Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03) (DG-03)

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ClinicalTrials.gov Identifier: NCT04379596

Recruitment Status : Recruiting

First Posted : May 7, 2020

Last Update Posted : April 26, 2024

See Contacts and Locations

View this study on the modernized ClinicalTrials.gov

Sponsor:

Collaborator:

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

Information provided by (Responsible Party):

AstraZeneca

Tracking Information

First Submitted Date ^ICMJE

May 5, 2020

First Posted Date ^ICMJE

May 7, 2020

Last Update Posted Date

April 26, 2024

Actual Study Start Date ^ICMJE

June 3, 2020

Estimated Primary Completion Date

July 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0 [ Time Frame: Safety will be assessed up to the follow-up period, approximately 24 months. ]
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
Part 1: Ocurrence of dose-limiting toxicities (DLTs) [ Time Frame: Safety will be assessed up to the follow-up period, approximately 24 months. ]
Occurrence of dose limiting toxicities
Part 1: Changes from baseline in laboratory parameters [ Time Frame: Safety will be assessed up to the follow-up period, approximately 24 months. ]
Changes in laboratory parameters (every in appropriate units) compared to baseline results.
Part 1: Changes from baseline in vital signs [ Time Frame: Safety will be assessed up to the follow-up period, approximately 24 months. ]
Changes in vital signs results compared to baseline results.
Part 1: Changes from baseline in electrocardiogram (ECG) results [ Time Frame: Safety will be assessed up to the follow-up period, approximately 24 months. ]
Changes in ECG results compared to baseline results.
Part 2, Part 3 and Part 4: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR) [ Time Frame: (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months ]
Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.

Original Primary Outcome Measures ^ICMJE

Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Safety will be assessed for approximately 24 months from informed consent. ]
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
Part 2: Objective Response Rate (ORR) [ Time Frame: An average of approximately 12 months. ]
Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.

Change History

Current Secondary Outcome Measures ^ICMJE

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

Original Secondary Outcome Measures ^ICMJE

Part 1: Objective Response Rate (ORR) [ Time Frame: An average of approximately 12 months. ]
Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.
Part 2: Occurrence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Safety will be assessed for approximately 24 months from informed consent. ]
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
Duration of Response (DoR) [ Time Frame: An average of approximately 18 months. ]
DOR is defined as the time from the date of first documented response until the date of documented progression or death
Disease Control Rate (DCR) [ Time Frame: An average of approximately 18 months. ]
DCR is the percentage of subjects who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD)
Progression Free Survival (PFS) [ Time Frame: An average of approximately 18 months. ]
PFS is the time from date of treatment assignment (Part 1) or date of randomization (Part 2) until the date of objective disease progression or death
Overall survival (OS) [ Time Frame: An average of approximately 30 months. ]
OS is the time from date of treatment assignment (Part 1) or date of randomization (Part 2) until death due to any cause
Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms [ Time Frame: An average of approximately 24 months. ]
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
Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab [ Time Frame: An average of approximately 24 months. ]
Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab.
Presence of ADAs for T-DXd and durvalumab (in study arms including T-DXd and durvalumab) [ Time Frame: An average of approximately 24 months. ]
Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd and durvalumab.

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

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)

Brief 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.

Detailed Description

Not Provided

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 2

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study will consist of 2 phases: a dose escalation phase (Part 1) and dose expansion phases (Part 2, Part 3 and Part 4). Part 1 will enroll HER2-overexpressing (IHC 3+ or IHC 2+/ISH+), previously treated gastric, gastro-esophageal junction (GEJ) or esophageal cancer patients, and Part 2 will enroll HER2-overexpressing patients who have not received prior treatment for metastatic or unresectable disease. Part 3 and Part 4 will enroll HER2-expressing patients who have not received prior treatment for metastatic or unresectable disease.

