Cabozantinib With Topotecan-Cyclophosphamide

Inclusion Criteria:

* Age ≥ 6 years and ≤ 30 years at time of enrollment. Note the requirement to swallow intact pills and BSA requirement immediately following.
* BSA ≥1.25m2 and \<2m2 is required.

  * Patients with BSA \< 1.25m2 are not eligible for enrollment due to percent deviation of daily cabozantinib dose being too extreme as a result of limitations in the size of dose forms available.
  * Patients with BSA \>2m2 are not eligible for enrollment due to inability to provide sufficient dose escalation and de-escalation for cabozantinib due to restraints imposed by dose of individual pills.
* Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 50% for patients \<16 years of age
* Disease Requirement: Participants must have relapsed or refractory Ewing sarcoma or osteosarcoma as follows:

  * For osteosarcoma, disease must be designated as a high-grade lesion (HGOS). Diagnosis of low-grade osteosarcoma (LGOS) and parosteal osteosarcoma (POS) are excluded.
  * Histologic diagnosis consistent with Ewing sarcoma or PNET with molecular evidence of translocation involving EWSR1 or FUS (also known as TLS), such as FISH, RT-PCR, or next generation sequencing. If the translocation partner is known, it must be of the ETS family (e.g.. FLI1 or ERG). For patients referred to the study center from outside institutions, the local institutional analysis of prior tumor material may serve to fulfill this requirement.
* Patients must have fully recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5 Grade ≤1) from the acute toxic effects of all prior anti-cancer therapy except organ function. Patients must meet the following minimum washout periods prior to enrollment:
* Myelosuppressive chemotherapy

  * ≥ 14 days since the last dose of myelosuppressive chemotherapy (≥ 42 days since the last dose of nitrosourea or mitomycin C);
  * Prior use of topotecan or cyclophosphamide is permitted. Patients treated with the combination of topotecan and cyclophosphamide must meet these additional criteria:

    * No progression on the combination of topotecan/cyclophosphamide.
    * If topotecan/cyclophosphamide is the regimen immediately preceding enrollment to this trial, then no more than two prior cycles prior to transitioning to this trial.
* Radiotherapy

  * ≥ 14 days after local palliative XRT (small port);
  * ≥ 90 days after craniospinal XRT or if \>50% radiation of pelvis;
  * ≥ 42 days after other substantial bone marrow radiation, including radionuclide therapy.
* Small molecule biologic therapy

  * ≥ 7 days following the last dose of a small molecule biologic agent.

    \--- For agents with known adverse events occurring beyond 7 days, this duration must be extended beyond the time in which adverse events are known to occur and this should be discussed and approved by the overall PI.
  * Prior use of cabozantinib is not allowed.
  * Prior use of tyrosine kinase inhibitors (TKI), other than cabozantinib, is allowed.
* Monoclonal antibody: ≥ 21 days must have elapsed after the last dose of antibody.
* Myeloid growth factors

  * ≥ 14 days following the last dose of long-acting growth factor (e.g., pegfilgrastim);
  * ≥ 7 days following short-acting growth factor (e.g., filgrastim).
* Immunotherapy: ≥ 4 weeks since the completion of immunotherapy (e.g. tumor vaccines) aside from monoclonal antibodies with immune effects.
* Cellular therapies (e.g. CAR-T, NK or autologous stem cell boost): ≥ 42 days must have elapsed after cellular therapy.
* Wound healing \& surgery

  * Patients with unhealed and/or chronic wounds are not eligible.
  * Patients with unhealed fractures are not eligible.
  * Patients must be ≥ 2 weeks from prior major surgical procedure.
  * Note: Biopsy and central line placement/removal are not considered major surgery.
* Participants must have normal organ function as defined below.

  * Hematologic requirements for subjects without known bone marrow involvement by disease:

    * Absolute neutrophil count \>1000/uL
    * Platelets ≥100,000/uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to CBC documenting eligibility.
  * Hematologic requirements for subjects with bone marrow involvement by disease as demonstrated on clinically-indicated bone marrow biopsy:

    * Absolute neutrophil count \>750/uL
    * Platelets ≥50,000/uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to CBC documenting eligibility.
    * Not known to be refractory to platelet or red cell transfusions.
  * Hepatic Function:

    * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (Patients with Gilbert's syndrome with a total bilirubin \< 2 x ULN for age and a direct bilirubin within normal limits are permitted.
    * ALT (SGPT) ≤ 135 U/L. For the purpose of this study, the ULN for ALT is 45 U/L
    * AST ≤ 90 U/L. For the purpose of this study, the ULN for AST is 40 U/L
    * Serum albumin \> 2 g/dL
  * Renal Function:

    * Serum creatinine based on age/sex as follows: Maximum Serum Creatinine (mg/dL)

      * Age 6 to \< 10 years Male: 1 Female: 1
      * Age 10 to \< 13 years Male: 1.2 Female1.2
      * Age 13 to \< 16 years Male: 1.5 Female:1.4
      * Age ≥ 16 years Male: 1.7 Female: 1.4
      * OR Creatinine clearance ≥ 60 mL/min/1.73 m2 as obtained by nuclear medicine GFR testing for participants with creatinine levels greater than the above age/sex maximum allowed values.
    * Proteinuria: Urinalysis with urine protein \< 1+ or \< 1.0g/24hrs on 24-hour urine collection analysis
* Adequate Cardiac Function

  * No history of congenital prolonged QTc syndrome, 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).
  * Shortening fraction of \> 27% or ejection fraction of \> 50% (while not receiving medications for cardiac function).
  * Adequate Blood Pressure (BP) Control, defined as:

    * For patients \< 18 years old, ≤ 95th percentile for age, height and sex
    * For patients ≥ 18 years old, ≤ 140/90 mmHg
  * BP should be measured as and patients should not be receiving medication for treatment of hypertension.
* Central Nervous System Function, defined as: Patients with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures may be enrolled.
* Adequate Coagulation, defined as: INR ≤ 1.5
* Adequate Pancreatic Function, defined as: Serum lipase ≤ 1.5 x ULN
* Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, using an institutionally approved informed consent procedure

Exclusion Criteria:

* Prior solid organ or allogeneic hematopoietic cell transplantation.
* Patients with primary or metastatic CNS Ewing sarcoma or osteosarcoma except patients with a history of CNS metastatic disease that has been resected and/or radiated without evidence of active CNS disease for 3 months preceding enrollment.
* Prohibited Concomitant Medications

  * Corticosteroids: 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.
  * Anti-hypertensive Medications: Patients who are currently receiving any maintenance or PRN anti-hypertensive medication are not eligible for study enrollment.
  * Investigational Drugs: Patients who are currently receiving an investigational drug are not eligible.
  * Concomitant anticoagulation with anticoagulants (e.g., warfarin, direct thrombin, Factor Xa inhibitors, heparins) or platelet inhibitors (e.g., clopidogrel, aspirin) is prohibited.
  * CYP3A4 active agents: specific CYP3A inducers and inhibitors, including enzyme-inducing anticonvulsants, are prohibited and are listed in Appendix B. They must not be taken within 7 days of starting cabozantinib.
  * QT prolonging agents: specific QT prolonging agents are prohibited. They must not be taken at the time of enrollment.
* Pregnant participants will not be entered on this study given that the effects of cabozantinib on the developing human fetus are unknown. Female participants of childbearing potential must have a documented negative pregnancy test during screening.
* Breastfeeding mothers are not eligible due to unknown risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib.
* Intercurrent illness including, but not limited to, ongoing/persistent infection (fevers \>38.5 for ≥ 5 days), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients with a known history of HIV and/or hepatitis B (testing not required as part of screening).
* Patients with gastrointestinal disease or disorder that could interfere with absorption of cabozantinib such as bowel obstruction or inflammatory bowel disease.
* Bleeding or thrombosis:

  * Current evidence of active bleeding, intratumoral hemorrhage or bleeding diathesis.
  * Within 6 months prior to study enrollment, having history of pulmonary embolism, DVT, or other venous thromboembolic event.
  * Within 6 months prior to study enrollment, having history of significant GI bleeding, GI perforation, intra-abdominal abscess or fistula.
  * Within 6 weeks prior to study enrollment, having history of hemoptysis.
  * Within 28 days prior to study enrollment, having history of significant traumatic brain injury.
* Patients who are unable to swallow intact tablets 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