Trametinib in Combination With Sorafenib in Patients With Advanced Hepatocellular Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to see whether the combination of trametinib and sorafenib can help people with hepatocellular cancer. Researchers also want to find out if the combination of trametinib and sorafenib is safe and tolerable.

Detailed Description
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Each cycle will last for 4 weeks. Sorafenib and trametinib will be administered orally on continuous basis. During the first cycle sorafenib will be started on day 1 and trametinib on day 8 to improve tolerance. Participants will get restaging scans every 2 cycles. Participants will continue to receive treatment if they have a stable disease or a better response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.

Official Title
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A Phase 1a/1b Trial of Trametinib in Combination With Sorafenib in Patients With Advanced Hepatocellular Cancer

Conditions
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Hepatocellular Cancer, Liver Cancer

Intervention / Treatment
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* Drug: Trametinib
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have radiographic or histological diagnosis of hepatocellular cancer (HCC), with advanced stage disease that is not amenable to curative surgical resection. Potential participants without histologic diagnosis must meet the radiographic criteria for HCC. Child Pugh score must be 5 or 6 (Child Pugh Class A) Must have measurable disease by RECIST criteria 1.1 Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Must have normal organ and marrow function Female participants of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male participants must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. For both male and female participants, effective methods of contraception must be used throughout the study and for four months following the last dose. Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Participants in the dose expansion part must have tumor that is amenable for biopsy. Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Have received radiation therapy, major surgery, other locoregional therapy, within 4 weeks prior to the first dose of study drug All prior treatment-related toxicities must be ≤ Grade 1. Have received sorafenib or other systemic therapies for treatment of HCC in the past Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures History or evidence of cardiovascular risk Known history of human immunodeficiency virus (HIV) positivity History of retinal vein occlusion (RVO) Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression History of interstitial lung disease or pneumonitis Are pregnant or lactating Any underlying condition that would significantly interfere with the absorption of an oral medication History of another active malignancy in last 3 years. Exception: Potential participants who have been disease-free for 3 years, or have a history of completely resected nonmelanoma skin cancer and/or potential participants with indolent second malignancies are eligible. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide Concurrent therapy with approved or investigational anticancer therapy Concomitant use of strong Cytochrome P450 3A4 (CYP3A4) inducers

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trametinib plus Sorafenib<br>Dose Escalation Followed by Dose Expansion. Trametinib: Daily (To start on day 8 during cycle 1 and on day 1 from cycle 2 onwards), according to dose level upon entry. Sorafenib: Twice daily, according to dose level upon entry. Each cycle is repeated every 28 days. | Drug: Trametinib<br>* Dose Escalation: Level 1: 1 mg daily. Level 2: 1.5 mg daily. Level 3: 1.5 mg daily. Level 4: 2 mg daily. Dose Expansion: Maximum Tolerated Dose (MTD)<br>* Other names: MEKINIST®;Drug: Sorafenib<br>* Dose Escalation: Level 1: 200 mg twice daily. Level 2: 200 mg twice daily. Level 3: 400 mg twice daily. Level 4: 400 mg twice daily. Dose Expansion: Maximum Tolerated Dose (MTD)<br>* Other names: Nexavar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The MTD for study is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity (DLT). | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Further, modified RECIST criteria for HCC will be used to evaluate response. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | Up to 3 years | 
| Response Rate | Response will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Further, modified RECIST criteria for HCC will be used to evaluate response. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Up to 3 years | 
| Overall Survival (OS) | Overall Survival is defined as the time period from start of treatment to death. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Neoplasms, Liver Diseases, Digestive System Diseases, Advanced, Mitogen-Activated Protein Kinase (MEK) Inhibitor, Kinase Inhibitor