3.2 Patient Eligibility Criteria:
3.2.1 Assessment criteria for eligibility, based on disease burden at start of most recent
line of therapy and corresponding response (patients must meet one of the following
criteria in order to be deemed eligible for enrollment):
1. Patients previously with measurable disease, at start of most recent line of therapy,
AND without evaluable disease (or for whom assessment of potential evaluable-only
disease would not be considered standard of care) are eligible based on "measurable
disease response" only in Section 3.1.2.a.i.
2. Patients previously with evaluable disease at start of most recent line of therapy,
AND without measurable disease at that time are eligible based on "evaluable disease"
definition alone only in Section 3.1.2.a.ii.
3. Patients previously with measurable AND evaluable disease at start of most recent line
of therapy must meet BOTH "measurable disease" and "evaluable disease" definitions
under Section 3.1.2.a.
3.2.2. Disease Strata. Patients need to meet any single definition of disease below:
1. Stratum 1: Neuroblastoma (target enrollment 30 patients)
1. Neuroblastoma BR1 at the end of frontline therapy with residual disease (less
than complete response (CR), including MIBG-avid stable disease as per Section
3.1.2.a.ii,.or >5% bone marrow involvement) but not progressive at time of
enrollment. 2. Neuroblastoma BR2 or later.
c. Stratum 3a: Relapsed/regractory Sarcomas and other solid tumors (target enrollment 36
patients)
1. Osteosarcoma, BR2 or later 2. Ewing sarcoma, BR2 or later 3. Rhabdomyosarcoma, with
positive surgical margins OR with primary extremity tumor with >2 metastases at diagnosis,
BR1 or later 4. Rhabdomyosarcoma, alveolar subtype or fusion-positive subtype, BR2 or later
5. Rhabdomyosarcoma, embryonal subtype, Group 4 at original diagnosis, BR2 or later 6.
Desmoplastic small round blue cell tumor, BR2 or later 7. Any other soft tissue sarcoma,
BR2 or later 8. Wilms tumor, diffuse anaplasia histology, any stage, BR2 or later 9. Wilms
tumor, any histology with relapse within 12 months of diagnosis, who have received prior
treatment with doxorubicin, and intraabdominal recurrence, BR2 or later 10. Wilms tumor,
BR3 or later. c. Stratum 3b: Metastatic sarcomas after frontline therapy (target enrollment 20 patients)
1. Metastatic osteosarcoma, BR1. 2. Ewing sarcoma with metastases not undergoing complete metastatectomy, BR1. 3.2.3 Inclusion Criteria for Eligibility:
1. Age: ≥ 18 months of age and <40 years of age at time of study enrollment. 2. Performance level: Patients must have a Lansky or Karnofsky performance status score
of ≥ 50, corresponding to 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 upright in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score. Patients should also
have recovery to baseline or ≤ Grade 1 CTCAE v4.03 from toxicities related to any
prior treatments, unless AE(s) are clinically nonsignificant and/or stable on
supportive therapy (see Section 3.2.3, criteria 4)
3. Patient Body Surface Area (BSA): Patients must be ≥0.35 m2 in BSA, using the Mosteller
formula, BSA = (((Height in cm) * (Weight in kg))/ 3600)½ within two weeks of study
enrollment. 4. Prior therapy: patients must have recovered from the acute toxic effects of prior
therapy, with the following time specifications:
1. Myelosuppressive chemotherapy: Patients must not have received myelosuppressive
chemotherapy within 3 weeks of enrollment on study (6 weeks if prior therapy
included nitrosourea)
2. Other medicinal anti-cancer agents: Patients must not have received
non-myelosuppressive anticancer agents, including any type of small molecule
kinase inhibitor, within 14 days of enrollment on study. 3. Biological anticancer therapy (including antibody therapy or cellular therapy):
Patients must not have received biological anticancer therapy within 21 days of
enrollment on study. 4. Radiation therapy: Patients must not have received external beam radiation
therapy to sites outside of the lungs within 2 weeks of study enrollment,
external beam radiation therapy to sites within the lungs within 4 weeks of study
enrollment, or I-131 MIBG therapy within 6 weeks of study enrollment. Subjects
with clinically relevant ongoing complications from prior radiation therapy MUST
be discussed with Study Chair or his proxy to determine suitability and safety of
enrollment.
