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

JRCT ID: jRCT2031200203

Registered date:17/11/2020

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: adenocarcinoma of the stomach, GEJ, or esophagus
• Date of first enrollment: 17/05/2021
• Target sample size: 250
• Countries of recruitment: Brazil,Japan,Canada,Japan,Germany,Japan,UK,Japan,Italy,Japan,Korea,Japan,Netherlands,Japan,Poland,Japan,Russia,Japan,Spain,Japan,Taiwan,Japan,United States,Japan,China,Japan
• Study type: Interventional

Intervention(s)

Experimental: Arm 1A: T-DXd and 5-fluorouracil (5-FU)
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 1B:T-DXd and capecitabine
Drug: Capecitabine/Capecitabine: administered orally
Drug: Trastuzumab deruxtecan/T-DXd: administered as an IV infusion
Other Name: DS-8201a

Experimental: Arm 1C:T-DXd and durvalumab
Biological: Durvalumab/ Durvalumab: administered as an IV infusion/ Other Name: MEDI4736
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 1Da:T-DXd, oxaliplatin and 5-FU
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Oxaliplatin/ Oxaliplatin: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 1Db:T-DXd, oxaliplatin and capecitabine
Drug: Capecitabine/ Capecitabine: administered orally
Drug: Oxaliplatin/ Oxaliplatin: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 1Ea:T-DXd, durvalumab and 5-FU
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Biological: Durvalumab/ Durvalumab: administered as an IV infusion/ Other Name: MEDI4736
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 1Eb:T-DXd, durvalumab and capecitabine
Drug: Capecitabine/ Capecitabine: administered orally
Biological: Durvalumab/ Durvalumab: administered as an IV infusion/ Other Name: MEDI4736
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Active Comparator: Arm 2A: Trastuzumab, 5-FU/capecitabine, and cisplatin/oxaliplatin
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine / Capecitabine: administered orally
Drug: Oxaliplatin/ Oxaliplatin: administered as an IV infusion
Biological: Trastuzumab/ Trastuzumab: administered as an IV infusion
Drug: Cisplatin/ Cisplatin: administered as an IV infusion

Experimental: Arm 2B: T-DXd monotherapy/ Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 2C: T-DXd, 5-FU or capecitabine, and oxaliplatin
Drug: Fluorouracil (5-FU) / 5-FU: administered as an IV infusion
Drug: Capecitabine / Capecitabine: administered orally
Drug: Oxaliplatin / Oxaliplatin: administered as an IV infusion
Drug: Trastuzumab deruxtecan / T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 2D: T-DXd, 5-FU or capecitabine, and Pembrolizumab
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine/ Capecitabine: administered orally
Biological: Pembrolizumab/ Pembrolizumab: administered as an IV infusion / Other Name: MK-3475
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 2E: T-DXd and Pembrolizumab
Biological: Pembrolizumab/ Pembrolizumab: administered as an IV infusion / Other Name: MK-3475
Drug: Trastuzumab deruxtecan /T-DXd: administered as an IV infusion / Other Name: DS-8201a

Experimental: Arm 2F: T-DXd, 5-FU or capecitabine, and Pembrolizumab
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine/ Capecitabine: administered orally
Biological: Pembrolizumab/ Pembrolizumab: administered as an IV infusion / Other Name: MK-3475
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 3A: T-DXd, 5-FU or capecitabine, and volrustomig
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine/ Capecitabine: administered orally
Drug: Volrustoming/ MEDI5752: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 3B: T-DXd, 5-FU or capecitabine, and volrustomig
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine/ Capecitabine: administered orally
Drug: Volrustoming/ MEDI5752: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 4A: T-DXd, 5-FU or capecitabine, and rilvegostomig
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine/ Capecitabine: administered orally
Drug: Rilvegostomig: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Experimental: Arm 4B: T-DXd, 5-FU or capecitabine, and rilvegostomig
Drug: Fluorouracil (5-FU)/ 5-FU: administered as an IV infusion
Drug: Capecitabine/ Capecitabine: administered orally
Drug: Rilvegostomig: administered as an IV infusion
Drug: Trastuzumab deruxtecan/ T-DXd: administered as an IV infusion/ Other Name: DS-8201a

Outcome(s)

Primary Outcome

Part 1: To assess safety and tolerability, and to determine the recommended Phase 2 dose (RP2D) or
the highest protocol-defined dose of T-DXd combinations with capecitabine, 5-fluorouracil,
oxaliplatin, or durvalumab
Occurrence of adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and changes from baseline in laboratory parameters, vital signs, and electrocardiogram (ECG) results

Part 2, Part3 and Part 4: To assess the antitumor activity of T-DXd combinations at the RP2D
Endpoint assessed by Investigator per RECIST v1.1:
- Confirmed Objective Response Rate (ORR)

Secondary Outcome

Part 1: To assess the antitumor activity of T-DXd combinations
Endpoints assessed by Investigator per RECIST v1.1:
- Confirmed ORR
- Disease control rate (DCR)
- Duration of response (DoR)
- Progression-free survival (PFS)
- Overall survival (OS)

Part 2, Part 3 and Part 4: To assess the antitumor activity of T-DXd combinations
Endpoints assessed by Investigator per RECIST v1.1:
- Disease control rate (DCR)
- Duration of response (DoR)
- Progression-free survival (PFS)
- Overall survival (OS)

Part 2, Part 3 and Part 4: To assess the safety and tolerability of T-DXd monotherapy and T-DXd combination
regimens
Occurrence of adverse events (AEs), serious adverse events (SAEs), and changes from baseline in laboratory parameters, vital signs, body weight, and electrocardiogram(ECG) results

To assess the pharmacokinetics of T-DXd, total anti-HER2 antibody, MAAA-1181, durvalumab, and
volrustomig and rilvegostomig in all arms
- Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms
- Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab
- Serum concentrations of volrustomig in study arms including T-DXd in combination with volrustomig
- Serum concentrations of rilvegostomig in study arms including T-DXd in combination with rilvegostomig

To investigate the immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig
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)

To assess antitumor activity based on comparison of local HER2 results with central retrospective HER2
testing from baseline tumor samples
Comparison of ORR, DCR, DoR, PFS, OS between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 130age old
• Gender: Both

Include criteria

1. Male and female participants must be at least 18 years of age (20 years of age in Japan)
2. Disease Characteristics:
Locally advanced, unresectable, or metastatic disease based on most recent imaging. For Part 1, 2, 3a and 4a pathologically documented adenocarcinoma of the stomach, GEJ, or esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH-positive) based on existing local tissue testing results. For Part 3b and 4b, pathologically documented adenocarcinoma of the stomach, GEJ, or esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on existing local tissue testing results.
3. For Part 1, progression on or after at least one prior trastuzumab-containing regimen. previously untreated for unresectable or metastatic adenocarcinoma of the stomach, GEJ, or esophagus, with HER2-positive (Part 2 and Part 3, Arm 3A, Part 4, Arm 4A) or HER2-low (Part 3, Arm 3B, 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 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 and for at least 7 months (female) or 6 months (male) after last dose of study drug.

Exclude criteria

1. History of active primary immunodeficiency, known HIV, active HBV or HCV infection, or active tuberculosis.
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 Information

• Primary Sponsor: Inoguchi Akihiro
• Secondary Sponsor: AstraZeneca
• Secondary ID(s): NCT04379596