| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced hepatocellular carcinoma without any prior systemic treatment. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced hepatocellular carcinoma without any prior systemic treatment. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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). |
|
| E.2.2 | Secondary objectives of the trial |
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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has an HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/ cholangiocarcinoma subtypes are not eligible).
- Radiologic confirmation of diagnosis is provided by the study site and confirmed by BICR. Clinically confirmed diagnosis of HCC as per the AASLD criteria, which requires:
o Radiographically evident cirrhosis AND
o A liver mass that shows arterial phase hyperenhancement on triphasic CT or MRI, AND EITHER:
- Is ≥20 mm with either nonperipheral portal washout or an enhancing capsule OR
- Is 10-19 mm with nonperipheral portal venous washout AND an
enhancing capsule
2. Has 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 ECOG PS of 0 to 1 within 7 days prior to first dose of study intervention.
7. Is at least 18 years of age at the time of providing documented informed consent.
8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after receiving the last dose of lenvatinib:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
- Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause )
- Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception
requirements in the local label for any of the study drugs is more stringent than the requirements above, the local label requirements should be followed.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least 120 days after MK-1308A and 30 days after lenvatinib, whichever occurs last after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
10. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study.
11. Participants with past or ongoing HCV infection will be eligible for the study. The treated participants must have completed their treatment at least 1 month prior to starting study intervention.
12. Participants with controlled hepatitis B will be eligible as long as they meet the following criteria:
- Antiviral therapy for 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. Participants on active HBV therapy with viral loads under 500 IU/mL should stay on the same therapy throughout study intervention.
- Participants who are positive for antihepatitis B core antibody HBc, negative for HBsAg, and negative or positive for antihepatitis B surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not require HBV antiviral prophylaxis.
13. Has adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1.
14. Has adequate organ function defined in the study protocol. (All screening labs must be collected within 14 days prior to randomization.)
|
|
| E.4 | Principal exclusion criteria |
1. Has had esophageal or gastric variceal bleeding within the last 6 months. All participants will be screened for esophageal or gastric varices unless such screening has been performed in the past 3 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting study intervention; esophageal or gastric varices that require interventional treatment within 28 days prior to first dose of study drug are excluded.
2. Has bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with low molecular weight heparin is permitted.
3. Has clinically apparent ascites on physical examination.
4. Has inferior vena cava or cardiac involvement of HCC based on imaging, confirmed by BICR.
5. Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy. Participants on rifaximin or lactulose during Screening to control their hepatic encephalopathy are not allowed.
6. Has medical contraindications that preclude all forms of contrast-enhanced imaging (CT or MRI).
7. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
8. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
9. Has active hemoptysis from any source or tumor bleeding within 2 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.
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 (ie, 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-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 (eg, CTLA-4, OX-40, or CD137).
16. Has received locoregional therapy to liver (transcatheter chemoembolization, transcatheter embolization, hepatic arterial infusion, radiation, radioembolization, or ablation) within 4 weeks prior to the first dose of study intervention.
17. Has received prior radiotherapy to a nonliver 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 (in dosing exceeding 10 mg daily of prednisone equivalent) 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, 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 (ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy is allowed.
25. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
26. Has urine protein ≥1 g/24 hours.
27. Has prolongation of QTcF interval to >480 ms.
28. Has LVEF below the institutional normal range as determined by MUGA or ECHO.
29. Has an active infection requiring systemic therapy, with the exception of HBV or HCV.
30. Has a known history of HIV infection.
31. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
32. 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.
33. Has a known psychiatric or substance abuse disorder that would interfere with the participants ability to cooperate with the requirements of the study.
34. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1 (Up to approximately 3 weeks)
2. Up to approximately 5 years
3. Up to approximately 5 years
4. Up to approximately 5 years
5. Up to approximately 5 years
6. Up to approximately 5 years
7. Up to approximately 5 years
|
|
| E.5.2 | Secondary end point(s) |
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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 28 months
2. Up to approximately 28 months
3. Up to approximately 28 months
4. Up to approximately 28 months
5. Up to approximately 28 months
6. Up to approximately 28 months
7. Up to approximately 28 months
8. Up to approximately 28 months
9. Up to approximately 28 months
10. Up to approximately 28 months
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| China |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| Poland |
| Spain |
| Switzerland |
| Italy |
| Russian Federation |
| Turkey |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS - The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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