Erlotinib in Combination With Docetaxel in Advanced Hepatocellular and Biliary Tract Carcinomas

Study Overview
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Brief Summary
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An unmet medical need exists for the successful therapy of patients with advanced hepatocellular and biliary tract malignances, with few and short lived disease responses to chemotherapy for both advanced stage hepatic and biliary carcinomas. Pre-clinical data shows cooperative antitumor activity between an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and taxanes. The efficacy of erlotinib in combination with docetaxel will be assessed in this trial.

Detailed Description
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Outline: This is a multi-center study. Patients who meet eligibility criteria will receive treatment as follows until disease progression or excessive toxicities: Erlotinib 150 mg p.o. daily on days 2-7, 9-14, 16-28 Docetaxel 30 mg/m2 IV over 30 min weekly x 3 weeks on days 1, 8, 15 Treatment cycle = 28 days Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 Life expectancy: At least 12 weeks Hematopoietic: Absolute neutrophil count (ANC) > 1000 mm3 Platelet count > 75,000 mm3 Hemoglobin > 8 g/dL Hepatic: Bilirubin < 2.0 x upper limit of normal (ULN) Transaminases (AST, ALT) < 5.0 x ULN if alkaline phosphatase is < 2.5 x ULN, or alkaline phosphatase < 5 x ULN if transaminases are < 1.5 x ULN. If not on anticoagulation: PT < 4 seconds above ULN; INR < 1.5; PTT < 1.3 x ULN. If on therapeutic anticoagulation, patients may have an INR > 1.5 and PTT within therapeutic range; INR will be monitored weekly until stable. Serum Albumin > 3.0 Renal: Creatinine clearance of > 60 ml/ min (by Cockcroft-Gault) Pulmonary: Not specified

Official Title
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Phase II Trial of Erlotinib in Combination With Docetaxel in Advanced Hepatocellular and Biliary Tract Carcinomas: Hoosier Oncology Group GI06-101

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of hepatocellular or biliary tract carcinomas, not amenable to curative resection or transplantation. Prior cancer treatment completed at least 30 days prior to being registered for protocol therapy and recovered from the acute toxicity effects of the regimen. Patients may have had radiofrequency ablation, cryosurgery or embolization, but must have documented progressive disease with the involved lesion, or at least one previously untreated lesion. Patients may have had ≤ 2 prior chemotherapy regimens. Prior radiation therapy allowed to < 25% of the bone marrow at least 30 days prior to being registered for protocol therapy. Patients with biliary obstruction must have percutaneous transhepatic drainage or endoscopic stent placement prior to starting study treatment. Patients with a history of malignancy are eligible provided they have been curatively treated and demonstrate no evidence for recurrence of that cancer. Peripheral neuropathy ≤ grade 1. Patients must agree to abstain from frozen or fresh grapefruit or grapefruit juice for 5 days prior to, and during treatment. Patients must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) while on treatment and for a 12 week period thereafter. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy. Written informed consent and HIPAA authorization for release of personal health information. Age ≥ 18 years at time of consent. Exclusion Criteria: No previous treatment with EGFR inhibitors. No treatment with any investigational agent within 30 days prior to being registered for protocol therapy. No symptomatic brain metastasis. A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic. No Child-Pugh B or C liver cirrhosis. No active corneal erosions or history of abnormal corneal sensitivity test. No history of aneurysm or arteriovenous malformation. No hemorrhage/bleeding event > CTCAE Grade 3 within 30 days prior to begin registered for protocol therapy. No clinically significant infections as judged by the treating investigator. No condition that impairs patient's ability to swallow whole pills. No history of hypersensitivity to docetaxel or other drugs formulated with polysorbate 80. Females must not be breastfeeding. Patients who cannot avoid the following medications will be ineligible for the trial: midazolam, anti-mycotic agents (ketoconazole and related compounds), macrolide antibiotics (erythromycin and related compounds), nifedipine, phenobarbital, phenytoin, carbamazepine, and rifampin (induction) and anti-retrovirals (including ritonavir, saquinavir).

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib and Docetaxel: Biliary<br>Erlotinib 150 mg p.o. daily, days 2-7, 9-14, 16-28 Docetaxel 30 mg/m2 IV over 30 min weekly x 3 weeks on days 1, 8 and 15 | Drug: Erlotinib<br>* Erlotinib 150 mg p.o. daily, days 2-7, 9-14, 16-28<br>Drug: Docetaxel<br>* Docetaxel 30 mg/m2 IV over 30 min weekly x 3 weeks on days 1, 8 and 15<br>|
| Experimental: Erlotinib and Docetaxel: Hepatocellular<br>Erlotinib 150 mg p.o. daily, days 2-7, 9-14, 16-28 Docetaxel 30 mg/m2 IV over 30 min weekly x 3 weeks on days 1, 8 and 15 | Drug: Erlotinib<br>* Erlotinib 150 mg p.o. daily, days 2-7, 9-14, 16-28<br>Drug: Docetaxel<br>* Docetaxel 30 mg/m2 IV over 30 min weekly x 3 weeks on days 1, 8 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 16 Weeks Progression-free Survival | To determine the rate of progression-free survival (PFS) at 16 weeks for the combination therapy of erlotinib and docetaxel for subjects in the Biliary stratum, per RECIST criteria. Progressive disease is defined as at least a 20% increase in the sum of the longest diameter of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions. | Start of treatment until disease progression per RECIST criteria up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Determine the Response Rate Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) | 18 months | 
| Overall Survival | Determine Overall Survival | 18 Months |