Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer
Conditions
Brief summary
Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase II trial is studying how well lapatinib ditosylate works in treating patients with unresectable liver or biliary tract cancer
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the objective response rate (complete response \[CR\] + partial response \[PR\]) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria in each group of patients. SECONDARY OBJECTIVES: I. To evaluate the progression free survival at 6 months. II. To evaluate the toxicity profile of this treatment in each group of patients. III. To evaluate median overall survival, 6 and 12 months survival rates. IV. To assess target-epidermal growth factor receptor (EGFR)/EGFR-P protein expression and the genes that regulate the cell cycle and apoptosis, which are either downstream of or cross-talk with the EGFR signaling pathway, to explore their association with clinical outcome. V. To measure expression profile and mutations of genes critical for EGFR and (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2 signaling pathways with particular relevance to GW572016, and to explore new gene-drug relationships as relating to hepatocellular and biliary carcinomas. OUTLINE: This is a multicenter study. Patients receive oral lapatinib ditosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study within 1 year.
Interventions
DRUGlapatinib ditosylate
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of 1 of the following: * Hepatocellular carcinoma (hepatoma) * Child-Pugh classification score ≤ 7 * Biliary tract carcinoma * Surgically unresectable disease * Measurable disease * At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan * Fresh tissue or paraffin embedded tissue from tumor blocks available * No ampulla of Vater tumors * No known brain metastases * Performance status - ECOG 0-1 * Performance status - Karnofsky 60-100% * More than 12 weeks * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 75,000/mm\^3 * Bilirubin ≤ 2 times upper limit of normal (ULN) * AST and ALT ≤ 3 times ULN * Albumin ≥ 2.5 mg/dL * INR ≤ 1.5 (for patients not receiving an anticoagulant) * Live metastases or stable chronic liver disease allowed * No current active hepatic or biliary disease except for Gilbert's syndrome or asymptomatic gallstone * Creatinine ≤ 2 mg/dL * Ejection fraction normal by echocardiogram or MUGA * No unstable angina pectoris * No cardiac arrhythmia * Able to swallow and retain oral medication * No gastrointestinal (GI) tract disease resulting in an inability to take oral medication * No malabsorption syndrome * No requirement for IV alimentation * No uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No significant traumatic injury within the past 3 weeks * No active or ongoing infection * No history of allergic reaction attributed to compounds of similar chemical or biological composition to lapatinib * No psychiatric illness or social situation that would preclude study compliance * No other uncontrolled illness * No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix * More than 4 weeks since prior biologic therapy * More than 4 weeks since prior immunotherapy * See Radiotherapy * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) * No prior cumulative doxorubicin dose \> 450 mg/m\^2 * At least 14 days since prior and no concurrent glucocorticoids (e.g., dexamethasone or equivalent \[dose \> 1.5 mg/day\]) * More than 4 weeks since prior radiotherapy * More than 12 weeks since prior radiotherapy with or without a fluoropyrimidine as a radiosensitizer (for patients with biliary carcinoma only) * No prior surgical procedure affecting absorption * More than 3 weeks since prior major surgery * Recovered from all prior therapy * No more than 1 prior systemic anticancer therapy, including chemoembolization * No prior epidermal growth factor receptor-targeting therapy * More than 6 weeks since prior cryotherapy, radiofrequency ablation, ethanol injection, transarterial chemoembolization, or photodynamic therapy AND meets both of the following criteria: * Indicator lesion is outside the area of prior treatment OR there is clear evidence of disease progression associated with the sole indicator lesion * Edges of indicator lesion are clearly distinct by CT scan * At least 7 days since prior and no concurrent H2 inhibitors or proton pump inhibitors * Concurrent antacids allowed provided they are administered \> 1 hour before and \> 1 hour after study drug administration * At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following: * Clarithromycin * Erythromycin * Troleandomycin * Delaviridine * Ritonavir * Indinavir * Saquinavir * Nelfinavir * Amprenavir * Lopinavir * Itraconazole * Ketoconazole * Voriconazole * Fluconazole (doses ≤ 150 mg/day are allowed) * Nefazodone * Fluvoxamine * Verapamil * Diltiazem * Cimetidine * Aprepitant * Grapefruit and grapefruit juice * Bitter orange * At least 6 months since prior and no concurrent amiodarone * At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the following: * Phenytoin * Carbamazepine * Phenobarbital * Oxcarbazepine * Efavirenz * Nevirapine * Rifampin * Rifabutin * Rifapentine * Roxithromycin * Telithromycin * Hypericum perforatum (St. John's wort) * Modafinil * No concurrent combination antiretroviral therapy for HIV-positive patients * No other concurrent investigational agents * No other concurrent anticancer therapy * Concurrent oral anticoagulants (e.g., coumadin or warfarin) allowed provided there is increased vigilance in monitoring INR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Demonstrating Objective Response (PR+CR) as Defined by RECIST | Up to 3 years | PR (Partial Response) definded as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. CR (Complete Response) is defined as the disappearance of all target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Profile Assessed Using NCI CTCAE Version 3.0 | Up to 3 years | Percentage of patients with Adverse events accordng to NCI CTCAE version 3.0 |
| Median Overall Survival | Up to 3 years | — |
| Progression-free Survival | up to 6 months | — |
| Target-EGFR/EGFR-P Protein Expression | Up to 3 years | EGFR (exons 18-21) |
| Expression Profile and Mutations of Genes Critical for EGFR and ERBB2 Signaling Pathways | Up to 3 years | — |
| Overall Survival | up to 12.6 months | — |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled between the dates of March 3, 2006-May 14, 2007.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients receive oral lapatinib ditosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
lapatinib ditosylate
laboratory biomarker analysis: Correlative studies | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Continuous | 58 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Performance status 0 | 12 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Performance status 1 | 14 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Prior treatments Chemo-embolization | 2 participants |
| Prior treatments Chemotherapy | 3 participants |
| Prior treatments Surgery | 16 participants |
| Prior treatments Unknown | 2 participants |
| Prior treatments X-ray treatment | 3 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 18 Participants |
| Sites of metastasis Adrenal gland | 1 participants |
| Sites of metastasis Bone | 1 participants |
| Sites of metastasis Chest wall | 1 participants |
| Sites of metastasis Hepatic mets | 1 participants |
| Sites of metastasis Lungs | 8 participants |
| Sites of metastasis Lymph nodes | 8 participants |
| Sites of metastasis Not available | 4 participants |
| Sites of metastasis Peritoneal mets | 1 participants |
| Sites of metastasis Spine | 1 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
Proportion of Patients Demonstrating Objective Response (PR+CR) as Defined by RECIST
PR (Partial Response) definded as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. CR (Complete Response) is defined as the disappearance of all target lesions.
Time frame: Up to 3 years
Population: Only 25 patients were evaluable for response (1 patient passed away before staging).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Proportion of Patients Demonstrating Objective Response (PR+CR) as Defined by RECIST | 0 patients |
Secondary
Expression Profile and Mutations of Genes Critical for EGFR and ERBB2 Signaling Pathways
Time frame: Up to 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Expression Profile and Mutations of Genes Critical for EGFR and ERBB2 Signaling Pathways | 0 patients with mutations |
Secondary
Median Overall Survival
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Median Overall Survival | 12.6 months |
Secondary
Overall Survival
Time frame: up to 12.6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Overall Survival | 12.6 months |
Secondary
Progression-free Survival
Time frame: up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I | Progression-free Survival | 1.9 months |
Secondary
Target-EGFR/EGFR-P Protein Expression
EGFR (exons 18-21)
Time frame: Up to 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Target-EGFR/EGFR-P Protein Expression | 0 patients with somatic mutations |
Secondary
Toxicity Profile Assessed Using NCI CTCAE Version 3.0
Percentage of patients with Adverse events accordng to NCI CTCAE version 3.0
Time frame: Up to 3 years
Population: All 26 patients were evaluable for toxicity analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I | Toxicity Profile Assessed Using NCI CTCAE Version 3.0 | Diarrhea | 73 percentage of patients |
| Arm I | Toxicity Profile Assessed Using NCI CTCAE Version 3.0 | Nausea | 54 percentage of patients |
| Arm I | Toxicity Profile Assessed Using NCI CTCAE Version 3.0 | Rash | 50 percentage of patients |