Clinical Trials /

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

NCT01465659

Description:

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.

Related Conditions:
  • Pancreatic Neuroendocrine Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Temozolomide and Pazopanib Hydrochloride in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors That Cannot Be Removed By Surgery
  • Official Title: A Phase I/II Study of the Combination of Temozolomide and Pazopanib in Advanced Pancreatic Neuroendocrine Tumors (PNET)

Clinical Trial IDs

  • ORG STUDY ID: NU 11I03
  • SECONDARY ID: NCI-2011-02939
  • SECONDARY ID: STU00053541
  • NCT ID: NCT01465659

Conditions

  • Pancreatic Alpha Cell Carcinoma
  • Pancreatic Beta Islet Cell Carcinoma
  • Pancreatic Delta Cell Carcinoma
  • Pancreatic G-cell Carcinoma
  • Recurrent Islet Cell Carcinoma

Interventions

DrugSynonymsArms
temozolomideSCH 52365, Temodal, Temodar, TMZTemozolomide 100 mg/m2 and Pazopanib 400 mg
pazopanib hydrochlorideGW786034, VotrientTemozolomide 100 mg/m2 and Pazopanib 400 mg

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Temozolomide 100 mg/m2 and Pazopanib 400 mgExperimentalTemozolomide 100 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
  • temozolomide
  • pazopanib hydrochloride
Temozolomide 75 mg/m2 and Pazopanib 400 mgExperimentalTemozolomide 75 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
  • temozolomide
  • pazopanib hydrochloride
Temozolomide 75mg/m2 and Pazopanib 200 mgExperimentalTemozolomide 75mg/m2 on days 1-7 and 15-21 , Pazopanib 200 mg on days 1-28
  • temozolomide
  • pazopanib hydrochloride
Temozolomide 150 mg/m2 and Pazopanib 400 mgExperimentalTemozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 400 mg on days 1-28
  • temozolomide
  • pazopanib hydrochloride
Temozolomide 150 mg/m2 and Pazopanib 800 mgExperimentalTemozolomide 150 mg/m2 on days 1-7 and 15-21 , Pazopanib 800 mg on days 1-28
  • temozolomide
  • pazopanib hydrochloride

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of dose limiting toxicities in patients treated with this regimen
Time Frame:After 28 days (1 course of treatment)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:For Patients in Phase I: Symptoms and Lab Results will be reviewed with patients according to this schedule.
Measure:Amount of pazopanib in the blood at various timepoints after administration
Time Frame:Multiple timepoints during Days 1-3 of course 1 (see description)
Safety Issue:
Description: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.
Measure:Number of years that patients survive without experiencing disease progression
Time Frame:Baseline and after every 2 courses of treatment (8 weeks)
Safety Issue:
Description: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.
Measure:Number of years that patients survive after undergoing study treatment
Time Frame:Baseline and after every 2 courses of treatment (8 weeks)
Safety Issue:
Description: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.
Measure:Number of patients experiencing response to treatment or stable disease
Time Frame:After every 2 courses of treatment (8 weeks)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:For Patients in Phase II Portion: The time patients start receiving treatment until disease progression will be calculated.
Measure:Determine the Relationship between tumor blood flow and Overall Response Rate
Time Frame:At Baseline and after two corurses of treatment (8 weeks)
Safety Issue:
Description:For Patients in Phase II Portion: Patients will have a perfusion functional computed tomography (fCT) scan at baseline and after two courses of treatment.
Measure: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)
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

Last Updated

October 10, 2016