5. Myeloablative therapy: Patients must not have received myeloablative therapy
within 2 months of study enrollment, must not have received a blood stem
cell/marrow infusion within 3 weeks of study enrollment, and must have attained
blood count recovery as per Section 3.2.3, criteria 5. 5. Bone Marrow Function: Patients must have adequate bone marrow function at time of
study enrollment, as defined as:
1. Absolute neutrophil count (ANC) ≥1000/mcL; patients cannot have received
filgrastim, pegfilgrastim or equivalent biosimilar within 14 days of study
enrollment. 2. Platelet count ≥ 100,000/mcL; patients can receive no more than 15 mL/kg of
platelet transfusions per week at time of enrollment to meet the parameters;
patients can receive a TPO agonist (e.g., eltrombopag or romiplostim) at time of
enrollment but must be on a stable dose for at least 14 days prior to enrollment. 3. Hemoglobin ≥ 8.0 g/dL; patients can receive no more than 10 mL/kg of packed red
blood cells (PRBCs)/week transfused at time of enrollment on therapy to meet the
parameters; patients may receive erythropoietin or biosimilar equivalent but must
have been on a stable dose and not require PRBC transfusions for at least 14 days
prior to study enrollment. 4. Patients with residual bone marrow metastases at end of most recent line of
therapy must have stable disease or better at two bone marrow evaluations at
least 4 weeks apart, with the second marrow assessment at least 4 weeks after end
of most recent therapy. Stable disease is defined as <2-fold change in marrow
burden between the two timepoints and ≤20% marrow involvement. When bilateral
bone marrow assessment is performed, average marrow involvement of the two sites
will be used for eligibility.
6. Renal Function: Patient must meet criteria for both a. and b. below to have adequate
renal function, within 2 weeks of study enrollment. 1. Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2, as per
institutional standard testing OR serum creatinine based on age/gender based on
table in protocol.
2. Urine protein: ≤ 30 mg/dl in urinalysis (clean catch recommended), equivalent to
≤ 1+ on dipstick. OR. quantitative urine protein < 1000 mg in a 24hr urine sample.
NOTE: If the initial urinalysis shows >1+ or 30 mg/dL urine protein, a 24 hour
quantitative urine protein should be utilized, as described above, for eligibility
consideration.
7. Hepatic function: Patient must meet ALL of the below criteria, within 14 days of study
enrollment, to have adequate hepatic function:
1. Total bilirubin < 2x institutional upper limit of normal (ULN) for age. 2. ALT<5x ULN. 3. Serum albumin >2.7 g/dL. 8. Cardiovascular Function: Patients must have adequate cardiovascular function as
defined as:
1. No significant arrhythmias, strokes, transient ischemic attacks, or myocardial
infarction within 6 months of study enrollment. 2. QTc ≤ 480 msec within 7 days of study enrollment (calculated using Bazett
calculation or Fridericia calculation as per institutional standard of care;
whichever calculation is used for eligibility must be used for all future QTc
calculations).
A single ECG with QTc meeting the above criterion is adequate. However, if an
initial ECG shows a QTc >480 ms, obtain two additional ECGs with each ECG at
least 30 minutes apart. Calculate each individual QTc by the same calculation
method and average the values; the resulting average QTc will be used for
eligibility.
3. Blood pressure ≤ 95th percentile for age, height, and gender for patients <18
years of age (78), or BP ≤140/90 for patients ≥18 years of age. At time of
enrollment, patients may be on one antihypertensive agent at a stable dose for at
least 2 weeks prior to enrollment.
9. Pancreatic function: Patient must have adequate pancreatic function, as defined by a
serum lipase <2x ULN. 10. Neurologic function: Patients with defined seizures who are on a stable anti-
convulsant regimen using drugs that do not induce hepatic metabolizing enzymes for at
least 4 weeks are eligible for enrollment. 11. Lung integrity: Patients must not have had any invasive pulmonary procedure (including
bronchoalveolar lavage, lung biopsy, transbronchial biopsy, or thoracotomy) or
pneumothorax within 4 weeks of enrollment on study.
12. Surgeries or trauma:
1. Patients must not have had any major surgical procedures, laparoscopic
procedures, sepsis, shock, or physical trauma requiring hospitalization within 4
weeks of enrollment on study. The primary surgeon of any major surgical
procedures must authorize antineoplastic treatment before enrollment on study.
2. Patients must not have had a central line or subcutaneous port placement,
revision, or removal (excluding a peripherally inserted central catheter (PICC))
within 7 days of study enrollment. Advise patients with a surgically placed
central line or subcutaneous port that removal of the port once enrolled on study
would require holding study treatment for 4 weeks prior, and surgical removal of
the central line or port would be recommended to be performed prior to
cabozantinib initiation.
3. Patients must not have had a core or fine needle biopsy within 7 days of study
enrollment.
4. Any surgical wounds or incisions must be healed, as determined by treating
physician, prior to enrollment on study.
5. Bone marrow aspiration and/or biopsy are not considered surgical procedures for
the purpose of this study.
13. Patients must be able to swallow tablets intact. Tablets cannot be cut or crushed.
14. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (eg, barrier methods, including male condom, female
condom, or diaphragm with spermicidal gel) during the course of the study and for 4
months after the last dose of study treatment. Post-menarchal females must be
confirmed to not be pregnant at time of enrollment.
15. Patient or legal guardian must be capable of understanding and complying with the
protocol requirements and must have signed the informed consent document.
16. Patient must be able to start study treatment no later than 12 weeks after end of
prior therapy, where 1 week = 7 days.
17. Patient must be enrolled on study within 14 days of qualifying radiographic imaging
studies demonstrating best response as per Section 3.1.2.
18. Patient must be able to start study treatment no later than 7 days from study
enrollment.
SEE PROTOCOL FOR ADDITIONAL EXCLUSION CRITERIA
