Trastuzumab Deruxtecan for Subjects with HER2-Positive Gastric Cancer or Gastro-Esophageal Junction Adenocarcinoma after Progression on or After a Trastuzumab-Containing Regimen

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Daiichi Sankyo Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Aug 2021 → ongoing

Decision date (initial)

2024-06-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Daiichi Sankyo Inc

External identifiers

EU CT number

2023-507963-20-00

EudraCT number

2020-004559-34

ClinicalTrials.gov

NCT04704934

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Others, Pharmacokinetic, Efficacy, Therapy, Safety, Pharmacogenomic

To compare overall survival (OS) in HER2-positive (defined as IHC 3+ or IHC 2+/ISH+) gastric cancer(GC) and GEJ adenocarcinoma subjects treated with TDXd vs. Ram + PTX.

Secondary objectives 7

1. To compare PFS in HER2-positive GC and GEJ adenocarcinoma subjects treated with TDXd or Ram + PTX;
2. To compare the clinical efficacy of TDXd and Ram + PTX by objective response rate (ORR based on Investigator assessment;
3. To compare the clinical efficacy of TDXd and Ram + PTX by DoR;
4. To compare the clinical efficacy of TDXd and Ram + PTX by DCR;
5. To evaluate the safety of T-DXd compared to Ram + PTX;
6. To evaluate the Pharmacokinetics (PK) of T-DXd;
7. To evaluate immunogenicity of TDXd

Conditions and MedDRA coding

Metastatic Gastric Adenocarcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 1. Sign and date the Tissue Screening and Main ICFs, prior to the start of any study-specific qualification procedures.
2. 2. Adults (according to local regulation) and able to provide informed consent for study participation.
3. 3. Pathologically documented gastric and GEJ adenocarcinoma that has been previously treated in the metastatic setting (unresectable, locally advanced, or metastatic disease).
4. 4. Progression on or after first-line therapy with a trastuzumab or approved trastuzumab biosimilar-containing regimen. Note: Prior neoadjuvant or adjuvant therapy with a trastuzumab containing regimen can be counted as a line of therapy if the subject progressed on or within 6 months of completing therapy neoadjuvant or adjuvant therapy. Prior neoadjuvant or adjuvant therapy that does not of the progression status of the subject
5. 5. Is willing and able to provide an adequate tumor sample for tissue screening to confirm HER2 status by local or central laboratory. See Section 8.1.2.
6. 6. Locally or centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) as classified by ASCO-CAP on a tumor biopsy obtained after progression on or after a first-line trastuzumab or approved trastuzumab biosimilar-containing regimen.
7. 7. Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening.
8. 8. Adequate laboratory parameters as evidenced by all blood counts (refer protocol for details) within 14 days of randomization.
9. 9. Has adequate treatment washout period before randomization/enrollment, as described in the protocol.
10. 10. LVEF ≥50% within 28 days before randomization per echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
11. 11. Recovered from the effects of any prior surgery or radiotherapy.
12. 12. Males and females of reproductive/childbearing potential must agree 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 subjects and 4 months for male subjects after the last dose of study drug. For subjects receiving Ram + PTX, sites should follow the locally approved label. - If the subject is a female of childbearing potential, she must have a negative serum or urine pregnancy test at Screening before the first dose of study drug and must be willing to use highly effective birth control, as detailed in Section 10.3.4 , upon randomization, during the Treatment Period, and for 7 months following the last dose of study drug. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). - If male, the subject must be surgically sterile or willing to use highly effective birth control upon enrollment, during the treatment period, and for 4 months following the last dose of study drug.
13. 13. Male subjects must not freeze or donate sperm starting from randomization and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to randomization/enrollment in this study. For Ram + PTX, sites should follow local label or institutional guidelines.
14. 14. Female subjects must not donate, or retrieve for their own use, ova from the time of randomization and throughout the study Treatment Period, and for at least 7 months after the final study drug administration. Preservation of ova may be considered prior to randomization in this study. For Ram + PTX, sites should follow local label or institutional guidelines.
15. 15. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

