Substudy 06C: Combination Therapies in Gastroesophageal Adenocarcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Sep 2024 → ongoing

Decision date (initial)

2024-08-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-509307-33-00

WHO UTN

U1111-1299-8084

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacokinetic, Efficacy

1. Safety Lead-In Phase: To evaluate the safety and tolerability of investigational agents plus pembrolizumab plus chemotherapy.
2. To estimate the ORR as assessed by BICR per RECIST 1.1 for selected dose.

Secondary objectives 5

1. To evaluate PFS as assessed by BICR per RECIST 1.1 for selected dose.
2. To evaluate the DOR as assessed by BICR per RECIST 1.1 for selected dose.
3. To evaluate OS for selected dose.
4. To evaluate the safety and tolerability of investigational treatment combinations based on the proportion of participants with AEs.
5. To characterize the immunogenicity of investigational agents

Conditions and MedDRA coding

Gastroesophageal cancer

Regulatory references

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Has histologically and/or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic 1L gastroesophageal adenocarcinoma
2. Is not expected to require tumor resection during the treatment course
3. Tumor tissue must be confirmed as negative for human epidermal growth factor receptor 2 (HER2) expression as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines.
4. Core/excisional biopsy of a tumor lesion not previously irradiated has been provided
5. Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to ≤ Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible
6. Has adequate organ function
7. Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by the local site investigator/radiology assessment and verified by blind independent review committee (BICR)
8. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 3 days before allocation/randomization
9. Has a life expectancy of at least 6 months
10. Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B Virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to allocation/randomization
11. Participants with history of Hepatitis C Virus (HCV) infection are eligible if HCV viral load is undetectable at screening
12. Human Immunodeficiency Virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy

Exclusion criteria 31

1. Has squamous cell or undifferentiated gastroesophageal cancer.
2. Has had previous therapy for locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ)/esophageal adenocarcinoma
3. Has experienced weight loss >20% over 3 months before the first dose of study intervention
4. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
5. Has Grade >2 peripheral neuropathy
6. Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
7. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within 6 months preceding study intervention
8. Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
9. Has history of human immunodeficiency virus (HIV) infection
10. Has received prior treatment with a trophoblast antigen 2 (TROP2)-targeted or anti-human epidermal growth factor (HER3) targeted agents.
11. Has received prior treatment with a topoisomerase 1 inhibitor-based ADC and/or a topoisomerase 1 inhibitor-based chemotherapy
12. Has received prior systemic anticancer therapy within 4 weeks before the first dose of study intervention
13. Has received prior therapy with an anti-Programmed Cell Death Protein 1 (PD-1), anti-Programmed Cell Death-Ligand 1 (PD-L1), anti-Programmed Cell Death-Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR)
14. Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation related toxicities, requiring corticosteroids
15. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
16. Has received a strong inducer/inhibitor of CYP3A4 that cannot be discontinued
17. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
18. Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
19. Has known additional malignancy that is progressing or has required active treatment within the past 3 years
20. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
21. Has Severe hypersensitivity (≥Grade 3) to pembrolizumab, sacituzumab tirumotecan, patritumab deruxtecan, or other biologic therapy, chemotherapy (ie, oxaliplatin, fluorouracil, capecitabine), leucovorin, levoleucovorin, or any of their excipients
22. Has active autoimmune disease that has required systemic treatment in the past 2 years
23. Has history of (noninfectious) pneumonitis or interstitial lung disease (ILD) that required steroids or has current pneumonitis or ILD, or where suspected ILD or pneumonitis cannot be ruled out by imaging at screening
24. Has an active infection requiring systemic therapy
25. Has concurrent active hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) and/or hepatitis C (defined as anti-hepatitis C virus [HCV] Ab positive and detectable HCV ribonucleic acid [RNA] infection or a known history of hepatitis B and/or C infection
26. Has history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's ability to cooperate with the requirements of the study
27. Has GI obstruction, poor oral intake, or difficulty in taking oral medication
28. Has poorly controlled diarrhea
29. Has had a major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention
30. Has history of allogeneic tissue/solid organ transplant
31. Have not adequately recovered from major surgery or have ongoing surgical complications

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs)
2. Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE)
3. Safety Lead-in Phase: Number of Participants Who Discontinued Study Intervention Due to an AE
4. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blind Independent Review Committee (BICR)

Secondary endpoints 6

1. Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR
2. Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
3. Overall Survival (OS)
4. Number of Participants Who Experience an Adverse Event (AE)
5. Number of Participants Who Discontinue Study Treatment Due to an AE
6. Incidence of Antidrug Antibodies (ADA) to investigational agents – (sacituzumab tirumotecan (sac-TMT, MK-2870) and patritumab deruxtecan (HER3-DXd))

Investigational products

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

Test 8

Comparator 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Sucharita Bhaumik

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Sucharita Bhaumik

Third parties 7

Locations

4 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

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

Documents 41 files

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

Application history

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