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Pilot Study of Cabozantinib for Recurrent or Progressive High-Grade Glioma in Children

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ClinicalTrials.gov Identifier: NCT02885324
Recruitment Status : Recruiting
First Posted : August 31, 2016
Last Update Posted : May 28, 2018
Sponsor:
Information provided by (Responsible Party):
Chie-Schin Shih, Indiana University

Brief Summary:
This pilot will study the feasibility and exploratory efficacy of using Cabozantinib for recurrent or refractory high grade glioma for which there are no curative options. Patients will also be followed for safety, time to progression, event free survival and overall survival

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Anaplastic Astrocytoma Malignant Brain Tumor High Grade Glioma Drug: Cabozantinib Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Cabozantinib for Recurrent or Progressive High-Grade Glioma in Children
Actual Study Start Date : May 18, 2017
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : January 2020


Arm Intervention/treatment
Experimental: Cabozantinib
Cabozantininb will be taken daily at a dose of 40 mg/m2. Drug cycles will last 28 days and be continuous for up to 12 months of therapy on study.
Drug: Cabozantinib
Subjects will receive Cabozantinib
Other Names:
  • XL 184
  • Cabometyx




Primary Outcome Measures :
  1. Disease response [ Time Frame: 6 months ]

    Response criteria are assessed based on the product of the longest diameter and its longest perpendicular diameter.

    Complete response (CR): Disappearance of all target lesions Partial response (PR): ≥50% decrease in the sum of the products of the two perpendicular diameters of all target lesions (up to 5), taking as reference the initial baseline measurements Stable disease (SD): Neither sufficient decrease in the sum of the products of the two perpendicular diameters of all target lesions to qualify for PR, nor sufficient increase in a single target lesion to qualify for PD.

    Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.




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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Age: Patients must be ≥2 years and ≤21 years of age
  2. Diagnosis: Patients with relapsed or refractory high grade glioma (HGG) defined was histologically confirmed WHO grade III or WHO grade IV glioma (i.e. glioblastoma multiforme or anaplastic astrocytoma). Patients must have had histologic verification of malignancy at original diagnosis or relapse. Metastatic disease to the spine is eligible. Patients may be in first, second, or third relapse. Subjects with intrinsic brain stem gliomas may be eligible if histologically confirmed. Please contact study chair prior to enrollment.
  3. Disease Status: Patients must have measurable disease. Linear enhancement of leptomeningeal without measurable mass is excluded.
  4. Therapeutic Options: Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life. For patients in whom surgery is feasible, maximal surgical resection must have occurred.
  5. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix 1). Note: Neurologic deficits in patients must have been relatively stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  6. Subjects must have a reasonable life expectancy of at least 2 months.
  7. Prior Therapy

    a. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy i. Cytotoxic chemotherapy (including investigational agents) or biologic agents (eg. Cytokines or antibodies): At least 3 weeks after the last dose.

    ii. Nitrosoureas/mitomycin C: At least 6 weeks from the last dose. iii. XRT: At least 14 days after local palliative XRT (small port); At least 150 days must have elapsed if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At least 42 days must have elapsed if other substantial BM radiation. e.g. Stem cell Infusion without TBI: No evidence of active graft vs. host disease and at least 56 days must have elapsed after transplant or stem cell infusion.

  8. Organ Function Requirements:

    a. Adequate bone marrow function defined as: absolute neutrophil count (ANC ≥1000/mm3) i. Platelet count ≥ 100,000/ mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) ii. Patients with bone marrow metastatic disease will not be eligible. b. Adequate renal function defined as: i. Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m² or a serum creatinine based on age/gender as follows:

    Age Maximum Serum Creatinine (mg/dL) Male Female 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

    ≥ 16 years 1.7 1.4 The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

    ii. Urine protein: ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample.

    c. Adequate Liver Function Defined as:

    i. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age ii. SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

    iii. Serum albumin ≥ 2.8 g/dL. d. Adequate coagulation status defined as:PT and INR

    • 1.5x ULN e. Adequate pancreatic function defined as: Serum amylase and lipase
    • 1.5 x ULN f. Adequate blood pressure control defined as: A blood pressure (BP) ≤ the 95th percentile for age, height and gender (Appendix II) despite optimal antihypertensive treatment within 7 days of the first dose of the study treatment. Please note that 3 serial blood pressures should be obtained and averaged to determine baseline BP.

      g. Central nervous system function defined as:Patients with seizure disorder may be enrolled if receiving non-enzyme inducing anticonvulsants and well controlled. See Appendix III for a list of recommended non-enzyme inducing anticonvulsants.

      h. Adequate cardiac function defined as: i. No history of congenital QTc syndrome, NYHA Class III or IV congestive heart failure (CHF) ii. No clinical significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment iii. QTc

    • 480 msec. Note: Three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 480 msec, the subject meets eligibility in this regard.Patients with Grade 1 prolonged QTc (450-480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e. electrolytes, medications). See Appendix IV for a list of drugs that prolong QTc.
  9. Informed consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate will be obtained according to institutional guidelines.
  10. Archival tumor tissue slides must be sent or available.

Exclusion Criteria

  1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogentic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control- a medically accepted barrier method of contraceptive method (e.g., male or female condom) and a second effective method of birth control- during protocol therapy and for at least 4 months after the last dose of cabozantinib. Abstinence is an acceptable method of birth control.
  2. Concomitant Medications:

    1. Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
    2. Investigational drugs: Patients who are currently receiving another investigational drug are not eligible.
    3. Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible.
    4. CYP3A4 active agents: Patients must not be receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's wort. A list of other known CYP3A4 inducers and inhibitors that should be discontinued prior to initiation of protocol therapy and should be avoided during study therapy if reasonable alternatives exist is included in Appendix V.
    5. Patients who are receiving systemic therapeutic treatment anticoagulation are not eligible. Patients receiving prophylactic systemic anticoagulation will be allowed with heparin or LMWH as long as eligibility PT/INR requirements are met. Concomitant anticoagulation with oral anticoagulations (e.g. warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg. Clopidogrel) are not allowed.
    6. Enzyme-inducing anticonvulsants: Patients must not have received enzyme-inducing anticonvulsants within 14 days prior to enrollment (See Appendix III for a list of unacceptable enzyme inducing anticonvulsants).
    7. QTc Agents: Patients who are receiving drugs that prolong QTc are not eligible (See Appendix IV for a list of agents).
  3. Patients must be able to swallow intact tablets. Patients who cannot swallow intact tablets are not eligible.
  4. Patients with active bleeding are not eligible. Specifically, no clinically significant GI bleeding, GI perforation, intra-abdominal abscess or fistula for 6 months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3 months prior to enrollment.
  5. Patients with evidence of an acute intracranial or intratumoral hemorrhage on CT or MRI are not eligible (patients with evidence of resolving hemorrhage will be eligible).
  6. Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible;
  7. Concurrent uncontrolled hypertension defined as sustained blood pressure>95% (systolic or diastolic) despite optimal antihypertensive treatment within 7 days of the first dose of study treatment.
  8. Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of this oral agent are not eligible.
  9. Infection: Patients who have an uncontrolled infection are not eligible.
  10. Patients who have received a prior solid organ transplantation are not eligible.
  11. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
  12. Subjects who have received cabozantinib or have an allergy to cabozantinib are excluded. Subjects who have previously received tyrosine kinase inhibitors are allowed.
  13. Subjects who have not received radiation therapy as part of their prior treatment are excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02885324


Contacts
Contact: Anne Bubnick 317-948-0101 abubnick@iu.edu
Contact: Chie-Schin Shih, MD 317-948-8568

Locations
United States, Indiana
Riley Hospital for Children at IU Health Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Chie-Schin Shih, MD    317-948-8586    shih2@iu.edu   
Contact: Anne Bubnick    317-948-0101    abubnick@iu.edu   
Principal Investigator: Chie-Schin Shih, MD         
Sub-Investigator: Kamnesh Pradhan, MD         
Sub-Investigator: Terry Vik, MD         
Riley Hospital for Children at IU Health Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Anne Bubnick    317-948-0101    abubnick@iu.edu   
Principal Investigator: Chie-Schin Shih, MD         
Riley Hospital for Children at IU Health Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Chie-Schin Shih, MD    317-948-8586    shih2@iu.edu   
Principal Investigator: Chie-Schin Shih, MD         
Sub-Investigator: Kamnesh Pradhan, MD         
Sub-Investigator: Terry Vik, MD         
Sponsors and Collaborators
Indiana University
Investigators
Principal Investigator: Chie-Schin Shih, MD Indiana University School of Medicine

Responsible Party: Chie-Schin Shih, Associate Professor in Clinical Pediatrics, Indiana University
ClinicalTrials.gov Identifier: NCT02885324     History of Changes
Other Study ID Numbers: IUSCC-0601
First Posted: August 31, 2016    Key Record Dates
Last Update Posted: May 28, 2018
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Chie-Schin Shih, Indiana University:
High Grade Glioma
Cabozantinib
GBM
Children
AA

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Brain Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases