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Temozolomide

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Temozolomide 100 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

Temozolomide 75 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

Temozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

temozolomide

pazopanib hydrochloride

Halla Nimeiri

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.

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

A Phase I/II Study of the Combination of Temozolomide and Pazopanib in Advanced Pancreatic Neuroendocrine Tumors (PNET)

For Patients in Phase II Portion: Patients will have a perfusion functional computed tomography (fCT) scan at baseline and after two courses of treatment.

For Patients in Phase II Portion: The level of expression of tissue methyl-guanine methytransferase (MGMT)will be measured in tissue from the diagnostic biopsy and these results will be correlated with response rate.

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.

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.

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.

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.

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

OS is defined as the time from first study treatment until death from any cause.

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

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

Robert H. Lurie Cancer Center

National Comprehensive Cancer Network

GlaxoSmithKline

Northwestern University

This contains data that has been collected and reported in the eCRFs on April 22nd 2020 and may be updated at the time of secondary outcome measure reporting. Due to the way that adverse events and serious adverse events are collect and reported in the eCRFs the "other" adverse events may contain some serious adverse event data.

Temozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

temozolomide: Given PO

pazopanib hydrochloride: Given PO

Cohort 1 - Temozolomide 150 mg/m2 and Pazopanib 400 mg

Temozolomide 100 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

temozolomide: Given PO

pazopanib hydrochloride: Given PO

Cohort -1 -Temozolomide 100 mg/m2 and Pazopanib 400 mg

Temozolomide 75 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

temozolomide: Given PO

pazopanib hydrochloride: Given PO

Cohort -2 - Temozolomide 75 mg/m2 and Pazopanib 400 mg

Temozolomide 75mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

temozolomide: Given PO

pazopanib hydrochloride: Given PO

Phase II -Temozolomide 75 mg/m2 and Pazopanib 400 mg

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

On review of the phase II data it was determined that the study did not meet continuation criteria according to Simon II stage design and would not meet criteria even with the remaining slot filled. The study was closed to further accrual.

Sheetal Kircher, MD

Temozolomide 75 - 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28

temozolomide: Given PO

pazopanib hydrochloride: Given PO

Cohort 1/Cohort -1/Cohort -2 - Temozolomide and Pazopanib

1 patient in Cohort -1 was not evaluable for this endpoint due to inability to absorb oral medications secondary to bowel edema

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

1 patient was determined not to be evaluable for response in phase II

Overall Response Rate (ORR) in Patients With Advanced Neuroendocrine Tumors (PNET) Treated With Temozolomide and Pazopanib Combination Treatment at the RP2D in Phase II

Any AE

AE related to treatment

SAE related to treatment

Grade 5 SAE

Came off treatment due to an AE

Number of Patients Who Experience Toxicity Events Undergoing This Treatment.

