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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Northwestern University
Sponsor:
Collaborators:
Robert H. Lurie Cancer Center
National Comprehensive Cancer Network
GlaxoSmithKline
Information provided by (Responsible Party):
Northwestern University
ClinicalTrials.gov Identifier:
NCT01465659
First received: October 4, 2011
Last updated: September 11, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Pancreatic Alpha Cell Carcinoma
Pancreatic Beta Islet Cell Carcinoma
Pancreatic Delta Cell Carcinoma
Pancreatic G-cell Carcinoma
Recurrent Islet Cell Carcinoma
Drug: temozolomide
Drug: pazopanib hydrochloride
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of the Combination of Temozolomide and Pazopanib in Advanced Pancreatic Neuroendocrine Tumors (PNET)

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • Number of dose limiting toxicities in patients treated with this regimen [ Time Frame: After 28 days (1 course of treatment) ] [ Designated as safety issue: Yes ]
    For patients in the Phase I portion: Toxicity will be assessed according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The number of patients experiencing dose limiting toxicities at a particular level will determine whether the dose can be tolerated.

  • Number of patients responding to treatment [ Time Frame: After two courses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    For patients in the Phase II portion: Patients will have a CT scan after two courses of treatment to determine whether their disease is responding to treatment.


Secondary Outcome Measures:
  • Number of toxicity events noted in patients undergoing this treatment. [ Time Frame: Weekly during the first course of treatment (Every 28 days) and then Bi-Weekly thereafter as long as patients are on treatment ] [ Designated as safety issue: Yes ]
    For Patients in Phase I: Symptoms and Lab Results will be reviewed with patients according to this schedule.

  • Amount of pazopanib in the blood at various timepoints after administration [ Time Frame: Multiple timepoints during Days 1-3 of course 1 (see description) ] [ Designated as safety issue: No ]
    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.

  • Number of years that patients survive without experiencing disease progression [ Time Frame: Baseline and after every 2 courses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    For Patients in Phase II Portion: The Length of time between when the patient begins treatment and when disease progression is first noted will be calculated.

  • Number of years that patients survive after undergoing study treatment [ Time Frame: Baseline and after every 2 courses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    For Patients in Phase II Portion: The Length of time between when the patient begins treatment and when and when the patient becomes deceased will be calculated.

  • Number of patients experiencing response to treatment or stable disease [ Time Frame: After every 2 courses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    For Patients in Phase II Portion: The number of patients demonstrating the complete response, partial response or stable disease after 8 weeks of treatment will be calculated.

  • Number of months that patients maintain a response to treatment until disease progression or death [ Time Frame: After every 2 courses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    For Patients in Phase II Portion: The time patients start receiving treatment until disease progression will be calculated.

  • Determine the Relationship between tumor blood flow and Overall Response Rate [ Time Frame: At Baseline and after two corurses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    For Patients in Phase II Portion: Patients will have a perfusion functional computed tomography (fCT) scan at baseline and after two courses of treatment.

  • Amount of a particular tumor biomarker in blood as correlated with progression free survival [ Time Frame: Baseline and at Response assessment after two courses of treatment (8 weeks) ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 39
Study Start Date: November 2011
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy and enzyme inhibitor)
Patients receive temozolomide PO 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.
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Drug: pazopanib hydrochloride
Given PO
Other Names:
  • GW786034
  • Votrient

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • Total bilirubin =< 2 mg/dL or =< 1.5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 5 times ULN
  • International normalized ratio (INR) =< 1.2 times upper limit of normal (ULN); subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation
  • Activated partial thromboplastin time (aPTT) =< 1.2 x ULN
  • Albumin >= 2.8 g/dL
  • Serum creatinine =< 1.5 times ULN OR if serum creatinine >= 1.5 mg/dL, calculated creatinine clearance >= 30 mL/min
  • Urine protein to creatinine ratio < 1 OR 24-hour urine protein < 1 g
  • Patients must be able to tolerate oral medications
  • Females of child-bearing potential must have a negative pregnancy test within 14 days of study enrollment and must agree to use an effective method of birth control during treatment and for three months after receiving their last dose of study drug; males must agree to use an effective method of birth control during treatment and for three months after receiving their last dose of study drug; all patients must notify treating provider immediately if any suspicion of pregnancy or conception;
  • Child-bearing potential is defined as any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has NOT undergone a hysterectomy or bilateral oophorectomy; OR has NOT been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
  • The eligibility of patients receiving any medications or substances known or with potential to affect the activity or pharmacokinetics of temozolomide and/or pazopanib will be determined following review of the case by the Principal Investigator and the Data Monitoring Committee (DMC); efforts should be made to switch patients who are taking enzyme-inducing agents to other medications
  • Patients must have given signed, informed consent prior to registration on study

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
  • Known intraluminal metastatic lesion/s with risk of bleeding
  • Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease)
  • Other gastrointestinal conditions with increased risk of perforation
  • Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment are NOT eligible for participation
  • Patients with clinically significant gastrointestinal abnormalities that may affect absorption of the investigational product including are NOT eligible for participation; these may include (but are not limited to):
  • Malabsorption syndrome
  • Major resection of the stomach or small bowel
  • Patients with a history of any one or more of the following cardiovascular conditions within the past 6 months prior to study enrollment are NOT eligible for participation:
  • Cardiac angioplasty or stenting
  • Myocardial infarction
  • Unstable angina
  • Coronary artery bypass graft surgery
  • Symptomatic peripheral vascular disease
  • Class III or IV congestive heart failure, as defined by the New York Heart Association
  • Patients with a corrected QT interval (QTc) > 480 msecs are NOT eligible for participation
  • Patients with a history of transient ischemic attack (TIA) or cerebrovascular accident (CVA) within the past 6 months prior to study enrollment are NOT eligible for participation
  • Patients with a history of any one or more of the following thromboembolic events within the past 6 months prior to study enrollment are NOT eligible for participation:
  • Pulmonary embolism
  • Untreated deep venous thrombosis (DVT); subjects with recent DVT who have been therapeutically coagulated for at least 6 weeks ARE eligible
  • Patients who have undergone major surgery or trauma within 28 days prior to the first dose of investigational product and/or present with any non-healing wound, fracture, or ulcer are NOT eligible for participation; procedures such as catheter placement not considered to be major surgery
  • Patients with known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage are NOT eligible for participation
  • Lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating, the vessels is acceptable; CT with contrast is strongly recommended to evaluate such lesions
  • Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed
  • Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of the bronchi are allowed
  • Patients who have had recent hemoptysis (>= 1/2 teaspoon of red blood within 8 weeks before first dose of study drug) are NOT eligible for participation
  • Patients who have any history of allergic reaction(s) attributed to compounds of similar composition to temozolomide, pazopanib, their metabolites, or any component of their formulation are NOT eligible for participation
  • Females who are pregnant or lactating, fertile males, or females of child-bearing potential who are not willing to comply with an effective double method of birth control are NOT eligible for participation
  • Patients with a psychiatric illness, other condition or significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements are NOT eligible for participation
  • Patients who have taken medications that are known strong inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) within 28 days prior to registration are NOT eligible for participation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01465659

Contacts
Contact: Study Coordinator 312-695-1301 cancertrials@northwestern.edu

Locations
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Halla null. Nimeiri    312-695-4381    h-nimeiri@northwestern.edu   
Principal Investigator: Halla null. Nimeiri         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Mark M. Zalupski    734-615-3969    zalupski@med.umich.edu   
Principal Investigator: Mark M. Zalupski         
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111-2497
Contact: Steven J. Cohen    215-728-2570    Steven.Cohen@fccc.edu   
Principal Investigator: Steven J. Cohen         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Jordan D. Berlin    615-936-8422    jordan.berlin@Vanderbilt.edu   
Principal Investigator: Jordan D. Berlin         
Sponsors and Collaborators
Northwestern University
Robert H. Lurie Cancer Center
National Comprehensive Cancer Network
GlaxoSmithKline
Investigators
Principal Investigator: Halla Nimeiri Northwestern University
  More Information

No publications provided

Responsible Party: Northwestern University
ClinicalTrials.gov Identifier: NCT01465659     History of Changes
Other Study ID Numbers: NU 11I03, NCI-2011-02939, STU00053541
Study First Received: October 4, 2011
Last Updated: September 11, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Carcinoma
Neuroendocrine Tumors
Carcinoma, Islet Cell
Adenoma, Islet Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Adenocarcinoma
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Adenoma
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 16, 2014