine

Group VII: Arm 2F Experimental Treatment 4 Interventions

T-DXd, pembrolizumab and 5-FU or capecitabine

Group VIII: Arm 2E Experimental Treatment 2 Interventions

T-DXd and pembrolizumab

Group IX: Arm 2D Experimental Treatment 4 Interventions

T-DXd, pembrolizumab and 5-FU or capecitabine

Group X: Arm 2C Experimental Treatment 4 Interventions

T-DXd, 5-FU or capecitabine

Group XI: Arm 2B Experimental Treatment 1 Intervention

T-DXd monotherapy

Group XII: Arm 1E(b) Experimental Treatment 3 Interventions

T-DXd, capecitabine, and durvalumab

Group XIII: Arm 1E(a) Experimental Treatment 3 Interventions

T-DXd, 5-FU, and durvalumab

Group XIV: Arm 1D(b) Experimental Treatment 3 Interventions

T-DXd, capecitabine, and oxaliplatin

Group XV: Arm 1C Experimental Treatment 2 Interventions

T-DXd and durvalumab

Group XVI: Arm 1B Experimental Treatment 2 Interventions

T-DXd and capecitabine

Group XVII: Arm 1A Experimental Treatment 2 Interventions

T-DXd and 5-fluorouracil (5-FU)

Group XVIII: Arm 2A Active Control 5 Interventions

Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin

Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo

Collaborator

Trials

3

Recruited

1,900+

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Published Research Related to This Trial

Adjuvant chemotherapy with the TEX regimen (Docetaxel, Oxaliplatin, and Capecitabine) after surgery for gastric cancer shows promising efficacy, with a 3-year relapse-free survival rate of 58% and a median overall survival of 71 months based on a study of 58 patients.

Despite its effectiveness, the TEX regimen has significant tolerability issues, with 40% of patients requiring dose reductions due to toxicity, and only 52% completing all planned six cycles of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel, Oxaliplatin and Capecitabine (TEX) triplet regimen as adjuvant chemotherapy in resected gastric adenocarcinoma. Thumaty, DB., Chacko, RT., John, AO., et al.[2022]

A lower dose of docetaxel (50 mg/m2) combined with 5-FU and cisplatin showed a 40% response rate in patients with metastatic gastric cancer, indicating its efficacy in treating this condition.

While the treatment was associated with significant toxicities, including 68% of patients experiencing grade 3/4 neutropenia, the overall toxicity profile was considered tolerable, suggesting that this lower dose may reduce severe side effects compared to higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of low-dose docetaxel/fluorouracil/cisplatin in metastatic gastric carcinoma. Park, SR., Chun, JH., Kim, YW., et al.[2019]

In a phase III trial involving 169 patients with radically resected gastric cancer, a combination therapy of fluorouracil, irinotecan, docetaxel, and cisplatin (arm A) was compared to mitomycin C monotherapy (arm B) in an adjuvant setting, showing that the combination therapy was well tolerated and feasible.

The main side effects observed were neutropenia (35%) and diarrhea (11%) in the combination therapy group, indicating manageable toxicity levels, while 76% of patients completed the treatment in arm A compared to 70% in arm B.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial. Di Bartolomeo, M., Buzzoni, R., Mariani, L., et al.[2018]

In a study of 44 previously untreated patients with advanced gastric cancer, the combination of cetuximab and XELOX chemotherapy resulted in a significant overall response rate of 52.3%, with median progression-free survival of 6.5 months and overall survival of 11.8 months.

The treatment was generally safe, with most side effects being mild to moderate (grade 1 or 2), such as anemia and asthenia, and serious hematologic toxicities were rare, indicating that cetuximab combined with XELOX is a viable first-line option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Kim, C., Lee, JL., Ryu, MH., et al.[2021]

The low-dose docetaxel and De Gramont regimen demonstrated a 56.6% overall response rate in 120 patients with metastatic gastric cancer, indicating significant efficacy while reducing toxicity compared to traditional high-dose regimens.

The treatment resulted in a median overall survival of 15 months and a median time to progression of 7 months, with manageable hematological toxicity, primarily leucopenia occurring in 20% of patients at grade 3/4 intensity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose docetaxel/cisplatin - leucovorin and 46 hour infusional fluorouracil in metastatic gastric carcinoma. Alici, S., Buyukberber, S., Alkis, N., et al.[2019]

In a feasibility study involving 21 patients with advanced gastric cancer, a triplet chemotherapy regimen of paclitaxel, cisplatin, and S-1 showed a promising overall response rate of 67%, indicating significant antitumor activity.

The treatment was well-tolerated, with most toxicities being manageable; serious side effects like grade 3 leucopenia and neutropenia occurred in only a minority of patients, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility study of triplet combination chemotherapy of paclitaxel, cisplatin and S-1 for advanced gastric cancer. Fujitani, K., Hasegawa, H., Hirao, M., et al.[2015]

Chemotherapy significantly increases survival and improves quality of life in patients with advanced gastric carcinoma compared to supportive measures alone.

Current standard treatments include infusional 5-FU combined with cisplatin or ECF, while newer third-generation combinations with taxanes and irinotecan show similar effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Patient with stomach cancer with metastases. What is the value of chemotherapy?]. Wilke, H., Stahl, M., Vanhoefer, U.[2013]

In a phase II study involving 58 patients with advanced gastric cancer, the combination of docetaxel, fluorouracil, and leucovorin (TFL) showed a moderate overall response rate of 26%, with 4 complete and 11 partial responses observed.

The TFL regimen was found to have manageable toxicity, with neutropenia being the most common severe side effect (30% of patients), and no toxic deaths reported, indicating a favorable safety profile for this chemotherapy combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination docetaxel (Taxotere), fluorouracil, and leucovorin (TFL), as first-line chemotherapy in advanced gastric cancer: a Hellenic Cooperative Oncology Group phase II study. Papakostas, P., Tsavdaridis, D., Kosmidis, P., et al.[2022]

The GASTFOX study is a phase III trial designed to compare the efficacy of the TFOX regimen (FOLFOX plus docetaxel at 50 mg/m2) against FOLFOX alone in treating advanced gastric cancer, with an expected improvement in progression-free survival (PFS) of 2 months for TFOX.

The trial aims to enroll 506 patients and will assess not only PFS but also overall survival, response rates, safety, and quality of life, addressing the need for effective treatments with manageable toxicity in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized trial comparing 5-fluorouracil and oxaliplatin with or without docetaxel in first-line advanced gastric cancer chemotherapy (GASTFOX study). Zaanan, A., Samalin, E., Aparicio, T., et al.[2022]

Trastuzumab deruxtecan (T-DXd) has shown superior efficacy compared to capecitabine-based chemotherapy and T-DM1 in patients with metastatic HER2-positive breast cancer, based on the latest phase III data from the DESTINY-Breast02 and DESTINY-Breast03 trials.

T-DXd may also be effective as a neoadjuvant treatment for HER2-low breast cancer, suggesting its potential for broader applications in HER2-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-DXd Keeps Shining in Breast Cancer. [2023]

The ECX combination chemotherapy (epirubicin, cisplatin, and capecitabine) demonstrated a high overall response rate of 59% in patients with metastatic or advanced gastric cancer, with a median survival of 9.6 months based on a study of 54 patients.

While the treatment was effective, it did have some side effects, with 31% of patients experiencing significant neutropenia, but most non-hematological toxicities were mild and reversible, indicating a tolerable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of epirubicin, cisplatin and capecitabine combination chemotherapy in patients with metastatic or advanced gastric cancer. Cho, EK., Lee, WK., Im, SA., et al.[2015]

The study evaluated the safety of a triple combination therapy of Paclitaxel (PTX), Cisplatin (CDDP), and 5-fluorouracil (5-FU) in 12 patients with unresectable or recurrent gastric cancer, finding it to be a safe treatment option despite some cases of hematological and non-hematological toxicities.

While there were instances of grade 3 or higher toxicities, including leukopenia and neutropenia, no infections occurred, and the maximum tolerated dose of 5-FU was determined to be 400 mg, indicating that the combination therapy can be administered with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of paclitaxel, cisplatin and 5-fluorouracil combination chemotherapy for unresectable / recurrent gastric cancer. Kato, J., Nagahara, A., Iijima, K., et al.[2015]

Citations

1. daiichisankyo.us daiichisankyo.us/press-releases/-/article/destiny-gastric05-phase-3-trial-of-enhertu-initiated-in-patients-with-previously-untreated-her2-positive-advanced-gastric-cancer

DESTINY-Gastric05 Phase 3 Trial of ENHERTU® Initiated ... DESTINY-Gastric05 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in combination with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11980183/

the multicentre, phase II randomized TRINITY trial - PMC Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of ...

3. datasourcebydaiichisankyo.com datasourcebydaiichisankyo.com/documents/20833/21697/ASCO%20GI%202025_T-DXd_Janjigian_Poster_FINAL.pdf

Updated results from the trastuzumab deruxtecan 5.4 mg/ ... – Here, we report updated efficacy and safety results (data cutoff [DCO] August 19, 2024) for the T-DXd 5.4 mg/kg combination with fluoropyrimidine and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04379596

NCT04379596 | Ph1b/2 Study of the Safety and Efficacy ... DESTINY-Gastric03 will investigate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of trastuzumab deruxtecan ...

5. cda-amc.ca cda-amc.ca/sites/default/files/DRR/2025/PC0367-Enhertu_Combined_Review.pdf

Trastuzumab Deruxtecan (Enhertu) ... gastric or GEJ cancer, DESTINY-. Gastric02, a single-arm trial assessing the efficacy and safety of trastuzumab deruxtecan as a second-line.

6. daiichisankyo.com daiichisankyo.com/files/news/pressrelease/pdf/202503/20250331_E2.pdf

DESTINY-Gastric05 Phase 3 Trial of ENHERTU® Initiated ... DESTINY-Gastric05 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in ...

7. enhertuhcp.com enhertuhcp.com/en/breast/safety

Safety Data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) The benefit-risk profile of ENHERTU was established in DESTINY-Breast031. The majority of adverse reactions were Grade 1 or 21,2.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/761139s011lbl.pdf

Trastuzumab deruxtecan - accessdata.fda.gov The most common side effects of ENHERTU, when used in people with stomach cancer, include: • low red blood cell counts. • low white blood cell counts. • low ...