Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)

Gastric Cancer Clinical Trial

— DG-03  

Official title:

A Phase 1b/2 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of Trastuzumab Deruxtecan (T-DXd) Monotherapy and Combinations in Adult Participants With HER2-expressing Gastric Cancer (DESTINY-Gastric-03)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04379596
• Other study ID #: D967LC00001
• Secondary ID: 2019-004483-22
• Status: Recruiting
• Phase: Phase 2
• Start date: June 3, 2020
• Est. completion date: July 30, 2026

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

DESTINY-Gastric03 will investigate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of trastuzumab deruxtecan (T-DXd) alone or in combination with chemotherapy and/or immunotherapy in HER2-expressing advanced/metastatic gastric/gastroesophageal junction (GEJ) and esophageal adenocarcinoma patients.

Study hypotheses: Combination of T-DXd with cytotoxic chemotherapy and/or immunotherapy administered to subjects at the recommended phase 2 dose will show manageable safety and tolerability and preliminary anti-tumor efficacy so as to permit further clinical testing. T-DXd in combination with cytotoxic chemotherapy or immune checkpoint inhibitor administered to HER2-expressing gastric, GEJ and esophageal cancer patients who have not received prior treatment for advanced/metastatic disease will show preliminary evidence of anti-tumour activity and the potential to become a therapeutic option for this patient population.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 413
• Est. completion date: July 30, 2026
• Est. primary completion date: July 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion criteria:

1. Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations

2. Disease Characteristics:

1. Locally advanced, unresectable, or metastatic disease based on most recent imaging

2. For Part 1, 2, 3a, 4a pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results

3. For Part 3b and 4b, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results

3. For Part 1, progression on or after at least one prior trastuzumabcontaining regimen For Part 2, Part 3 and Part 4, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with 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

4. Has measurable target disease assessed by the Investigator based on RECIST version 1.1

5. Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function

6. If of reproductive potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study.

Exclusion criteria:

1. History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C infection.

2. Uncontrolled intercurrent illness

3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.

4. Lung-specific intercurrent clinically significant severe illnesses.

5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.

6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).

7. Has spinal cord compression or clinically active central nervous system metastases.

Related Conditions & MeSH terms

• Gastric Cancer
• Stomach Neoplasms

Intervention

Drug:
• Fluorouracil (5-FU)
5-FU: administered as an IV infusion
• Capecitabine
Capecitabine: administered orally

Biological:
• Durvalumab
Durvalumab: administered as an IV infusion

Drug:
• Oxaliplatin
Oxaliplatin: administered as an IV infusion

Biological:
• Trastuzumab
Trastuzumab: administered as an IV infusion

Drug:
• Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
• Cisplatin
Cisplatin: administered as an IV infusion

Biological:
• Pembrolizumab
Pembrolizumab: administered as an IV infusion
• Volrustomig
Volrustomig: administered as an IV infusion
• Rilvegostomig
Rilvegostomig: administered as an IV infusion

