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Pancreatic Alpha Cell CarcinomaPhase 1/2NCT01465659

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

A Phase 1/2 study testing temozolomide and pazopanib hydrochloride in people with Pancreatic Alpha Cell Carcinoma and Pancreatic Beta Islet Cell Carcinoma, run by Northwestern University at 5 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
temozolomide and pazopanib hydrochloride
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
5 sitesUnited States
Study dates
12 Dec 2011to 27 Jan 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

United States5 sites

  • University of Michigan

    Ann Arbor, Michigan, 48109

  • Northwestern University

    Chicago, Illinois, 60611

  • Vanderbilt University

    Nashville, Tennessee, 37232

  • Fox Chase Cancer Center

    Philadelphia, Pennsylvania, 19111-2497

  • University of Washington Seattle Cancer Care Alliance

    Seattle, Washington, 98109

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Being tested
temozolomide, pazopanib hydrochloride
Medical subject headings
Carcinoma, Islet Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • temozolomideDrug

    Also called SCH 52365, Temodal, Temodar, TMZ

    Given PO

  • pazopanib hydrochlorideDrug

    Also called GW786034, Votrient

    Given PO

Study groups in NCT01465659
Study groupRoleWhat they receive
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
Receives: Drug: temozolomide; Drug: 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
Receives: Drug: temozolomide; Drug: 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
Receives: Drug: temozolomide; Drug: pazopanib hydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    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.

    Measured: After 28 days (1 cycle of treatment)

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

    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.

    Measured: After two cycles of treatment (8 weeks)

Secondary outcomes (6)

  1. Number of Patients Who Experience Toxicity Events Undergoing This Treatment.

    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.

    Measured: 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.

  2. Plasma Temozolomide Concentration in the Blood at Various Timepoints After Administration

    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.

    Measured: Multiple timepoints during Days 1-3 of cycle 1 and cycle 2 (1 cycle =28 days)

  3. Progression Free Survival (PFS)

    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

    Measured: Baseline and after every 2 cycles of treatment (8 weeks) for up to 40 months

  4. Overall Survival (OS)

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

    Measured: Baseline and after every 2 cycles of treatment (8 weeks) and up to 60 months

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

    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

    Measured: After every 2 courses of treatment (8 weeks) for up to 41 cycles where 1 cycle =28 days.

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

    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

    Measured: After every 2 courses of treatment (8 weeks)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Nov 2011 (estimated)
  2. Study start12 Dec 2011
  3. Primary completion30 Jul 2018
  4. Study completion27 Jan 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01465659
Sponsor's protocol ID
NU 11I03
Other IDs
NCI-2011-02939, STU00053541
Status last verified
Jul 2021
First submitted
4 Oct 2011
Last updated
5 Aug 2021
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing temozolomide and pazopanib hydrochloride in people with Pancreatic Alpha Cell Carcinoma and Pancreatic Beta Islet Cell Carcinoma, run by Northwestern University at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01465659.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2021.

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