Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors

Status: Recruiting
DFCI Protocol ID: 17-716

This phase II trial studies how well cabozantinib-s-malate works in treating younger patients with sarcomas, Wilms tumor, or other rare tumors that have come back, do not respond to therapy, or are newly diagnosed. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for tumor growth and tumor blood vessel growth.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute, Massachusetts General Hospital

Overall PI:

Suzanne Shusterman, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

David Ebb, MD, Massachusetts General Hospital


Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP,
Massachusetts General Hospital: Cancer Trials Call Center, 877-789-6100

Eligibility Criteria

Inclusion Criteria:

  -  Upper age limit of =< 18 years of age for medullary thyroid carcinoma (MTC), renal
     cell carcinoma (RCC) and hepatocellular carcinoma (HCC)

  -  Patients must have a body surface area >= 0.35 m^2

  -  Patients must have recurrent or refractory disease, or newly diagnosed disease with no
     known curative therapy or therapy proven to prolong survival with an acceptable
     quality of life; patients must have had histologic verification of one of the
     malignancies listed below at original diagnosis or at relapse:

       -  Ewing sarcoma

       -  Rhabdomyosarcoma (RMS)

       -  Non-rhabdomyosarcoma soft tissue sarcomas (STS) including microphthalmia
  transcription factor associated STS (alveolar soft part sarcoma [ASPS] and clear
  cell sarcoma [CCS])

       -  Wilms tumor

       -  Rare tumors

    -  Medullary thyroid carcinoma (MTC)

    -  Renal cell carcinoma (RCC)

    -  Hepatocellular carcinoma (HCC)

    -  Hepatoblastoma

    -  Adrenocortical carcinoma

    -  Pediatric solid tumors (including central nervous system [CNS] tumors) with
       known molecular alterations in the targets of XL184 (i.e., MET
       amplification, overexpression, activating mutation, MET translocation, MET
       exon skipping mutations, activating RET mutations, overexpression or
       activation of AXL); documentation of the alteration from a Clinical
       Laboratory Improvement Act (CLIA) certified laboratory will be required

  -  Patients must have radiographically measurable disease; measurable disease is defined
     as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed
     tomography (CT) scan that can be accurately measured with the longest diameter a
     minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5

       -  Note: The following do NOT qualify as measurable disease:

    -  Malignant fluid collections (e.g., ascites, pleural effusions)

    -  Bone marrow infiltration

    -  Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
       positron emission tomography [PET] scans)

    -  Elevated tumor markers in plasma or cerebrospinal fluid (CSF)

    -  Previously radiated lesions that have not demonstrated clear progression
       post radiation

    -  Leptomeningeal lesions that do not meet the measurement parameters noted

  -  Patients must have a Lansky or Karnofsky performance status score of >= 50,
     corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use
     Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age;
     patients who are unable to walk because of paralysis, but who are up in a wheelchair,
     will be considered ambulatory for the purpose of assessing the performance score

  -  Patients must have fully recovered from the acute toxic effects of all prior
     chemotherapy, immunotherapy, or radiotherapy prior to entering this study

  -  Patients with solid tumors must not have received myelosuppressive chemotherapy within
     3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)

  -  At least 7 days must have elapsed since the completion of therapy with a growth
     factor; at least 14 days must have elapsed after receiving pegfilgrastim

  -  At least 7 days must have elapsed since completion of therapy with a biologic agent;
     for agents that have known adverse events occurring beyond 7 days after
     administration, this period prior to enrollment must be extended beyond the time
     during which adverse events are known to occur.

  -  At least 3 half-lives must have elapsed since prior therapy that included a monoclonal

  -  >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small
     port); >= 6 weeks must have elapsed since treatment with therapeutic doses of
     M-Iodobenzylguanidine (MIBG); >= 3 months must have elapsed if prior craniospinal XRT
     was received, if >= 50% of the pelvis was irradiated, or if total-body irradiation
     (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow
     irradiation was given

       -  Subjects should not have any clinically relevant ongoing complications from prior
  radiation therapy (i.e., radiation esophagitis or other inflammation of the

  -  No evidence of active graft versus (vs.) host disease and >= 2 months must have
     elapsed since transplant

  -  Not previously received XL184 or another MET/HGF inhibitor (tivantinib or crizotinib);
     there are no limits on number of prior therapeutic regimens; patients who have been
     treated with prior VEGF pathway, or RET inhibitors (except XL184) may be eligible

  -  Peripheral absolute neutrophil count (ANC) >= 1000/uL for patients with solid tumors
     without bone marrow involvement

  -  Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
     platelet transfusions within a 7 day period prior to enrollment) for patients with
     solid tumors without bone marrow involvement

  -  Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) for patients
     with solid tumors without bone marrow involvement

  -  Peripheral absolute neutrophil count (ANC) >= 750/uL for patients with solid tumors
     and known bone marrow metastatic disease

  -  Platelet count >= 50,000/uL for patients with solid tumors and known bone marrow
     metastatic disease

  -  Hemoglobin >= 8.0 g/dL for patients with solid tumors and known bone marrow metastatic

  -  Transfusions are permitted to meet both the platelet and hemoglobin criteria; patients
     must not be known to be refractory to red blood cell or platelet transfusions

  -  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 of age

    -  Male and female: 0.8 (maximum serum creatinine [mg/dL])

       -  6 to < 10 years of age

    -  Male and female: 1 (maximum serum creatinine [mg/dL])

       -  10 to < 13 years of age

    -  Male and female: 1.2 (maximum serum creatinine [mg/dL])

       -  13 to < 16 years of age

    -  Male 1.5 (maximum serum creatinine [mg/dL])

    -  Female: 1.4 (maximum serum creatinine [mg/dL])

       -  >= 16 years of age

    -  Male: 1.7 (maximum serum creatinine [mg/dL])

    -  Female: 1.4 (maximum serum creatinine [mg/dL])

  -  Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative
     protein is < 1000 mg in a 24 hour (h) urine sample

  -  Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

  -  Serum glutamate pyruvate 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

  -  No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart
     Association (NYHA) class III or IV congestive heart failure (CHF)

  -  No clinically significant cardiac arrhythmias, stroke or myocardial infarction within
     6 months prior to enrollment

  -  QTc =< 480 msec; Note: 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)

  -  Patients with a known seizure disorder who are receiving non-enzyme inducing
     anticonvulsants and have well-controlled seizures may be enrolled

  -  CNS toxicity =< grade 2

  -  A blood pressure (BP) =< the 95th percentile for age, height, and gender measured and
     not receiving medication for treatment of hypertension (except patients with Wilms
     tumor and RCC who may be eligible if on stable doses of no more than one
     anti-hypertensive medication with a baseline BP =< 95th percentile for age, height,
     and gender); please note that 3 serial blood pressures should be obtained and averaged
     to determine baseline BP

  -  International normalized ratio (INR) =< 1.5

  -  Serum amylase =< 1.5 ULN

  -  Serum lipase =< 1.5 ULN

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 XL184; abstinence is an acceptable
     method of birth control

  -  Growth factors that support platelet or white cell number or function must not have
     been administered within the 7 days prior to enrollment (14 days if pegfilgrastim)

  -  Patients requiring corticosteroids who have not been on a stable or decreasing dose of
     corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify
     immune adverse events related to prior therapy, >= 14 days must have elapsed since
     last dose of corticosteroid

  -  Previous treatment with XL184 (cabozantinib) or another MET/HGF inhibitor (tivantinib,

  -  Patients who are currently receiving another investigational drug are not eligible

  -  Patients who are currently receiving other anti-cancer agents are not eligible

  -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either
     graft-versus-host disease post bone marrow transplant or organ rejection
     post-transplant are not eligible for this trial

  -  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

  -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin,
     and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel) are prohibited

       -  Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and
  low dose, low molecular weight heparins (LMWH) are permitted; anticoagulation
  with therapeutic doses of LMWH is allowed in subjects without radiographic
  evidence of brain metastasis, who are on a stable dose of LMWH for at least 6
  weeks before first dose of study treatment, and who have had no complications
  from a thromboembolic event or the anticoagulation regimen

  -  Patients must not have received enzyme-inducing anticonvulsants within 14 days prior
     to enrollment

  -  Patients who are receiving drugs that prolong QTc are not eligible

  -  Patients who are unable to swallow intact tablets are not eligible

  -  Patients who have an uncontrolled infection 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

  -  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 CT or MRI are not eligible (patients with
     evidence of resolving hemorrhage will be eligible); in patients with CNS tumors, an
     MRI with ECHO gradient sequences would be required to exclude presence of petechial

  -  Patients who have had or are planning to have the following invasive procedures are
     not eligible:

       -  Major surgical procedure, laparoscopic procedure, or open biopsy within 28 days
  prior to enrollment

       -  Central line placement or subcutaneous port placement is not considered major
  surgery but must be placed at least 3 days prior to enrollment for external lines
  (e.g., Hickman or Broviac catheter, peripherally inserted central catheter
  [PICC]) and at least 7 days prior to enrollment for a subcutaneous port

       -  Core biopsy within 7 days prior to enrollment

       -  Fine needle aspirate within 7 days prior to enrollment

       -  Surgical or other wounds must be adequately healed prior to enrollment

       -  NOTE: For purposes of this study, bone marrow aspirate and biopsy are not
  considered surgical procedures and therefore are permitted within 14 days prior
  to start of protocol therapy

  -  Patients who have had significant traumatic injury within 28 days prior to enrollment
     are not eligible

  -  Patients with any medical or surgical conditions that would interfere with
     gastrointestinal absorption of the study drug are not eligible

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