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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01465659
Recruitment Status : Active, not recruiting
First Posted : November 6, 2011
Results First Posted : June 17, 2020
Last Update Posted : June 17, 2020
Sponsor:
Collaborators:
Robert H. Lurie Cancer Center
National Comprehensive Cancer Network
GlaxoSmithKline
Information provided by (Responsible Party):
Northwestern University

Tracking Information
First Submitted Date  ICMJE October 4, 2011
First Posted Date  ICMJE November 6, 2011
Results First Submitted Date  ICMJE May 12, 2020
Results First Posted Date  ICMJE June 17, 2020
Last Update Posted Date June 17, 2020
Actual Study Start Date  ICMJE December 12, 2011
Actual Primary Completion Date July 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2020)
  • Determine the Maximum Tolerated Dose (MTD) of Temozolomide and Pazopanib Combination in Patients With Advanced Pancreatic Neuroendocrine Tumor (PNET) in Phase I [ Time Frame: After 28 days (1 course of treatment) ]
    MTD and recommended phase II dose (RP2D) determination for the combination of temozolomide and 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 (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 courses 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2011)
  • Number of dose limiting toxicities in patients treated with this regimen [ Time Frame: After 28 days (1 course of treatment) ]
    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) ]
    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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2011)
  • 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 ]
    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) ]
    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) ]
    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) ]
    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) ]
    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) ]
    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) ]
    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) ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Temozolomide and Pazopanib Hydrochloride in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors That Cannot Be Removed By Surgery
Official Title  ICMJE A Phase I/II Study of the Combination of Temozolomide and Pazopanib in Advanced Pancreatic Neuroendocrine Tumors (PNET)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pancreatic Alpha Cell Carcinoma
  • Pancreatic Beta Islet Cell Carcinoma
  • Pancreatic Delta Cell Carcinoma
  • Pancreatic G-cell Carcinoma
  • Recurrent Islet Cell Carcinoma
Intervention  ICMJE
  • Drug: temozolomide
    Given PO
    Other Names:
    • SCH 52365
    • Temodal
    • Temodar
    • TMZ
  • Drug: pazopanib hydrochloride
    Given PO
    Other Names:
    • GW786034
    • Votrient
Study Arms  ICMJE
  • Experimental: 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
    Interventions:
    • Drug: temozolomide
    • Drug: pazopanib hydrochloride
  • Experimental: 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
    Interventions:
    • Drug: temozolomide
    • Drug: pazopanib hydrochloride
  • Experimental: 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
    Interventions:
    • Drug: temozolomide
    • Drug: pazopanib hydrochloride
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 27, 2019)
29
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2011)
39
Estimated Study Completion Date  ICMJE August 2021
Actual Primary Completion Date July 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01465659
Other Study ID Numbers  ICMJE NU 11I03
NCI-2011-02939 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STU00053541 ( Other Identifier: Northwestern University IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE
  • Robert H. Lurie Cancer Center
  • National Comprehensive Cancer Network
  • GlaxoSmithKline
Investigators  ICMJE
Principal Investigator: Halla Nimeiri Northwestern University
PRS Account Northwestern University
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP