A study of Trastuzumab Deruxtecan to assess its safety, tolerability, immune response, and inhibition of tumor activity when given alone or in combination with other agents in patients with HER2- expressing Gastric Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Oct 2020 → ongoing

Decision date (initial)

2024-10-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-504888-16-00

EudraCT number

2019-004483-22

ClinicalTrials.gov

NCT04379596

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

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, durvalumab

Part 2, Part 3, Part 4, and Part 5: To assess the anti-tumor activity of T-DXd combinations at the RP2D

Secondary objectives 1

1. Part 1: To assess anti-tumor activity of T-DXd combinations Part 2, Part 3, Part 4 and Part 5: To assess the anti-tumor activity of T-DXd combinations Part 2, Part 3, Part 4 and Part 5: To assess the safety and tolerability of T-DXd monotherapy and T-DXd combination regimens Part 2, Part 3, Part 4 and Part 5: To assess the pharmacokinetics of T-DXd, total anti-HER2 antibody, MAAA-1181 durvalumab, volrustomig and rilvegostomig in all arms To investigate the immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig To assess anti-tumor activity based on comparison of local HER2 results with centralretrospective HER2 testing from baseline tumor samples

Conditions and MedDRA coding

Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-expressing gastric, GEJ and esophageal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Male and female participants must be at least 18 years of age. Other age restrictions mayapply as per local regulations
2. 2. Disease Characteristics: a/Locally advanced, unresectable, or metastatic disease based on most recent imaging b/For Parts 1, 2, 3a and 4a, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results c/For Parts 3b, 4b and Part 5 pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results
3. 3. For Part 1, progression on or after at least one prior trastuzumab-containing regimen For Part 2, 3, 4 and 5, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with HER2-positive (Part 2, Part 3 [Arm 3A] and Part 4[Arm 4A]) or HER2-low (Part 3 [Arm 3B] , Part 4 [Arm 4B] and Part 5) status.
4. 4. Has measurable target disease assessed by the Investigator based on RECIST version 1.1
5. 5. Has protocol-defined adequate bone marrow and organ function including cardiac, renal and hepatic function
6. 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 for female and 6 months (all treatment arms except Arm 2B) or 4 months (Arm 2B) for male patients

Exclusion criteria 8

1. 1. Part 1 to 4: Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, active, chronic, or past hepatitis B infection, or hepatitis C infection. Part 5: Evidence of the following infections: Uncontrolled HIV infection, Active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV) or active hepatitis A.
2. 2. Uncontrolled intercurrent illness.
3. 3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.
4. 4. Lung-specific intercurrent clinically significant severe illnesses.
5. 5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
6. 6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
7. 7. Has spinal cord compression or clinically active central nervous system metastases.
8. 8. For Part 5: Any serious cardiac conditions, such as: Cardiomyopathy of any etiology or history of myocarditis, Heart failure, Uncontrolled hypertension, Unstable angina pectoris, Clinically significant coronary, carotid, or peripheral artery stenosis, Acute coronary syndrome/acute myocardial infarction etc.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0, dose-limiting toxicities (DLTs), and changes from baseline in laboratory parameters, vital signs, and electrocardiogram (ECG) results
2. Part 2, Part 3, Part 4 and Part 5: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR)

Secondary endpoints 5

1. Part 1: Endpoints assessed by Investigator per RECIST v1.1: Confirmed Objective ResponseRate (ORR), Disease control rate (DCR), Duration of response (DoR), Progression-freesurvival (PFS), Overall survival (OS)
2. Part 2, Part 3, Part 4 and Part 5: Endpoints assessed by Investigator per RECISIT v1.1: Diseasecontrol rate (DCR), Duration of response (DoR), Progression-free survival (PFS), Overallsurvival (OS)
3. Part 2, Part 3, Part 4 and Part 5: Occurrence of adverse events (AEs) and serious adverse events(SAEs), dose-limiting toxicities (DLTs) and changes from baseline in laboratory parameters, vital signs, body weight and electrocardiogram (ECG) results
4. Part 2, Part 3, Part 4 and Part 5: -Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms; -Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab; -Serum concentrations of volrustomig and rilvegostomig in study arms including T-DXd incombination with volrustomig and T-DXd in combination with rilvegostomig,
5. -Presence of ADAs for T-DXd, durvalumab, volrustomig and rilvegostomig (in study arms including T-DXd and durvalumab T-DXd and volrustomig, and T-DXd and rilvegostomig, respectively) -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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 11

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Locations

5 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications