Phase 2 Study of MK-1308A (Coformulated MK-1308/MK-3475), plus Lenvatinib (E7080/MK-7902) in First-line Therapy of Advanced Hepatocellular Carcinoma

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

13 Jul 2021 → 29 Jul 2025

Decision date (initial)

2023-09-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC · Eisai

External identifiers

EU CT number

2023-505698-34-00

EudraCT number

2020-004490-52

WHO UTN

U1111-1292-3158

ClinicalTrials.gov

NCT04740307

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Therapy, Pharmacodynamic, Pharmacokinetic, Pharmacoeconomic, Dose response, Pharmacogenetic, Safety, Diagnosis, Efficacy

1. To assess the safety and tolerability of study intervention with MK-1308A/lenvatinib.
2. To evaluate the efficacy of MK-1308A/lenvatinib with respect to objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).

Secondary objectives 6

1. To evaluate the efficacy of MK-1308A/lenvatinib with respect to duration of response (DOR) per RECIST 1.1 as assessed by BICR
2. To evaluate the efficacy of MK-1308A/lenvatinib with respect to disease control rate (DCR) per RECIST 1.1 as assessed by BICR
3. To evaluate the efficacy of MK-1308A/lenvatinib with respect to progression-free survival (PFS) per RECIST 1.1 as assessed by BICR
4. To evaluate the efficacy of MK-1308A/lenvatinib with respect to time to progression (TTP) per RECIST 1.1 as assessed by BICR
5. To evaluate the efficacy of MK-1308A/lenvatinib with respect to overall survival (OS)
6. To evaluate efficacy outcomes of MK-1308A/lenvatinib per modified RECIST (mRECIST) assessed by BICR

Conditions and MedDRA coding

Hepatocellular carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Has an HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)
2. Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach
3. Has a Child-Pugh class A liver score within 7 days prior to first dose of study intervention.
4. Has a predicted life expectancy of >3 months
5. Has at least 1 measurable HCC lesion based on RECIST 1.1, confirmed by BICR
6. Has an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 to 1 within 7 days prior to first dose of study intervention.
7. Participants with controlled hepatitis B will be eligible as long as they meet the following criteria: antiviral therapy for Hepatitis B virus (HBV) must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study drug
8. Has adequately controlled blood pressure with or without antihypertensive medications
9. Has adequate organ function.

Exclusion criteria 31

1. Has had esophageal or gastric variceal bleeding within the last 6 months.
2. Has bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring therapeutic international normalized ratio (INR) monitoring, e.g., warfarin or similar agents
3. Has clinically apparent ascites on physical examination
4. Has inferior vena cava or cardiac involvement of HCC based on imaging
5. Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy
6. Has medical contraindications that preclude all forms of contrast-enhanced imaging (computed tomography [CT] or magnetic resonance imaging [MRI])
7. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
8. Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula
9. Has clinically active hemoptysis (bright red blood of a least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
10. Has clinically significant cardiovascular impairment within 12 months of the first dose of study intervention, including New York Heart Association (NYHA) Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
11. Has had major surgery to the liver within 4 weeks prior to the first dose of study intervention
12. Has had a minor surgery (i.e., simple excision) within 7 days prior to the first dose of study intervention (Cycle 1 Day 1)
13. Has serious nonhealing wound, ulcer, or bone fracture
14. Has received any systemic chemotherapy, including anti- vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agents for treatment of HCC
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
16. Has received locoregional therapy to liver within 4 weeks prior to the first dose of study intervention
17. Has received prior radiotherapy to a non-liver region within 2 weeks of start of study intervention
18. Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug
19. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
20. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
21. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
22. Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator
23. Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of their excipients
24. Has an active autoimmune disease that has required systemic treatment in past 2 years
25. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
26. Has an active infection requiring systemic therapy, with the exception of HBV or Hepatitis C virus (HCV)
27. Has a known history of human immunodeficiency virus (HIV) infection
28. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV antibody [Ab] positive and detectable HCV RNA) at study entry
29. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
30. Has a known psychiatric or substance abuse disorder that would interfere with the participants ability to cooperate with the requirements of the study
31. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Number of participants with a Dose-Limiting Toxicity (DLT) in the Safety Lead-in Phase
2. Number of participants with ≥1 adverse event (AE)
3. Number of participants with ≥1 serious adverse event (SAE)
4. Number of participants with ≥1 immune-related AE (irAE)
5. Number of participants with ≥1 hepatic AEs
6. Number of participants discontinuing study treatment due to an AE
7. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR)

Secondary endpoints 10

1. Duration of Response (DOR) per RECIST 1.1 as assessed by BICR
2. Disease Control Rate (DCR) per RECIST 1.1 as assessed by BICR
3. Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR
4. Time-To-Progression (TTP) per RECIST 1.1 as assessed by BICR
5. Overall Survival (OS)
6. ORR per modified RECIST (mRECIST) as assessed by BICR
7. DOR per mRECIST as assessed by BICR
8. DCR per mRECIST as assessed by BICR
9. PFS per mRECIST as assessed by BICR
10. TTP per mRECIST as assessed by BICR

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Ken Hatogai

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Ken Hatogai

Third parties 2

Locations

3 EU/EEA countries · 8 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

Layperson summary Annex V

Documents 30 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