Locations

Country	Name	City	State
Brazil	Research Site	Florianopolis
Brazil	Research Site	Londrina
Brazil	Research Site	Natal
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Ribeirão Preto
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	Santa Maria
Brazil	Research Site	São Jose do Rio Preto
Brazil	Research Site	Sao Paulo
Brazil	Research Site	São Paulo
Brazil	Research Site	São Paulo
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
China	Research Site	Chengdu
China	Research Site	Guangzhou
China	Research Site	Guiyang
China	Research Site	Hangzhou
China	Research Site	Hefei
China	Research Site	Hefei
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Urumqi
China	Research Site	Wuhan
China	Research Site	Xiamen
China	Research Site	Zhengzhou
Germany	Research Site	Frankfurt
Germany	Research Site	Frankfurt
Germany	Research Site	Hamburg
Germany	Research Site	Leipzig
Germany	Research Site	Mannheim
Germany	Research Site	München
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Roma
Italy	Research Site	Verona
Japan	Research Site	Chuo-ku
Japan	Research Site	Kashiwa
Japan	Research Site	Kita-gun
Japan	Research Site	Ota-shi
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Utrecht
Poland	Research Site	Gdansk
Poland	Research Site	Konin
Poland	Research Site	Koszalin
Poland	Research Site	Kraków
Poland	Research Site	Lublin
Poland	Research Site	Opole
Poland	Research Site	Tomaszów Mazowiecki
Poland	Research Site	Warszawa
Russian Federation	Research Site	Kostroma
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Sankt-Peterburg
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Santander
Spain	Research Site	Sevilla
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taoyuan
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Dundee
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Sutton
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Durham	North Carolina
United States	Research Site	Fairfax	Virginia
United States	Research Site	Houston	Texas
United States	Research Site	New York	New York
United States	Research Site	Santa Monica	California
United States	Research Site	Westwood	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  China,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0	Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0	Safety will be assessed up to the follow-up period, approximately 24 months.
Primary	Part 1: Ocurrence of dose-limiting toxicities (DLTs)	Occurrence of dose limiting toxicities	Safety will be assessed up to the follow-up period, approximately 24 months.
Primary	Part 1: Changes from baseline in laboratory parameters	Changes in laboratory parameters (every in appropriate units) compared to baseline results.	Safety will be assessed up to the follow-up period, approximately 24 months.
Primary	Part 1: Changes from baseline in vital signs	Changes in vital signs results compared to baseline results.	Safety will be assessed up to the follow-up period, approximately 24 months.
Primary	Part 1: Changes from baseline in electrocardiogram (ECG) results	Changes in ECG results compared to baseline results.	Safety will be assessed up to the follow-up period, approximately 24 months.
Primary	Part 2, Part 3 and Part 4: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR)	Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.	(Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months
Secondary	Part 1: Objective Response Rate (ORR)	Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.	Efficacy will be assessed at an average of approximately 12 months
Secondary	Part 2, Part 3 and Part 4: Occurrence of adverse events (AEs) and serious adverse events (SAEs)	Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0	Safety will be assessed up to follow-up period, approximately 24 months
Secondary	Part 2, Part 3 and Part 4: Changes from baseline in laboratory parameters	Changes in laboratory parameters (every in appropriate units) compared to baseline results.	Safety will be assessed up to follow-up period, approximately 24 months
Secondary	Part 2, Part 3 and Part 4: Changes from baseline in vital signs	Changes in vital signs results compared to baseline results.	Safety will be assessed up to follow-up period, approximately 24 months
Secondary	Part 2, Part 3 and Part 4: Changes from baseline in body weight	Changes in body weight in kilograms compared to baseline results.	Safety will be assessed up to follow-up period, approximately 24 months
Secondary	Part 2, Part 3 and Part 4: Changes from baseline in electrocardiogram (ECG) results	Changes in ECG results compared to baseline results.	Safety will be assessed up to follow-up period, approximately 24 months
Secondary	Duration of Response (DoR)	DOR is defined as the time from the date of first documented response until the date of documented progression or death	Until progression or death, efficacy (DoR) will be assessed up to approximately 24 months
Secondary	Disease Control Rate (DCR)	DCR is the percentage of subjects who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD)	Efficacy will be assessed at an average of approximately 12 months
Secondary	Progression Free Survival (PFS)	PFS is the time from date of first dose until the date of objective disease progression or death	Until progression or death, efficacy (PFS) will be assessed up to approximately 24 months
Secondary	Overall survival (OS)	OS is the time from date of first dose until death due to any cause	Until death, efficacy (OS) will be assessed up to approximately 24 months
Secondary	Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms	Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for each dose level for T-DXd, total anti-HER2 antibody, MAAA-1181a	While on study drug up to study completion, approximately 24 months
Secondary	Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab	Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab.	While on study drug up to study completion, approximately 24 months
Secondary	Presence of ADAs for T-DXD, durvalumab, volrustomig and rilvegostomig (in study arms including T-DXd and durvalumab, and T-DXd and volrustomig, and T-DXd and rilvegostomig respectively)	Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd and durvalumab.	While on study drug up to study completion, approximately 24 months
Secondary	Serum concentrations of volrustomig and rilvegostomig in study arms including T-DXd in combination with volrustomig and T-DXd in combination with rilvegostomig	Individual participant data and descriptive statistics will be provided for data at each time point for rilvegostomig and volrustomig	While on study drug up to study completion, approximately 24 months
Secondary	Comparison of ORR	Comparison of objective response rate between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results	While on study drug up to study completion, approximately 24 months
Secondary	Comparison of DCR	Comparison of disease control rate between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results	While on study drug up to study completion, approximately 24 months
Secondary	Comparison of DoR	Comparison of duration of response between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results	While on study drug up to study completion, approximately 24 months
Secondary	Comparison of PFS	Comparison of progression-free survival between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results	While on study drug up to study completion, approximately 24 months
Secondary	Comparison of OS	Comparison of overall survival between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results	While on study drug up to study completion, approximately 24 months