A Multicenter Phase I/II Study of Enzalutamide With and Without Sorafenib in Advanced Hepatocellular Carcinoma Patients
Overview
- Phase
- Phase 1
- Intervention
- Enzalutamide
- Conditions
- Hepatocellular Carcinoma
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 28
- Locations
- 5
- Primary Endpoint
- Progression-free survival
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
The purpose of this study is to test the safety of enzalutamide with or without sorafenib at different doses. Enzalutamide is approved by the Food and Drug Administration (FDA) for the treatment of advanced prostate cancer. Enzalutamide blocks a protein called the androgen receptor. Experiments on liver cancer cells and animal models show that blocking the androgen receptor causes liver cancer to stop growing. Enzalutamide has not been approved to treat liver cancer. The investigators want to see if enzalutamide is safe for patients with liver cancer who have had their tumors grow on sorafenib. The investigators also want to see how safe and effective sorafenib and enzalutamide are for liver cancer patients that have never been treated with sorafenib. This is the first time enzalutamide and sorafenib are being used together. This treatment may not help treat the participant's cancer.
Detailed Description
This is a multicenter, open label, phase I/II study of enzalutamide with or without sorafenib to define the safety, MTD, and pharmacokinetic parameters of each regimen in advanced HCC patients. The study will have 4 parts as indicated in the Study Schema, an enzalutamide dose escalation (Part 1A), a sorafenib and enzalutamide dose escalation (Part 1B), and dose expansion cohorts for the Part 1A and Part 1B MTDs (Part 2). Dose escalation will occur using a standard 3 + 3 design and is described in Section 4.2.1. For Part 2, the enzalutamide expansion cohort (Part 2A), will enroll 10 patients and is exploratory in nature; however, it will allow for acquisition of additional PK sampling at the MTD, for determination of safety and efficacy. The MTD sorafenib and enzalutamide combination expansion (Part 2B) will be designed using a Simon minimax design to formally evaluate the 4-month PFS.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologic proof of HCC reviewed and confirmed at per the local standard of care.
- •Advanced unresectable or metastatic disease
- •Measurable disease as defined by RECIST version 1.1
- •Tissue available for the evaluation of AR by IHC on pretreatment HCC samples. If tissue is not available, a pretreatment biopsy will not be necessary for eligibility
- •Age ≥ 18 years-old
- •ECOG performance status ≤ 2
- •Child-Pugh category A
- •Adequate hepatic function defined by:
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 x upper limit of normal (ULN)
- •Total Bilirubin ≤ 1.5 x ULN
Exclusion Criteria
- •Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
- •For patients who will receive enzalutamide monotherapy, failure or intolerance of prior sorafenib is required for enrollment. For patients who will receive combination therapy, prior sorafenib is excluded.
- •Patients may not have received cytotoxic, biologic or small molecule kinase inhibitor systemic therapy f or at least 3 weeks prior to the first dose of study treatment.
- •Patients must not have received prior regional therapy such as ablation, embolization, or radiation therapy for at least 2 weeks prior to the first dose of study treatment. Patients who receive such therapy should have evidence of radiologic progression at this site or other progressing measurable disease.
- •Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before study enrollment. Eligible subjects must be without corticosteroid treatment at the time of study enrollment.
- •History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with antiepileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months of enrollment.
- •Clinically significant cardiovascular disease including:
- •Myocardial infarction within six months prior to Screening;
- •Uncontrolled angina within three months prior to Screening;
- •Congestive heart failure NYHA class 3 or 4, or subjects with history of congestive heart
Arms & Interventions
Enzalutamide without Sorafenib
Will get enzalutamide, at the dose approved by the FDA for prostate cancer. If this dose has serious side effects, a lower dose will be given to new patients as they take part in the study. At the end of this part of the study, the recommended dose of enzalutamide will be set for all patients on this study. More patients will then be treated with this dose.
Intervention: Enzalutamide
Enzalutamide with Sorafenib
Will get enzalutamide and sorafenib. The first group of patients will get the recommended dose of enzalutamide with sorafenib by mouth either once or twice daily. The dose of sorafenib you receive will depend on when the patient starts the study. At the beginning of the study, patients will be treated with a lower dose of sorafenib. If this dose does not have serious side effects, a higher dose will be given to new patients as they take part in the study.
Intervention: Enzalutamide
Enzalutamide with Sorafenib
Will get enzalutamide and sorafenib. The first group of patients will get the recommended dose of enzalutamide with sorafenib by mouth either once or twice daily. The dose of sorafenib you receive will depend on when the patient starts the study. At the beginning of the study, patients will be treated with a lower dose of sorafenib. If this dose does not have serious side effects, a higher dose will be given to new patients as they take part in the study.
Intervention: Enzalutamide with Sorafenib
Outcomes
Primary Outcomes
Progression-free survival
Time Frame: 4 months
survival is defined as the time from the initiation of study treatment to HCC radiographic progression or death. Four month PFS is defined as the proportion of patients alive and progression free at 4 months. Patients that come out of study before evaluation of the 4 month endpoint without documented progression will be considered as events for the primary endpoint of 4 month PFS. Progression will be by RECIST 1.1.