A Study to Evaluate Investigational Agents With or Without Pembrolizumab (MK-3475) in Participants With Advanced Esophageal Cancer Previously Exposed to Programmed Cell Death 1 Protein (PD-1)/ Programmed Cell Death Ligand 1 (PD-L1) Treatment (MK-3475-06B)

Esophageal Squamous Cell Carcinoma Clinical Trial

Official title:

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer Previously Exposed to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06B

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05319730
• Other study ID #: 3475-06B
• Secondary ID: jRCT203122058220
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 16, 2023
• Est. completion date: September 20, 2028

Study information

• Verified date: May 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1/2, multicenter, randomized, open-label umbrella platform study to evaluate the safety and efficacy of investigational agents with or without pembrolizumab and/or chemotherapy, for the treatment of participants with second line (2L) esophageal squamous cell carcinoma (ESCC) who have previously been exposed to PD-1/PD-L1 based treatment.

Description:

The master protocol is MK-3475-U06.

As of Protocol Amendment 5, the Pembrolizumab Plus MK-4830 Plus Paclitaxel/Irinotecan arm and the Pembrolizumab Plus MK-4830 Plus Lenvatinib arm are no longer actively enrolling participants.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: September 20, 2028
• Est. primary completion date: November 7, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable ESCC.

• Has experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy, that includes a platinum agent and previous exposure to an anti-PD1/PD-L1 based therapy.

• Has an evaluable baseline tumor sample (newly obtained or archival) for analysis.

• Has adequately controlled blood pressure (BP) with or without antihypertensive medications.

• 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 or participants who have =Grade 2 neuropathy are eligible.

Exclusion Criteria:

• Direct invasion into adjacent organs such as the aorta or trachea.

• Has experienced weight loss >10% over approximately 2 months prior to first dose of study therapy.

• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.

• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.

• Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.

• 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 medication.

• Known additional malignancy that is progressing or has required active treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that has undergone potentially curative therapy.

• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

• Active autoimmune disease that has required systemic treatment in past 2 years.

• History of human immunodeficiency virus (HIV) infection.

• History of Hepatitis B or known active Hepatitis C virus infection.

• History of allogenic tissue/solid organ transplant.

• Clinically significant cardiovascular disease within 12 months from first dose of study intervention.

• Known GI malabsorption or any other condition that may affect the absorption of lenvatinib. (Not applicable to actively enrolling arms as of Amendment 5)

• Has risk for significant GI bleeding such as a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization, significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization. (Not applicable to actively enrolling arms as of Amendment 5)

Related Conditions & MeSH terms

• Esophageal Neoplasms
• Esophageal Squamous Cell Carcinoma

Intervention

Drug:
• Paclitaxel
80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle.
• Irinotecan
180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle.

Biological:
• Pembrolizumab
200 mg IV infusion, administered every Q3W.
• MK-4830
800 mg IV infusion, administered Q3W up to 35 infusions.

Drug:
• Lenvatinib
20 mg oral administration every day.

Biological:
• Sacituzumab tirumotecan
4 mg/kg IV infusion on Days 1, 15, and 29 of each 42-day cycle.

Drug:
• Antihistamine
Administered per product label.
• H2 Receptor Antagonist
Administered per product label.
• Acetaminophen (or equivalent)
Administered per product label.
• Dexamethasone (or equivalent)
Administered per product label.

Locations

Country	Name	City	State
Brazil	Liga Norte Riograndense Contra o Câncer ( Site 4303)	Natal	Rio Grande Do Norte
Brazil	Hospital Nossa Senhora da Conceição ( Site 4301)	Porto Alegre	Rio Grande Do Sul
Brazil	ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 4300)	São Paulo	Sao Paulo
Chile	Clínica las Condes ( Site 4403)	Santiago	Region M. De Santiago
Chile	FALP-UIDO ( Site 4400)	Santiago	Region M. De Santiago
China	Beijing Cancer hospital-Digestive Oncology ( Site 3500)	Beijing	Beijing
China	Zhejiang Cancer Hospital-Thoracic oncology ( Site 3511)	Hangzhou	Zhejiang
China	Anhui Provincil Hospital South District ( Site 3501)	Hefei	Anhui
China	First Huai'an Hospital Affiliated to Nanjing Medical University ( Site 3506)	Huai'an	Jiangsu
China	Shanghai Chest Hospital-Esophageal surgery department ( Site 3513)	Shanghai	Shanghai
China	The First Affiliated Hospital of Xinxiang Medical University-Oncology ( Site 3510)	Xinxiang	Henan
Germany	Charité Campus Virchow-Klinikum-Klinik Hämatologie Onkologie Tumorimmunologie ( Site 4804)	Berlin
Germany	Institut für Klinisch Onkologische Forschung-Klink für Onkologie und Hämatologie ( Site 4801)	Frankfurt	Hessen
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 3200)	Milan	Lombardia
Italy	Istituto Europeo di Oncologia IRCCS-Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative (	Milano
Italy	Ospedale San Raffaele-Oncologia Medica ( Site 3202)	Milano	Lombardia
Japan	National Cancer Center Hospital ( Site 3700)	Chuo-ku	Tokyo
Japan	Saitama Prefectural Cancer Center ( Site 3703)	Ina-machi	Saitama
Japan	National Cancer Center Hospital East ( Site 3701)	Kashiwa	Chiba
Japan	Shizuoka Cancer Center ( Site 3704)	Nagaizumi-cho,Sunto-gun	Shizuoka
Japan	Aichi Cancer Center Hospital ( Site 3702)	Nagoya	Aichi
Korea, Republic of	Asan Medical Center-Department of Oncology ( Site 3901)	Seoul
Korea, Republic of	Samsung Medical Center-Division of Hematology/Oncology ( Site 3900)	Seoul
Norway	Oslo universitetssykehus, Radiumhospitalet ( Site 4501)	Oslo
Singapore	National University Hospital ( Site 3800)	Singapore	South West
Switzerland	Kantonsspital Graubünden-Medizin ( Site 4700)	Chur	Grisons
Switzerland	Hôpitaux Universitaires de Genève (HUG) ( Site 4702)	Genève	Geneve
Taiwan	Chang Gung Memorial Hospital at Kaohsiung ( Site 4003)	Kaohsiung Niao Sung Dist	Kaohsiung
Taiwan	China Medical University Hospital ( Site 4007)	Taichung
Taiwan	Taichung Veterans General Hospital-Radiation Oncology ( Site 4008)	Taichung
Taiwan	National Cheng Kung University Hospital ( Site 4001)	Tainan
Taiwan	National Taiwan University Hospital ( Site 4000)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 4005)	Taipei
Taiwan	Chang Gung Medical Foundation-Linkou Branch ( Site 4006)	Taoyuan
Thailand	Faculty of Medicine Siriraj Hospital ( Site 4102)	Bangkok	Krung Thep Maha Nakhon
Turkey	Ankara Bilkent City Hospital-Medical Oncology ( Site 3405)	Ankara
Turkey	Hacettepe Universite Hastaneleri-oncology hospital ( Site 3402)	Ankara
Turkey	Atatürk Üniversitesi-onkoloji ( Site 3416)	Erzurum
Turkey	TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi-oncology ( Site 3403)	Istanbul

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

Brazil,  Chile,  China,  Germany,  Italy,  Japan,  Korea, Republic of,  Norway,  Singapore,  Switzerland,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) During Safety Lead-in Phase	A DLT is defined as any drug-related AE according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0, observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next cycle.	Up to approximately 3 weeks
Primary	Number of Participants Experiencing Adverse Events (AEs) During Safety Lead-in Phase	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to approximately 3 weeks
Primary	Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.	Up to approximately 3 weeks
Primary	Objective Response Rate (ORR)	ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.	Up to approximately 92 weeks
Secondary	Progression-Free Survival (PFS)	PFS is defined as the time from allocation to the first documented progressive disease (PD) as assessed by RECIST 1.1 or death due to any cause, whichever occurs first. PD is defined as =20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of =5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.	Up to approximately 189 weeks
Secondary	Duration of Response (DOR)	For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.	Up to approximately 189 weeks
Secondary	Overall Survival (OS)	OS is defined as the time from the date of allocation to death from any cause.	Up to approximately 189 weeks
Secondary	Number of Participants Experiencing at Least One Adverse Event (AE) During the Efficacy Phase	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 189 weeks
Secondary	Number of Participants Who Discontinue Study Treatment Due to An AE During the Efficacy Phase	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 189 weeks

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary