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

 I. To determine the objective response rate (complete response + partial response) of
 cabozantinib-s-malate (XL184) in children and young adults.

 II. To estimate whether XL184 therapy either improves the disease control rate at 4 months in
 patients with recurrent measurable osteosarcoma as compared to a historical Childrens
 Oncology Group (COG) experience or produces an objective response rate.

 SECONDARY OBJECTIVES:

 I. To further define XL184 related toxicities in pediatric, adolescent and young adult
 patients.

 II. To further define XL184 pharmacokinetics in the pediatric and adolescent patients.

 III. To estimate 1-year time to progression, progression free survival (PFS) and overall
 survival for each stratum, and if feasible to compare to historical controls.

 EXPLORATORY OBJECTIVES:

 I. To assess the effect of XL184 on patients' immune cell subsets. II. To obtain tumor tissue
 (snap frozen, formalin-fixed and paraffin-embedded [FFPE] blocks, or unstained slides) from
 diagnosis, recurrence, or both, for possible future studies.

 OUTLINE:

 Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Cycles
 repeat every 28 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days, every 6 months for
 1 year and then annually for up to 5 years.
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])

 -  Osteosarcoma

 -  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, RET rearrangement,
 overexpression or activation of AXL); documentation of the alteration from a
 Clinical Laboratory Improvement Act (CLIA) certified laboratory will be
 required

 -  Note: Documentation of any known tumor molecular alterations and RET
 mutation status for patients with MTC (germline) must be uploaded via
 the RAVE system

 -  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
 mm)

 -  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
 above

 -  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

 -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced
 platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of
 agent

 -  Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and
 toxicity related to prior antibody therapy must be recovered to grade =< 1

 -  >= 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
 viscera)

 -  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
 disease

 -  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]) =< 135
 U/L (3 x ULN) (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 with the exception of decreased tendon reflex (DTR); any grade
 of DTR is eligible

 -  A blood pressure (BP) =< the 95th percentile for age, height, and gender for pediatric
 patients < 18 years old and =< 140/90 mmHg for patients >= 18 years old; patients
 should not be 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 =< ULN for pediatric patients and =<
 140/90 for adult patients); 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 due to risks of
 fetal and teratogenic 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 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,
 crizotinib)

 -  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
 hemorrhages

 -  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