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Cabozantinib S-malate in Treating Children with Recurrent or Refractory High Grade Glioma

Trial Status: Active

This phase II trial studies the side effects and how well cabozantinib S-malate works in treating children with high grade glioma that has come back or does not respond to treatment. Cabozantinib S-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Patients with relapsed or refractory high grade glioma (HGG) defined was histologically confirmed World Health Organization (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 with or without histological confirmation; please contact study chair prior to enrollment
  • Patients must have measurable disease; linear enhancement of leptomeningeal without measurable mass is excluded
  • 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
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age * 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
  • Subjects must have a reasonable life expectancy of at least 2 months
  • Prior Therapy * Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy ** Cytotoxic chemotherapy (including investigational agents) or biologic agents (e.g. cytokines or antibodies): At least 3 weeks after the last dose ** Nitrosoureas/mitomycin C: At least 6 weeks from the last dose ** Radiotherapy (XRT): At least 14 days after local palliative XRT (small port); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation; e.g. stem cell Infusion without TBI: no evidence of active graft versus (vs.) host disease and at least 56 days must have elapsed after transplant or stem cell infusion
  • Absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 100,000/ mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Patients with bone marrow metastatic disease will not be eligible
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: * 2 to < 6 years: Maximum serum creatinine for both male and female 0.8 mg/dL * 6 to < 10 years: Maximum serum creatinine for both male and female 1 mg/dL * 10 to < 13 years: Maximum serum creatinine for both male and female 1.2 mg/dL * 13 to < 16 years: Maximum serum creatinine for male 1.5 mg/dL and for female 1.4 mg/dL * >= 16 years: Maximum serum creatinine for male 1.7 mg/dL and for female 1.4 mg/dL
  • Urine protein =< 30 mg/dL in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2.8 g/dL
  • Prothrombin time (PT) and international normalized ratio (INR) =< 1.5 x ULN
  • Serum amylase and lipase =< 1.5 x ULN
  • A blood pressure (BP) =< the 95th percentile for age, height and gender 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
  • Patients with seizure disorder may be enrolled if receiving non-enzyme inducing anticonvulsants and well controlled
  • Adequate cardiac function defined as * No history of congenital corrected QT (QTc) syndrome, New York Heart Association (NYHA) class III or IV congestive heart failure (CHF) * No clinical significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment * QTc =< 480 msec; Note: Three electrocardiograms (ECGs) must be performed for eligibility determination; if the average of these three consecutive results for corrected QT using Fridericia's formula (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)
  • 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
  • Archival tumor tissue slides must be sent or available, except for patients with intrinsic pontine glioma meeting the remainder of the inclusion criteria

Exclusion Criteria

  • Pregnant or breast-feeding women will not be entered on this study; 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
  • Concomitant Medications * 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 * Investigational drugs: Patients who are currently receiving another investigational drug are not eligible * Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible * 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 * Patients who are receiving systemic therapeutic treatment anticoagulation are not eligible; patients receiving prophylactic systemic anticoagulation will be allowed with heparin or low-molecular-weight heparin (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 (e.g. clopidogrel) are not allowed * Enzyme-inducing anticonvulsants: Patients must not have received enzyme–inducing anticonvulsants within 14 days prior to enrollment * QTc Agents: Patients who are receiving drugs that prolong QTc are not eligible
  • Patients must be able to swallow intact tablets; patients who cannot swallow intact tablets are not eligible
  • Patients with active bleeding are not eligible; specifically, no clinically significant gastrointestinal (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
  • Patients with evidence of an acute intracranial or intratumoral hemorrhage on computed tomography (CT) or magnetic resonance imaging (MRI) are not eligible (patients with evidence of resolving hemorrhage will be eligible)
  • 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
  • Concurrent uncontrolled hypertension defined as sustained blood pressure > 95th percentile for age, height and gender (systolic or diastolic) despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
  • Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of this oral agent are not eligible
  • Patients who have an uncontrolled infection are not eligible
  • Patients who have received a prior solid organ transplantation are not eligible
  • 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
  • Subjects who have received cabozantinib or have an allergy to cabozantinib are excluded; subjects who have previously received tyrosine kinase inhibitors are allowed
  • Subjects who have not received radiation therapy as part of their prior treatment are excluded

Indiana

Indianapolis
Riley Hospital for Children
Status: ACTIVE
Contact: Scott L. Coven
Phone: 317-944-2143
Email: scoven@iu.edu

PRIMARY OBJECTIVES:

I. Assess the safety and tolerability of cabozantinib S-malate (cabozantinib) in refractory and/or recurrent pediatric high grade glioma (HGG) who have previously received radiation therapy.

II. Assess the disease control rate (complete response [CR], partial response [PR], or stable disease [SD]) for at least 6 months of cabozantinib in refractory and/or recurrent pediatric HGG who have previously received radiation therapy.

SECONDARY OBJECTIVES:

I. Assess the 6 month progression free survival (PFS) in subjects with refractory or recurrent HGG who have previously received radiation therapy treated with cabozantinib.

II. Assess the utilization of corticosteroid use in subjects with recurrent or refractory HGG treated with cabozantinib.

III. Assess the objective response rate of target lesion in subjects with recurrent or refractory HGG treated with cabozantinib.

IV. Assess the overall survival (OS) rate at 6 months and 12 months in subjects with refractory or recurrent HGG treated with cabozantinib.

V. Assess the 12 month PFS in subjects with refractory or recurrent HGG treated with cabozantinib.

OUTLINE:

Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Riley Hospital for Children

Principal Investigator
Scott L. Coven

  • Primary ID IUSCC-0601
  • Secondary IDs NCI-2018-00096
  • Clinicaltrials.gov ID NCT02885324