Recurrent Lymphoepithelioma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Stage IV Lymphoepithelioma of the Nasopharynx, Stage IV Squamous Cell Carcinoma of the Nasopharynx
Conditions
Brief summary
This phase II trial studies the side effects and how well pazopanib hydrochloride works in treating patients with stage IV or recurrent nasopharyngeal cancer. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
Detailed description
PRIMARY OBJECTIVES: I. Determine the efficacy of pazopanib hydrochloride in patients with stage IV or recurrent nasopharyngeal carcinoma. II. Determine the progression-free survival of patients treated with this drug. III. Determine the toxicity of this drug in these patients. IV. Determine the effect of this drug on angiogenesis inhibition using dynamic contrast-enhanced computed tomography (CT) scan. V. Determine the pharmacokinetic profile of this drug in these patients. VI. Correlate the effect of this drug on angiogenesis inhibition with the clinical benefit rate and pharmacokinetics. OUTLINE: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 12 months.
Interventions
DRUGpazopanib hydrochloride
Given PO
OTHERpharmacological study
Correlative studies
PROCEDUREcomputed tomography
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 or cytologically confirmed nasopharyngeal carcinoma, meeting the following criteria: * World Health Organization (WHO) type II-III disease * Stage IV or recurrent disease * Must have failed at least 1 prior line of chemotherapy for metastatic or recurrent disease * Measurable disease, defined as \>= 1 unidimensionally measurable lesion \>= 20 mm by conventional techniques OR \>= 10 mm by spiral CT scan * No known brain metastases * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 or Karnofsky PS 70-100% * Life expectancy \> 3 months * WBC \>= 3,000/mm³ * Absolute neutrophil count \>= 1,500/mm³ * Platelet count \>= 100,000/mm³ * Bilirubin normal * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 times upper limit of normal (ULN) * Creatinine normal OR creatinine clearance \>= 60 mL/min * Proteinuria =\< 1+ on 2 consecutive dipsticks taken \>= 1 week apart * Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) =\< 1.2 times ULN * Systolic blood pressure (BP) =\< 140 mm Hg and diastolic BP =\< 90 mm Hg * Initiation or adjustment of BP medication allowed provided the average of 3 BP readings are \< 140/90 mm Hg prior to study entry * No history of allergic reaction attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or to other study agents * No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days * No cerebrovascular accident within the past 6 months * No history of any of the following diseases within the past 12 weeks: * Myocardial infarction * Cardiac arrhythmia * Admission for unstable angina * Cardiac angioplasty or stenting * Venous thrombosis * No New York Heart Association (NYHA) class III-IV heart failure * Patients with a history of NYHA class II heart failure are eligible provided they are asymptomatic on treatment * No significant electrocardiogram (ECG) abnormalities, including QTc prolongation (i.e., QTc \>= 500 msec) * No serious or non-healing wound, ulcer, or bone fracture * No condition that would impair the ability to swallow and retain pazopanib hydrochloride, including any of the following: * Gastrointestinal tract disease resulting in an inability to take oral medication * Requirement for IV alimentation * Prior surgical procedures affecting absorption * Active peptic ulcer disease * No concurrent uncontrolled illness including, but not limited to, the following: * Coagulopathy * Ongoing or active infection * Psychiatric illness or social situation that would preclude study compliance * No known allergy to CT contrast agents * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered * More than 4 weeks since prior radiotherapy * At least 4 weeks since prior surgery * No prior antiangiogenesis therapy * No other concurrent investigational agents * No other concurrent anticancer therapy * No concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib hydrochloride, as determined by the Principal Investigator * No concurrent medications that have the potential to interact with the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4 * No concurrent therapeutic warfarin * Low molecular weight heparin or prophylactic low-dose warfarin allowed * No concurrent antiretroviral therapy for human immunodeficiency virus (HIV)-positive patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | 12 weeks of treatment | Clinical benefit rate (CBR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST ver 1.0) and assessed by CT or MRI. CBR includes 1) Complete response (CR): disappearance of all lesions; 2) partial response (PR): \>=30% decrease in the sum of the longest diameter of target lesions and 3) stable disease (SD): non-PR and non progressive disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From the date of enrollment to the date of first documented progression or death, whichever occurs first, or to the date when the patient was last known to be alive, up to 3 years. | Progression will be evaluated in this study using the new international criteria proposed by RECIST Committee. The sample proportion and associated 95% confidence interval will be reported. |
| Overall Survival | From date of enrollment to the study to the date of death from any cause or to the date when the patient was last known to be alive, up to 3 years. | — |
| Toxicity Profile: Percentage of Participants With Significant (Grade 3/4) Related Adverse Event (AE) | From the time of first treatment with pazopanib hydrochloride to up to 30days after completion of treatment | The frequencies of grade 3/4 related toxicities were recorded among all participants, and the percentage of participants who experienced significant AEs were reported. |
| Pharmacodynamic Study: Tumor Blood Flow at Baseline | Pretreatment | Dynamic-contrast enhanced computed tomography (DCE-CT) was performed at baseline and Day 28, tumor blood flow was measured.19 of 33 patients had evaluable DCE-CT data. |
| Pharmacodynamic Study: Tumor Blood Flow on Day 28 | 28 days post treatment | DCE-CT was performed on Day 28 and tumor blood flow was measured. 19 of 33 patients had evaluable DCE-CT data. |
| Response Rate (PR) | 12 weeks of treatment | Per response evaluation criteria in solid tumors (RECIST v1.0) and assessed by MRI or CT: Partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions and non-PD (PD: progressive disease) of non-target lesions. |
| Pharmacokinetic Study: AUC0-24h/Dose on Day 1 | Day 1 of treatment | AUC 0-24h/dose were measured on day 1 for 26 evaluable participants. Blood sampling is done at zero (pre-dose), 0.5 hr, 1, 2, 3, 4, 5, 6 and 8 hrs after the first dose. |
| Pharmacokinetic Study: Area Under Curve (AUC) 0-24h/Dose on Day 28 | Day 28 of treatment | AUC 0-24h/dose were measured on day 28 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after day 28 dose. |
| Pharmacokinetic Study: Volume of Distribution (Vd/F/Dose) on Day 1 | Day 1 of treatment | Volume of distribution (Vd/F/dose) were measured on day 1 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 hrs after first dose. |
| Pharmacokinetic Study: Volume of Distribution at Steady State (Vss/F/Dose) on Day 28 | Day 28 of treatment | Volume of distribution at steady state (Vss/F/Dose) were measured on day 28 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after day 28 dose. |
| Pharmacokinetic Study: Percentage of Participants With Trough Concentration at Steady State (Day 28) Above 15 µg/mL | Day 28 of treatment | Pazopanib pharmacokinetic parameters were estimated on Day 1 and Day 28 (steady state). Trough concentration of pazopanib was measured on Day 28 with blood sampling at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after Day 28 dose. |
Countries
Singapore
Participant flow
Recruitment details
Subjects were screened and enrolled from 2 sites in Singapore, 27 were enrolled from National Cancer Centre Singapore and 6 were enrolled from National University Hospital.
Pre-assignment details
Once a subject signed the informed consent form, the required screening procedures would be performed.Eligible subjects would undergo 2 times of DCE-CT scan before study drug administration.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Tyrosine Kinase Inhibitor) Patients receive pazopanib hydrochloride PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
computed tomography : Correlative studies
pharmacological study : Correlative studies
pazopanib hydrochloride : Given PO | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Tyrosine Kinase Inhibitor) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants |
| Age, Continuous | 50 years STANDARD_DEVIATION 8.4 |
| Region of Enrollment Singapore | 33 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 33 |
| serious Total, serious adverse events | 10 / 33 |
Outcome results
Primary
Clinical Benefit Rate
Clinical benefit rate (CBR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST ver 1.0) and assessed by CT or MRI. CBR includes 1) Complete response (CR): disappearance of all lesions; 2) partial response (PR): \>=30% decrease in the sum of the longest diameter of target lesions and 3) stable disease (SD): non-PR and non progressive disease.
Time frame: 12 weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Clinical Benefit Rate | 54.5 percentage of participants |
Secondary
Overall Survival
Time frame: From date of enrollment to the study to the date of death from any cause or to the date when the patient was last known to be alive, up to 3 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Overall Survival | 10.8 months |
Secondary
Pharmacodynamic Study: Tumor Blood Flow at Baseline
Dynamic-contrast enhanced computed tomography (DCE-CT) was performed at baseline and Day 28, tumor blood flow was measured.19 of 33 patients had evaluable DCE-CT data.
Time frame: Pretreatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacodynamic Study: Tumor Blood Flow at Baseline | 52.2 ml/100ml/min | Standard Deviation 13.6 |
Secondary
Pharmacodynamic Study: Tumor Blood Flow on Day 28
DCE-CT was performed on Day 28 and tumor blood flow was measured. 19 of 33 patients had evaluable DCE-CT data.
Time frame: 28 days post treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacodynamic Study: Tumor Blood Flow on Day 28 | 35.7 ml/100ml/min | Standard Deviation 18.5 |
Secondary
Pharmacokinetic Study: Area Under Curve (AUC) 0-24h/Dose on Day 28
AUC 0-24h/dose were measured on day 28 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after day 28 dose.
Time frame: Day 28 of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacokinetic Study: Area Under Curve (AUC) 0-24h/Dose on Day 28 | 1192.35 hr*ng/mL/mg |
Secondary
Pharmacokinetic Study: AUC0-24h/Dose on Day 1
AUC 0-24h/dose were measured on day 1 for 26 evaluable participants. Blood sampling is done at zero (pre-dose), 0.5 hr, 1, 2, 3, 4, 5, 6 and 8 hrs after the first dose.
Time frame: Day 1 of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacokinetic Study: AUC0-24h/Dose on Day 1 | 836.23 hr*ng/mL/mg |
Secondary
Pharmacokinetic Study: Percentage of Participants With Trough Concentration at Steady State (Day 28) Above 15 µg/mL
Pazopanib pharmacokinetic parameters were estimated on Day 1 and Day 28 (steady state). Trough concentration of pazopanib was measured on Day 28 with blood sampling at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after Day 28 dose.
Time frame: Day 28 of treatment
Population: Patients (total 26) with both Day 1 and Day 28 pharmacokinetic parameters were included.The trough concentration of pazopanib on Day 28 was observed to be above 15ug/ml in approximately 92% of patients at steady state.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacokinetic Study: Percentage of Participants With Trough Concentration at Steady State (Day 28) Above 15 µg/mL | 92 percentage of participants |
Secondary
Pharmacokinetic Study: Volume of Distribution at Steady State (Vss/F/Dose) on Day 28
Volume of distribution at steady state (Vss/F/Dose) were measured on day 28 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 and 24 hrs after day 28 dose.
Time frame: Day 28 of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacokinetic Study: Volume of Distribution at Steady State (Vss/F/Dose) on Day 28 | 80.23 mL/mg |
Secondary
Pharmacokinetic Study: Volume of Distribution (Vd/F/Dose) on Day 1
Volume of distribution (Vd/F/dose) were measured on day 1 for 26 evaluable participants. Blood sampling was done at zero (pre dose), 0.5 hr, 1, 2, 3, 4, 5, 6, 8 hrs after first dose.
Time frame: Day 1 of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Pharmacokinetic Study: Volume of Distribution (Vd/F/Dose) on Day 1 | 18.09 mL/mg |
Secondary
Progression-free Survival
Progression will be evaluated in this study using the new international criteria proposed by RECIST Committee. The sample proportion and associated 95% confidence interval will be reported.
Time frame: From the date of enrollment to the date of first documented progression or death, whichever occurs first, or to the date when the patient was last known to be alive, up to 3 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Progression-free Survival | 4.4 months |
Secondary
Response Rate (PR)
Per response evaluation criteria in solid tumors (RECIST v1.0) and assessed by MRI or CT: Partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions and non-PD (PD: progressive disease) of non-target lesions.
Time frame: 12 weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Response Rate (PR) | 6.1 percentage of participants |
Secondary
Toxicity Profile: Percentage of Participants With Significant (Grade 3/4) Related Adverse Event (AE)
The frequencies of grade 3/4 related toxicities were recorded among all participants, and the percentage of participants who experienced significant AEs were reported.
Time frame: From the time of first treatment with pazopanib hydrochloride to up to 30days after completion of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pazopanib Hydrochloride) | Toxicity Profile: Percentage of Participants With Significant (Grade 3/4) Related Adverse Event (AE) | 48 percentage of participants |