Patient #1 : Cycle 1 Day 1 at time 0 hours

Patient #1 : Cycle 1 Day 1 at time 0.17 hours

Patient #1 : Cycle 1 Day 1 at time 0.5 hours

Patient #1 : Cycle 1 Day 1 at time 1 hours

Patient #1 : Cycle 1 Day 1 at time 2 hours

Patient #1 : Cycle 1 Day 1 at time 3 hours

Patient #1 : Cycle 1 Day 1 at time 4 hours

Patient #1 : Cycle 1 Day 1 at time 6 hours

Patient #1 : Cycle 1 Day 1 at time 8 hours

Patient #1 : Cycle 1 Day 1 at time 24 hours

Patient #1 : Cycle 2 Day 1 at time 0 hours

Patient #1 : Cycle 2 Day 1 at time 0.17 hours

Patient #1 : Cycle 2 Day 1 at time 0.5 hours

Patient #1 : Cycle 2 Day 1 at time 1 hours

Patient #1 : Cycle 2 Day 1 at time 2 hours

Patient #1 : Cycle 2 Day 1 at time 3 hours

Patient #1 : Cycle 2 Day 1 at time 4 hours

Patient #1 : Cycle 2 Day 1 at time 6 hours

Patient #1 : Cycle 2 Day 1 at time 8 hours

Patient #1 : Cycle 2 Day 1 at time 24 hours

Patient #2 : Cycle 1 Day 1 at time 0 hours

Patient #2 : Cycle 1 Day 1 at time 0.17 hours

Patient #2 : Cycle 1 Day 1 at time 0.5 hours

Patient #2 : Cycle 1 Day 1 at time 1 hours

Patient #2 : Cycle 1 Day 1 at time 2 hours

Patient #2 : Cycle 1 Day 1 at time 3 hours

Patient #2 : Cycle 1 Day 1 at time 4 hours

Patient #2 : Cycle 1 Day 1 at time 6 hours

Patient #2 : Cycle 1 Day 1 at time 8 hours

Patient #2 : Cycle 1 Day 1 at time 24 hours

Patient #2 : Cycle 2 Day 1 at time 0 hours

Patient #2 : Cycle 2 Day 1 at time 0.17 hours

Patient #2 : Cycle 2 Day 1 at time 0.5 hours

Patient #2 : Cycle 2 Day 1 at time 1 hours

Patient #2 : Cycle 2 Day 1 at time 2 hours

Patient #2 : Cycle 2 Day 1 at time 3 hours

Patient #2 : Cycle 2 Day 1 at time 4 hours

Patient #2 : Cycle 2 Day 1 at time 6 hours

Patient #2 : Cycle 2 Day 1 at time 8 hours

Patient #2 : Cycle 2 Day 1 at time 24 hours

Patient #3 : Cycle 1 Day 1 at time 0 hours

Patient #3 : Cycle 1 Day 1 at time 0.17 hours

Patient #3 : Cycle 1 Day 1 at time 0.5 hours

Patient #3 : Cycle 1 Day 1 at time 1 hours

Patient #3 : Cycle 1 Day 1 at time 2 hours

Patient #3 : Cycle 1 Day 1 at time 3 hours

Patient #3 : Cycle 1 Day 1 at time 4 hours

Patient #3 : Cycle 1 Day 1 at time 6 hours

Patient #3 : Cycle 1 Day 1 at time 8 hours

Patient #3 : Cycle 1 Day 1 at time 24 hours

Patient #3 : Cycle 2 Day 1 at time 0 hours

Patient #3 : Cycle 2 Day 1 at time 0.17 hours

Patient #3 : Cycle 2 Day 1 at time 0.5 hours

Patient #3 : Cycle 2 Day 1 at time 1 hours

Patient #3 : Cycle 2 Day 1 at time 2 hours

Patient #3 : Cycle 2 Day 1 at time 3 hours

Patient #3 : Cycle 2 Day 1 at time 4 hours

Patient #3 : Cycle 2 Day 1 at time 6 hours

Patient #3 : Cycle 2 Day 1 at time 8 hours

Patient #3 : Cycle 2 Day 1 at time 24 hours

Patient #4 : Cycle 1 Day 1 at time 0 hours

Patient #4 : Cycle 1 Day 1 at time 0.17 hours

Patient #4 : Cycle 1 Day 1 at time 0.5 hours

Patient #4 : Cycle 1 Day 1 at time 1 hours

Patient #4 : Cycle 1 Day 1 at time 2 hours

Patient #4 : Cycle 1 Day 1 at time 3 hours

Patient #4 : Cycle 1 Day 1 at time 4 hours

Patient #4 : Cycle 1 Day 1 at time 6 hours

Patient #4 : Cycle 1 Day 1 at time 8 hours

Patient #4 : Cycle 1 Day 1 at time 24 hours

Patient #4 : Cycle 2 Day 1 at time 0 hours

Patient #4 : Cycle 2 Day 1 at time 0.17 hours

Patient #4 : Cycle 2 Day 1 at time 0.5 hours

Patient #4 : Cycle 2 Day 1 at time 1 hours

Patient #4 : Cycle 2 Day 1 at time 2 hours

Patient #4 : Cycle 2 Day 1 at time 3 hours

Patient #4 : Cycle 2 Day 1 at time 4 hours

Patient #4 : Cycle 2 Day 1 at time 6 hours

Patient #4 : Cycle 2 Day 1 at time 8 hours

Patient #4 : Cycle 2 Day 1 at time 24 hours

Patient #5 : Cycle 1 Day 1 at time 0 hours

Patient #5 : Cycle 1 Day 1 at time 0.17 hours

Patient #5 : Cycle 1 Day 1 at time 0.5 hours

Patient #5 : Cycle 1 Day 1 at time 1 hours

Patient #5 : Cycle 1 Day 1 at time 2 hours

Patient #5 : Cycle 1 Day 1 at time 3 hours

Patient #5 : Cycle 1 Day 1 at time 4 hours

Patient #5 : Cycle 1 Day 1 at time 6 hours

Patient #5 : Cycle 1 Day 1 at time 8 hours

Patient #5 : Cycle 1 Day 1 at time 24 hours

Patient #5 : Cycle 2 Day 1 at time 0 hours

Patient #5 : Cycle 2 Day 1 at time 0.17 hours

Patient #5 : Cycle 2 Day 1 at time 0.5 hours

Patient #5 : Cycle 2 Day 1 at time 1 hours

Patient #5 : Cycle 2 Day 1 at time 2 hours

Patient #5 : Cycle 2 Day 1 at time 3 hours

Patient #5 : Cycle 2 Day 1 at time 4 hours

Patient #5 : Cycle 2 Day 1 at time 6 hours

Patient #5 : Cycle 2 Day 1 at time 8 hours

Patient #5 : Cycle 2 Day 1 at time 24 hours

Temozolomide 75 mg/m2 and Pazopanib 400 mg

Data that was collected but not analyzed. The data that was collected is reported below for each patient at each timepoint.

Plasma Temozolomide Concentration in the Blood at Various Timepoints After Administration

The study did not reach its anticipated sample size and anticipated endpoints for phase II. Due to this and relatively small number of patients it was determined by the PI to have no merit or statistical significance to calculate PFS per dose cohort and dose cohorts were combined to summarize PFS.

Progression Free Survival (PFS)

The study did not reach its anticipated sample size and anticipated endpoints for phase II. Due to this and relatively small number of patients it was determined by the PI to have no merit or statistical significance to calculate OS per dose cohort and dose cohorts were combined to summarize OS.

Overall Survival (OS)

The study did not reach its anticipated sample size and anticipated endpoints for phase II. Due to this and relatively small number of patients it was determined by the PI to have no merit or statistical significance to calculate DCR per dose cohort and dose cohorts were combined to summarize DCR.

Number of Patients Experiencing Response to Treatment or Stable Disease (Disease Control Rate)

Data not collected or analyzed for this outcome measure

Number of Months That Patients Maintain a Response to Treatment Until Disease Progression or Death (Duration of Response)

Determine the Relationship Between Tumor Blood Flow and Overall Response Rate

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Temozolomide and Pazopanib Hydrochloride in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors That Cannot Be Removed By Surgery	NCT01465659	Pancreatic Alph... Pancreatic Beta... Pancreatic Delt... Pancreatic G-ce... Recurrent Islet...	temozolomide pazopanib hydro...	18 Years -	Northwestern University
Capecitabine and Streptozocin With or Without Cisplatin in Treating Patients With Unresectable or Metastatic Neuroendocrine Tumors	NCT00602082	Gastrointestina... Islet Cell Tumo...	capecitabine cisplatin streptozocin DNA analysis RNA analysis protein analysi... proteomic profi... laboratory biom...	18 Years -	National Cancer Institute (NCI)
Collecting Medical Information and Tissue Samples From Patients With Pancreatic Cancer or Other Pancreatic Disorders	NCT00830557	Islet Cell Tumo... Pancreatic Canc... Pancreatic Dise...	medical chart r... survey administ... biospecimen col...	18 Years - 120 Years	Mayo Clinic
Collecting Medical Information and Tissue Samples From Patients With Pancreatic Cancer or Other Pancreatic Disorders	NCT00830557	Islet Cell Tumo... Pancreatic Canc... Pancreatic Dise...	medical chart r... survey administ... biospecimen col...	18 Years - 120 Years	Mayo Clinic

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