In addition to safety and tolerability, this study will also assess ORR, DoR, DCR, OS, PFS and other measures of antitumor activity among treatment groups. Tumor evaluation using RECIST v1.1 will be conducted at screening and every 6 weeks until RECIST 1.1 objective disease progression or withdrawal of consent.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Gastric Cancer

Intervention ^ICMJE

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

Other Name: MEDI4736
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

Other Name: DS-8201a
Drug: Cisplatin
Cisplatin: administered as an IV infusion
Biological: Pembrolizumab
Pembrolizumab: administered as an IV infusion
Biological: Volrustomig
Volrustomig: administered as an IV infusion

Other Name: MEDI5752
Biological: Rilvegostomig
Rilvegostomig: administered as an IV infusion

Other Name: AZD2936

Study Arms ^ICMJE

Experimental: Arm 1A
T-DXd and 5-fluorouracil (5-FU)
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Trastuzumab deruxtecan
Experimental: Arm 1B
T-DXd and capecitabine
Interventions:
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
Experimental: Arm 1C
T-DXd and durvalumab
Interventions:
- Biological: Durvalumab
- Drug: Trastuzumab deruxtecan
Experimental: Arm 1D(b)
T-DXd, capecitabine, and oxaliplatin
Interventions:
- Drug: Capecitabine
- Drug: Oxaliplatin
- Drug: Trastuzumab deruxtecan
Experimental: Arm 1E(a)
T-DXd, 5-FU, and durvalumab
Interventions:
- Drug: Fluorouracil (5-FU)
- Biological: Durvalumab
- Drug: Trastuzumab deruxtecan
Experimental: Arm 1E(b)
T-DXd, capecitabine, and durvalumab
Interventions:
- Drug: Capecitabine
- Biological: Durvalumab
- Drug: Trastuzumab deruxtecan
Active Comparator: Arm 2A
Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Oxaliplatin
- Biological: Trastuzumab
- Drug: Cisplatin
Experimental: Arm 2B
T-DXd monotherapy

Intervention: Drug: Trastuzumab deruxtecan
Experimental: Arm 2C
T-DXd, 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
Experimental: Arm 2D
T-DXd, pembrolizumab and 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
- Biological: Pembrolizumab
Experimental: Arm 2E
T-DXd and pembrolizumab
Interventions:
- Drug: Trastuzumab deruxtecan
- Biological: Pembrolizumab
Experimental: Arm 2F
T-DXd, pembrolizumab and 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
- Biological: Pembrolizumab
Experimental: Arm 3A
T-DXd, Volrustomig and 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
- Biological: Volrustomig
Experimental: Arm 3B
T-DXd, Volrustomig and 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
- Biological: Volrustomig
Experimental: Arm 4A
T-DXd, Rilvegostomig and 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
- Biological: Rilvegostomig
Experimental: Arm 4B
T-DXd, Rilvegostomig and 5-FU or capecitabine
Interventions:
- Drug: Fluorouracil (5-FU)
- Drug: Capecitabine
- Drug: Trastuzumab deruxtecan
- Biological: Rilvegostomig

Publications *

Not Provided

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

413

Original Estimated Enrollment ^ICMJE

220

Estimated Study Completion Date ^ICMJE

July 30, 2026

Estimated Primary Completion Date

July 30, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion criteria:

Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations
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
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
Has measurable target disease assessed by the Investigator based on RECIST version 1.1
Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function
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:

History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C infection.
Uncontrolled intercurrent illness
History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.
Lung-specific intercurrent clinically significant severe illnesses.
Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
Has spinal cord compression or clinically active central nervous system metastases.

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years to 130 Years (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact: AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Listed Location Countries ^ICMJE

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

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT04379596

Other Study ID Numbers ^ICMJE

D967LC00001
2019-004483-22 ( EudraCT Number )

Has Data Monitoring Committee

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

IPD Sharing Statement ^ICMJE

Plan to Share IPD:	Yes
Plan Description:	Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials:	Informed Consent Form (ICF)
Time Frame:	Study start to completion date
Access Criteria:	When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL:	https://astrazenecagroup-dt.pharmacm.com/DT/Home