This phase I/II trial studies the side effects and best dose of temozolomide and pazopanib hydrochloride when given together and to see how well they work in treating patients with advanced pancreatic neuroendocrine tumors (PNET) that cannot be removed by surgery. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for tumor growth. Giving temozolomide together with pazopanib hydrochloride may be an effective treatment for patients with PNET.
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of temozolomide and pazopanib (pazopanib hydrochloride) combination in patients with advanced PNET. (Phase I) II. Determine the overall response rate (ORR). (Phase II) SECONDARY OBJECTIVES: I. Determine safety and toxicity profile of the combination of temozolomide and pazopanib in this population. (Phase I) II. Describe the pharmacokinetics of temozolomide alone and in combination with pazopanib. (Phase I) III. Observe the ORR. (Phase I) IV. Determine progression-free survival (PFS) and overall survival (OS), disease control rate (DCR), and duration of response (DOR). (Phase II) V. Determine the safety and toxicity profile of the combination in a larger cohort of patients. (Phase II) TERTIARY OBJECTIVES: I. Examine the relationship between tumor blood flow, as measured by perfusion functional computed tomography (f CT), and overall response. II. Correlate the expression of tissue methyl-guanine methyl transferase (MGMT) as measured by immunohistochemistry (IHC) with ORR and PFS. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive temozolomide orally (PO) once daily (QD) on days 1-7 and 15-21 and pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Given PO
Given PO
Northwestern University
Chicago, Illinois, United States
University of Michigan
Ann Arbor, Michigan, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Vanderbilt University
Nashville, Tennessee, United States
University of Washington Seattle Cancer Care Alliance
Seattle, Washington, United States
Determine the Maximum Tolerated Dose (MTD) of Temozolomide in Combination With 400 mg Pazopanib in Patients With Advanced Pancreatic Neuroendocrine Tumor (PNET) in Phase I
MTD and recommended phase II dose (RP2D) determination for the combination of temozolomide in combination with 400mg pazopanib in patients with advanced PNET will be achieved using a standard "3+3" dose escalation/de-escalation design. After each 3 patients are enrolled into the study, further enrollment will be temporarily suspended until safety has been reviewed for the first 28 days of treatment to determine if dose limiting toxicities have been experienced by patients and if a further 3 patients should be enrolled at the current dose or dose escalation/de-escalation for the next 3 patients should occur.
Time frame: After 28 days (1 cycle of treatment)
Overall Response Rate (ORR) in Patients With Advanced Neuroendocrine Tumors (PNET) Treated With Temozolomide and Pazopanib Combination Treatment at the RP2D in Phase II
Overall response rate will be determined by the number of patients who's best response as assessed by RECIST 1.1 is complete response (CR) and partial response (PR) in patients with PNET that are enrolled at the recommended phase II dose (RP2D) (PK cohort included). CR= Disappearance of all target lesions PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: After two cycles of treatment (8 weeks)
Number of Patients Who Experience Toxicity Events Undergoing This Treatment.
Safety and toxicity will be reported in the number of patients who experience adverse events during treatment, graded using CTCAE 4.03. In general the severity of an AE is graded as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.
Time frame: During treatment and up to one month post last dose of study drug. Range of cycles completed by patients was 1-41 where one cycle =28 days.
Plasma Temozolomide Concentration in the Blood at Various Timepoints After Administration
For the Six Patients in Phase I portion who are enrolled in the PK cohort: Blood will be drawn on Day 1 before beginning treatment and again at 10 minutes, 30 minutes, 1, 2, 3, 4, 6 and 8 hours after beginning treatment. On Day 2- 24 hours after the first dose from Day 1, and again 10 minutes, 30 minutes, 1, 2, 3, 4, 6 and 8 hours after taking the second dose. Day 3 - 24 hours after the second dose from Day 2. Cycle 1 Day 1 only temozolomide will be taken by the patient and on Cycle 2 Day 2, temozolomide and pazopanib will be taken by the patient. Data that was collected but not analyzed. The data that was collected is reported below in raw form.
Time frame: Multiple timepoints during Days 1-3 of cycle 1 and cycle 2 (1 cycle =28 days)
Progression Free Survival (PFS)
PFS will be defined as will be defined as the time from the first study treatment to the first occurrence of progression or death. Progressive disease will be assessed using RECIST v1.1 criteria where in general the following definition is true: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study AND an absolute increase in the sum of at least 5 mm OR the appearance of one or more new lesions
Time frame: Baseline and after every 2 cycles of treatment (8 weeks) for up to 40 months
Overall Survival (OS)
OS is defined as the time from first study treatment until death from any cause.
Time frame: Baseline and after every 2 cycles of treatment (8 weeks) and up to 60 months
Number of Patients Experiencing Response to Treatment or Stable Disease (Disease Control Rate)
Disease Control Rate (DCR) is defined as the number of patients demonstrating the complete response, partial response or stable disease. In general the following is true: Complete Response (CR) Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study
Time frame: After every 2 courses of treatment (8 weeks) for up to 41 cycles where 1 cycle =28 days.
Number of Months That Patients Maintain a Response to Treatment Until Disease Progression or Death (Duration of Response)
Duration of response (DOR) is defined at the time from documented overall response (compete response, partial response, stable disease) until disease progression where the following are true: Complete Response (CR) Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study
Time frame: After every 2 courses of treatment (8 weeks)
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