Exclusion criteria 23

1. 1. Use of anticancer therapy after trastuzumab-containing treatment.
2. 2. Medical history of myocardial infarction (MI) within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation before enrollment to rule out MI.
3. 3. Has a QT interval corrected by Fridericia’s formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate 12-lead electrocardiogram.
4. 4. Criterion removed.
5. 5. Has a history of (non-infectious) interstitial lung disease (ILD/pneumonitis) that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
6. 6. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disease (eg, pulmonary emboli within the previous 3 months of the study randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.).
7. 7. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented (or a suspicion of) pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the electronic case report form for patients who are included in the study.
8. 8. Prior complete pneumonectomy.
9. 9. Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. a. Subjects with clinically inactive brain metastases may be included in the study. b. Subjects with brain metastases who were treated and are no longer symptomatic, and subjects who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy (WBRT) and randomization/study enrollment.
10. 10. Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.
11. 11. History of severe hypersensitivity reactions to either the T-DXd or inactive ingredients in T-DXd.
12. 12. History of severe hypersensitivity reactions to other monoclonal antibodies, including ramucirumab or any of its excipients.
13. 13. Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy.
14. 14. Current uncontrolled infection requiring antibiotics, antivirals, or antifungals or an unexplained fever >38.0°C during Screening visits or on the first scheduled day of dosing (at the discretion of the investigator, subjects with tumor fever may be enrolled), which in the investigator’s opinion might compromise the subject’s participation in the study or affect the study outcome
15. 15. Substance abuse or any other medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results
16. 16. Social, familial, or geographical factors that would interfere with study participation or follow-up
17. 17. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Subjects with past or resolved hepatitis B virus infection are eligible if hepatitis B virus surface antigen(-) and anti- hepatitis B core(+). Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board (IRB)/independent ethics committee (IEC).
18. 18. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Note: Subjects may be enrolled with chronic, stable, Grade 2 toxicities (defined as not worsening to >Grade 2 for at least 3 months prior to randomization and managed with standard-of-care treatment) that the investigator deems related to previous anticancer therapy, such as the following: · Chemotherapy-induced neuropathy · Fatigue · Residual toxicities from prior immuno-oncology treatment: Grade 1 or Grade 2 endocrinopathies, which may include the following: - Hypothyroidism/hyperthyroidism - Type I diabetes - Hyperglycemia - Adrenal insufficiency - Adrenalitis - Skin hypopigmentation (vitiligo)
19. 19. Prior treatment with an antibody-drug conjugate (ADC) consisting of an exatecan derivative that is a topoisomerase I inhibitor
20. 20. Pregnant, breastfeeding, or planning to become pregnant. In addition, for subjects enrolled in the study, breastfeeding should not commence until at least 7 months after the last dose of study drug.
21. 21. Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of Screening or otherwise considered inappropriate for the study by the investigator
22. 22. Clinically significant gastrointestinal disorder (eg, including hepatic disorders, bleeding, inflammation, occlusion, ileus, diarrhea Grade >1, jaundice, intestinal paralysis, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or partial bowel obstruction) in the opinion of investigator
23. 23. Has history of receiving live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Survival (OS)

Secondary endpoints 7

1. Progression-Free Survival (PFS)
2. Objective Response Rate (ORR)
3. Duration of Response (DoR)
4. Disease Control Rate (DCR)
5. TEAEs and other safety parameters during the study
6. PK profile
7. Immunogenicity (Incidence of ADA and NAb)

Investigational products

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

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Daiichi Sankyo Inc.

Sponsor organisation

Daiichi Sankyo Inc.

Address

211 Mount Airy Road

City

Basking Ridge

Postcode

07920-2311

Country

United States

Scientific contact point

Organisation

Daiichi Sankyo Inc.

Contact name

EU Clinical Trial Office

Public contact point

Organisation

Daiichi Sankyo Inc.

Contact name

EU Clinical Trial Office

Third parties 6

Locations

10 EU/EEA countries · 40 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 148 files

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

Application history

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