Phase II Trial of Vandetanib in Children and Adults With Wild-Type Gastrointestinal Stromal Tumors
Condition: GIST
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: Vandetanib
Intervention description: Vandetanib administered orally once per day continuously using a 28 day cycle until disease progression or unacceptable toxicity
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 3 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: GIST; Small Molecule; Mesenchymal Tumor; Receptor Tyrosine Kinase; Survival

Summary:

      Background:

      -Some people with wild-type gastrointestinal stromal tumors (WT-GIST) have a deficiency in
      one of their proteins called succinate dehydrogenase (SDH). Vandetanib is a cancer drug that
      has been approved to treat thyroid cancer and has been used with some success in other tumors
      that have a similar loss of SDH. Researchers want to see if this drug can also decrease tumor
      growth in people with WT-GIST.

      Objectives:

      -To test whether the study drug will benefit people with WT-GIST.

      Eligibility:

      -Adults and children 3 years old and older with WT-GIST.

      Design:

        -  Researchers will test participants tumor tissue to confirm it is the wild type of GIST.

        -  Participants will be screened with a medical history, physical exam, and blood tests.
           They will also have electrical recording of the heart (Eastern Cooperative Oncology
           Group (ECOG)) and scans of the tumor.

        -  Participants will take the study drug in 28-day cycles. Their doctor will decide how
           many cycles they can complete.

             -  They will take the study drug once every day and record it in a diary.

             -  On Day 14, they will also visit their doctor to look for side effects.

        -  Before cycles 2, 3 and 4, participants will have a physical exam, urine tests, blood
           pressure check, and blood tests. These tests will then be done periodically for as long
           as they are in the study.

        -  Before cycle 4, scans will be done to check the size of the cancer. Most of these will
           be repeated every 3-6 cycles.

        -  When they stop taking the study drug, participants will return to the clinic for a
           physical exam and blood tests.
    

Eligibility criteria:

        -INCLUSION CRITERIA

        Age:

        -greater than or equal to 3 years of age and Body Surface Area (BSA) greater than or equal
        to 0.5 m(2)

        Diagnosis

          -  Histologically or cytologically confirmed Gastrointestinal Stromal Tumors (GIST) by
             the Laboratory of Pathology, National Cancer Institute (NCI).

          -  Absence of Kit and platelet derived growth factor receptor alpha (PDGFRA) mutation
             confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory.

          -  Participants must have measurable disease as defined in Response Evaluation Criteria
             in Solid Tumors (RECIST (v1.1) as the presence of at least one lesion not previously
             irradiated, that can be accurately measured at baseline greater than or equal to 10mm
             in the longest diameter (except lymph nodes which must have short axis greater than or
             equal to 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and
             which is suitable for accurate repeated measurements.

        Prior therapy:

        There are no standard chemotherapy regimens known to be effective for wt-GIST. Therefore,
        previously untreated participants are eligible if their tumor(s) are measurable.

          -  Participants must be at least 4 weeks from prior surgical procedures and surgical
             incisions must be healed.

          -  Participants must have had their last fraction of external beam radiation therapy at
             least 4 weeks prior to enrollment.

          -  Participants must have had their last dose of cytotoxic chemotherapy at least 28 days
             prior to enrollment, their last dose of biological therapy, such as biological
             response modifiers (e.g., cytokines), immunomodulatory agents, vaccines,
             differentiating agents, used to treat their cancer at least 7 days prior to
             enrollment, their last dose of a monoclonal antibody at least 30 days prior to
             enrollment, and their last dose of any investigational agent at least 30 days prior to
             enrollment.

          -  Participants must have received their last dose of short acting colony stimulating
             factor, such as filgrastim or sargramostim at least 72 hours prior to enrollment and
             their last dose of long-acting colony stimulating factors, such as PEG-filgrastim at
             least 7 days prior to enrollment.

          -  Participants must have recovered from the acute toxic effects of prior therapy to a
             grade 1 (Common Terminology Criteria in Adverse Events (CTCAE v.4.0)) level prior to
             enrollment (does not apply to alopecia).

        Performance Status: Lansky (for participants 10 years of age or younger) or Karnofsky (for
        participants older than 10 years) performance score greater than 50

        Patients must have normal organ and marrow function as defined below:

          -  Hematological Function: The peripheral absolute neutrophil count must be at least
             1,500/microL and the platelet count must be at least 100,000/microL within 72 hours
             prior to enrollment.

          -  Coagulation: Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must not be
             more than 1.5 x upper limit of normal (ULN) within 72 hours prior to enrollment. PT
             and PTT should drawn by venipuncture, rather than from a central venous catheter when
             feasible.

          -  Hepatic Function: Bilirubin must not be more than 1.5 x ULN (does not apply to
             patients with Gilberts Disease) and the aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) must not be more than 2.5 x ULN within 72 hours prior to
             enrollment, or greater than 5.0 X ULN if in the Investigator s judgment it is related
             to liver metastases. AST and ALT may be up to 5 x ULN within 72 hours prior to
             enrollment in participants with hepatic metastases.

          -  Renal Function: Participants must have an age-adjusted normal serum creatinine (see
             Table) or a creatinine clearance of at least 50 ml/min/1.73 m(2).

        Age (years) Male Female

        3 to 5 = .42

        5 to <10 = 1

        10 to <13 = 1.2

        13 to <16 = 1.5 male and 1.4 female

        16 and older = 1.7 male and 1.4 female

        Hypertension:

        -Participants should have normal blood pressure according to age. Participants 18 years of
        age and younger should have a blood pressure 95th percentile for age, height and gender,
        and should not be receiving medication for treatment of hypertension. Preexisting
        hypertension in adults should be controlled (either with pharmacological or
        non-pharmacological methods) at the time of enrollment.

