A Phase I/II Study of the Combination of Temozolomide and Pazopanib in Advanced Pancreatic Neuroendocrine Tumors (PNET)
Overview
- Phase
- Phase 1
- Intervention
- temozolomide
- Conditions
- Pancreatic Alpha Cell Carcinoma
- Sponsor
- Northwestern University
- Enrollment
- 29
- Locations
- 5
- Primary Endpoint
- Overall Response Rate (ORR) in Patients With Advanced Neuroendocrine Tumors (PNET) Treated With Temozolomide and Pazopanib Combination Treatment at the RP2D in Phase II
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed islet cell carcinoma (PNET) not amenable to surgical resection
- •Patients may have had 0-2 prior therapies; prior chemoembolization or local ablative therapies are permitted if completed \>= 6 weeks prior to study enrollment
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
- •Patients must have a life expectancy \> 3 months
- •Patients must have radiographically measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
- •Patients' baseline blood pressure must be adequately controlled with or without antihypertensive medications prior to enrollment (systolic \< 140 mmHg, diastolic \< 90 mmHg)
- •Patients must have left ventricular ejection fraction (LVEF) \>= 50 as measured by echocardiogram or multi gated acquisition scan (MUGA)
- •Absolute neutrophil count (ANC) \>= 1,500/µL
- •Platelets \>= 100,000/µL
- •Hemoglobin \>= 9.0 g/dL
Exclusion Criteria
- •Patients taking immunosuppressive medications (including systemic corticosteroids unless used for adrenal replacement), appetite stimulants, acute therapy for asthma or acute bronchitis exacerbation, or antiemetics are NOT eligible for participation
- •Patients with known human immunodeficiency virus (HIV) infection are NOT eligible for participation
- •Patients with uncontrolled hypertension (\>= 140/90 mmHg) are NOT eligible for participation
- •Patients with uncontrolled hyperlipidemia (total cholesterol \> 350 or triglycerides \> 300) are NOT eligible for participation
- •Patients who have had a transfusion within 7 days of screening are NOT eligible for participation
- •Patients with symptomatic brain or bone metastasis (mets) are NOT eligible for participation; prior radiation and/or steroid therapy for brain or bone mets must be completed \>= 2 weeks prior to study enrollment
- •Patients with a history of seizure disorder requiring antiepileptic medication or brain metastases with seizures are NOT eligible for participation
- •Patients with an active second malignancy (other than non-melanoma skin cancer or cervical carcinoma in situ) are NOT eligible for participation; patients who have a history of malignancy are not considered to have a currently active malignancy if they have completed therapy and are now considered by their physician to be at \< 30% risk for relapse
- •Patients with clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding are NOT eligible for participation; these may include (but are not limited to):
- •Active peptic ulcer disease
Arms & Interventions
Temozolomide 100 mg/m2 and Pazopanib 400 mg
Temozolomide 100 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
Intervention: temozolomide
Temozolomide 100 mg/m2 and Pazopanib 400 mg
Temozolomide 100 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
Intervention: pazopanib hydrochloride
Temozolomide 75 mg/m2 and Pazopanib 400 mg
Temozolomide 75 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
Intervention: temozolomide
Temozolomide 75 mg/m2 and Pazopanib 400 mg
Temozolomide 75 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
Intervention: pazopanib hydrochloride
Temozolomide 150 mg/m2 and Pazopanib 400 mg
Temozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
Intervention: temozolomide
Temozolomide 150 mg/m2 and Pazopanib 400 mg
Temozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
Intervention: pazopanib hydrochloride
Outcomes
Primary Outcomes
Overall Response Rate (ORR) in Patients With Advanced Neuroendocrine Tumors (PNET) Treated With Temozolomide and Pazopanib Combination Treatment at the RP2D in Phase II
Time Frame: After two cycles of treatment (8 weeks)
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.
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
Time Frame: After 28 days (1 cycle of treatment)
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.
Secondary Outcomes
- 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.)
- 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))
- Progression Free Survival (PFS)(Baseline and after every 2 cycles of treatment (8 weeks) for up to 40 months)
- Overall Survival (OS)(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)(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)(After every 2 courses of treatment (8 weeks))