Temozolomide and Pazopanib Hydrochloride in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors That Cannot Be Removed By Surgery

Brief summary public domain (ClinicalTrials.gov)

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.

Detailed description public domain (ClinicalTrials.gov)

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.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

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 [After 28 days (1 cycle of treatment)]. Number, mg/m2. Cohort 1/Cohort -1/Cohort -2 - Temozolomide and Pazopanib (n=17): 75.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Overall Response Rate (ORR) in Patients With Advanced Neuroendocrine Tumors (PNET) Treated With Temozolomide and Pazopanib Combination Treatment at the RP2D in Phase II [After two cycles of treatment (8 weeks)]. Count Of Participants, Participants. Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=10): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Number of Patients Who Experience Toxicity Events Undergoing This Treatment. [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.]. Number, patients. Any AE: Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg (n=7): 7; Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg (n=5): 5; Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 6; Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=11): 11. AE related to treatment: Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg (n=7): 7; Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg (n=5): 5; Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 6; Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=11): 11. SAE: Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg (n=7): 3; Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg (n=5): 3; Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 1; Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=11): 1. SAE related to treatment: Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg (n=7): 3; Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg (n=5): 1; Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 1; Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=11): 1. Grade 5 SAE: Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg (n=7): 0; Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg (n=5): 1; Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0; Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=11): 0. Came off treatment due to an AE: Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg (n=7): 3; Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg (n=5): 3; Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 3; Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=11): 2.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Plasma Temozolomide Concentration in the Blood at Various Timepoints After Administration [Multiple timepoints during Days 1-3 of cycle 1 and cycle 2 (1 cycle =28 days)]. Number, ng/mL. Patient #1 : Cycle 1 Day 1 at time 0 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #1 : Cycle 1 Day 1 at time 0.17 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #1 : Cycle 1 Day 1 at time 0.5 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 91.8. Patient #1 : Cycle 1 Day 1 at time 1 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 425.5. Patient #1 : Cycle 1 Day 1 at time 2 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 462. Patient #1 : Cycle 1 Day 1 at time 3 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 583. Patient #1 : Cycle 1 Day 1 at time 4 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 210.5. Patient #1 : Cycle 1 Day 1 at time 6 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 105. Patient #1 : Cycle 1 Day 1 at time 8 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 44. Patient #1 : Cycle 1 Day 1 at time 24 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #1 : Cycle 2 Day 1 at time 0 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #1 : Cycle 2 Day 1 at time 0.17 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #1 : Cycle 2 Day 1 at time 0.5 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 25.2. Patient #1 : Cycle 2 Day 1 at time 1 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 90.8. Patient #1 : Cycle 2 Day 1 at time 2 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 516.5. Patient #1 : Cycle 2 Day 1 at time 3 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 255. Patient #1 : Cycle 2 Day 1 at time 4 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 519. Patient #1 : Cycle 2 Day 1 at time 6 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 154. Patient #1 : Cycle 2 Day 1 at time 8 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 99.9. Patient #1 : Cycle 2 Day 1 at time 24 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #2 : Cycle 1 Day 1 at time 0 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #2 : Cycle 1 Day 1 at time 0.17 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 0. Patient #2 : Cycle 1 Day 1 at time 0.5 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 54.9. Patient #2 : Cycle 1 Day 1 at time 1 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 494. Patient #2 : Cycle 1 Day 1 at time 2 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 660.5. Patient #2 : Cycle 1 Day 1 at time 3 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 557.5. Patient #2 : Cycle 1 Day 1 at time 4 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 99. Patient #2 : Cycle 1 Day 1 at time 6 hours: Temozolomide 75 mg/m2 and Pazopanib 400 mg (n=6): 105.5. Patient #2 : Cycle 1 Day 1

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression Free Survival (PFS) [Baseline and after every 2 cycles of treatment (8 weeks) for up to 40 months]. Median, months (95% Confidence Interval). Cohort 1/Cohort -1/Cohort -2 - Temozolomide and Pazopanib (n=29): 9.38 (6.18 to 13.3).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) [Baseline and after every 2 cycles of treatment (8 weeks) and up to 60 months]. Median, months (95% Confidence Interval). Cohort 1/Cohort -1/Cohort -2 - Temozolomide and Pazopanib (n=29): 24.2 (18.3 to NA) [Upper limit was not reached].

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Number of Patients Experiencing Response to Treatment or Stable Disease (Disease Control Rate) [After every 2 courses of treatment (8 weeks) for up to 41 cycles where 1 cycle =28 days.]. Count Of Participants, Participants. Cohort 1/Cohort -1/Cohort -2 - Temozolomide and Pazopanib (n=29): 20.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Number of Months That Patients Maintain a Response to Treatment Until Disease Progression or Death (Duration of Response) [After every 2 courses of treatment (8 weeks)].