        Birth Control:

          -  Participants of child-bearing or child-fathering potential must be willing to use a
             medically effective form of birth control, which includes abstinence, while taking
             vandetanib and for 4 months after the last dose. [Female patients must be 1 year
             postmenopausal, surgically sterile, or using an acceptable method of contraception (an
             acceptable method of contraception is defined as a barrier method in conjunction with
             a spermicide) for the duration of the study (from the time they sign the informed
             consent form [ICF]) and for 3 months after the last dose of vandetanib to prevent
             pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term
             injectable contraception, intrauterine device, or tubal ligation are allowed. Oral
             contraception alone is not acceptable; additional barrier methods in conjunction with
             spermicide must be used.

          -  Male patients must be surgically sterile or using an acceptable method of
             contraception (defined as barrier methods in conjunction with spermicides) for the
             duration of the study (from the time they sign the ICF) and for 4 months after the
             last dose of vandetanib to prevent pregnancy in a partner.]

          -  Negative pregnancy test for women of childbearing potential.

        Informed Consent:

        -Participants who are greater than or equal to 18 years of age or Legally Authorized
        Representative (LAR) of participants who are younger than 18 years must sign an informed
        consent for the Pediatric Oncology Branch (POB) Screening Protocol (01-C-0157: Eligibility
        Screening and Tissue Procurement for the National Cancer Institute (NCI), Pediatric
        Oncology Branch (POB) Clinical Research Protocols) prior to participating in studies
        required to determine eligibility for this trial. After confirmation of eligibility,
        participants who are greater than or equal to 18 years of age or LAR of minor participants
        must sign an informed consent document for this trial, indicating that they are aware of
        the investigational nature of the proposed treatment, the risks and benefits of
        participating and the alternatives to participating, prior to the conduct of any study
        procedures.

        EXCLUSION CRITERIA

        Presence of any of the following will prevent a subject from participation:

          -  Pregnant or breast feeding females because vandetanib may be harmful to the developing
             fetus or nursing infant and has been found to be embryotoxic, fetotoxic and
             teratogenic in rats.

          -  Subjects who are receiving any other investigational agents or who have received an
             investigational agent within 28 days prior to enrollment (does not apply to
             participation in survival follow up), or who have previous exposure to vandetanib.

          -  Abnormal Electrolyte Levels: Participants with a serum potassium less than 3.5 mmol/L
             or a serum ionized calcium or magnesium below the lower limits of normal (or above
             Common Terminology Criteria in Adverse Events (CTCAE) Grade 1 upper limit). Correction
             of these electrolyte abnormalities with supplements is allowed. (Serum calcium above
             the CTCAE Grade 1 upper limit. In cases where the serum calcium is below the normal
             range, the calcium adjusted for albumin is to be obtained and substituted for the
             measured serum value. Exclusion is to then be based on the calcium adjusted for
             albumin values falling below the normal limit: Corrected Calcium = Ca + 0.8 x (4-serum
             albumin).)

          -  Presence of hypertension: Diastolic blood pressure above the 95% for age in children
             (Appendix 2) and > 160 mmHg systolic or >100 mmHg diastolic in adults on at least 2 of
             3 measurements with an appropriate-size cuff who are unable to achieve blood pressure
             control with optimal anti-hypertensive therapy. Patients who are treated with
             antihypertensive medications with good response are eligible.

        History of Cardiac Disorder:

          -  Participants with a history of arrhythmia (multifocal premature ventricular
             contractions, bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial
             fibrillation, left bundle branch block) that is symptomatic or requires treatment
             (except for controlled atrial fibrillation).

          -  History of any significant cardiac event (e.g. myocardial infarction), superior vena
             cava syndrome, New York Heart Association (NYHA) classification of heart disease
             greater than or equal 2 within 12 weeks before starting treatment, or presence of
             cardiac disease that in the opinion of the Investigator increases the risk of
             ventricular arrhythmia.

          -  Participants with a history of congenitally prolonged corrected QT interval (QTc), a
             first degree relative with unexplained sudden death under 40 years of age, or a
             measured QTcB (Bazetts correction) longer than 480 msec on electrocardiography (ECG).
             ECGs should be performed after correction of electrolyte abnormalities. Participants
             with a prolonged QTcB should have a repeat ECG twice, at least 24 hour apart, and the
             average of the 3 QTcBs should not exceed 480 msec. History of QT prolongation
             associated with other medications that required discontinuation of that medication.

          -  Participants receiving a medication that has a known risk of QTc prolongation or is
             associated with Torsades de Pointes or any prohibited medications, concomitantly or
             within 14 days (28 days for levomethadyl) of enrollment.

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of vandetanib as evidenced by uncontrolled nausea,
             vomiting or diarrhea and/or current need for parenteral support with iron or Vitamin
             B.

          -  Other clinically severe or uncontrolled systemic illness or any concurrent condition
             that in the view of the principal investigator could compromise the participant's
             ability to tolerate vandetanib or could compromise study procedures or endpoints,
             including interstitial lung disease, drug-induced interstitial disease, radiation
             pneumonitis which required steroid treatment or any evidence of clinically active
             interstitial lung disease.

          -  Unstable brain metastases or spinal cord compression that requires treatment, unless
             the treatment ended at least 4 weeks before starting treatment and the condition has
             been stable without steroid treatment for at least 10 days.

          -  Major surgery (includes surgery that carries significant risk of blood loss, extended
             periods of general anesthesia, or requires at least an overnight hospital admission)
             within 28 days before starting treatment.

          -  Involvement in the planning and/or conduct of the study.

          -  Previous enrollment in the present study.

          -  Previous or current malignancies of other histologies within the last 5 years, with
             the exception of in situ carcinoma of the cervix and adequately treated basal cell or
             squamous cell carcinoma of the skin.