Cabozantinib to Prevent Progression or Recurrence in Patients with High-Risk Pediatric Solid Tumors

Inclusion Criteria

• 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): * 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 * 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 * Patients previously with measurable AND evaluable disease at start of most recent line of therapy must meet BOTH “measurable disease” and “evaluable disease”
• Patients need to meet any single definition of disease below: * Stratum 1: Neuroblastoma (target enrollment 30 patients) ** Neuroblastoma best response (BR)1 at the end of frontline therapy with residual disease (less than complete response (CR), including MIBG-avid stable disease, or > 5% bone marrow involvement) but not progressive at time of enrollment ** Neuroblastoma BR2 or later * Stratum 3a: Relapsed/refractory sarcomas and other solid tumors (target enrollment 36 patients) ** Osteosarcoma, BR2 or later ** Ewing sarcoma, BR2 or later ** Rhabdomyosarcoma, with positive surgical margins OR with primary extremity tumor with > 2 metastases at diagnosis, BR1 or later ** Rhabdomyosarcoma, alveolar subtype or fusion-positive subtype, BR2 or later ** Rhabdomyosarcoma, embryonal subtype, group 4 at original diagnosis, BR2 or later ** Desmoplastic small round blue cell tumor, BR2 or later ** Any other soft tissue sarcoma, BR2 or later ** Wilms tumor, diffuse anaplasia histology, any stage, BR2 or later ** Wilms tumor, any histology with relapse within 12 months of diagnosis, who have received prior treatment with doxorubicin, and intraabdominal recurrence, BR2 or later ** Wilms tumor, BR3 or later * Stratum 3b: Metastatic sarcomas after frontline therapy (target enrollment 20 patients) ** Metastatic osteosarcoma, BR1 ** Ewing sarcoma with metastases not undergoing complete metastatectomy, BR1
• Age: ≥ 18 months of age and < 40 years of age at time of study enrollment
• Patients must have a Lansky or Karnofsky performance status score of ≥ 50, corresponding to Easter 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 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 Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03 from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically nonsignificant and/or stable on supportive therapy
• Patients must be ≥ 0.35 m^2 in body surface area (BSA), using the Mosteller formula, within two weeks of study enrollment
• Patients must have recovered from the acute toxic effects of prior therapy, with the following time specifications: * Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment on study (6 weeks if prior therapy included nitrosourea) * 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 * Biological anticancer therapy (including antibody therapy or cellular therapy): Patients must not have received biological anticancer therapy within 21 days of enrollment on study * 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 * 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
• Absolute neutrophil count (ANC) ≥ 1000/mcL; patients cannot have received filgrastim, pegfilgrastim or equivalent biosimilar within 14 days of study enrollment
• 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 thrombopoietin (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
• 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
• 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
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2, as per institutional standard testing OR serum creatinine based on age/gender as follows: (within 2 weeks of study enrollment) * Age 2 to < 6 years: male 0.8, female 0.8 * Age 6 to < 10 years: male 1, female 1 * Age 10 to < 13 years: male 1.2, female 1.2 * Age 13 to < 16 years: male 1.5, female 1.4 * Age ≥ 16 years: male 1.7, female 1.4
• 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 (within 2 weeks of study enrollment) NOTE: If the initial urinalysis shows >30 mg/dL urine protein (or > 1+ on dipstick), a 24-hour quantitative urine protein should be utilized, as described above, for eligibility consideration
• Total bilirubin < 2 x institutional upper limit of normal (ULN) for age (within 14 days of study enrollment)
• Alanine aminotransferase (ALT) < 5 x ULN (within 14 days of study enrollment)
• Serum albumin > 2.7 g/dL (within 14 days of study enrollment)
• No significant arrhythmias, strokes, transient ischemic attacks, or myocardial infarction within 6 months of study enrollment
• Corrected QT interval (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 electrocardiogram (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
• 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
• Patient must have adequate pancreatic function, as defined by a serum lipase < 2 x ULN
• 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
• 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
• 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
• 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
• Patients must not have had a core or fine needle biopsy within 7 days of study enrollment
• Any surgical wounds or incisions must be healed, as determined by treating physician, prior to enrollment on study
• Bone marrow aspiration and/or biopsy are not considered surgical procedures for the purpose of this study
• Patients must be able to swallow tablets intact. Tablets cannot be cut or crushed
• 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
• Patient or legal guardian must be capable of understanding and complying with the protocol requirements and must have signed the informed consent document
• Patient must be able to start study treatment no later than 12 weeks after end of prior therapy, where 1 week = 7 days
• Patient must be enrolled on study within 14 days of qualifying radiographic imaging studies demonstrating best response
• Patient must be able to start study treatment no later than 7 days from study enrollment

Exclusion Criteria

• Patients previously treated with cabozantinib are ineligible
• Women who are pregnant or breastfeeding will not be enrolled on this study due to potential teratogenic or development toxicities
• 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. Patients may not be on other chronic immunosuppressive agents for at least 14 days prior to enrollment on study
• Patients with graft versus host disease requiring any therapy other than topical corticosteroids (e.g., systemic immunosuppression, photopheresis, octreotide, etc.) within 14 days of enrollment on study are ineligible; patients with prior graft versus host disease must have discontinued systemic immunosuppression
• Patients continuing to receive other anticancer agents, either as experimental therapies, standard of care or off-label are not eligible for enrollment
• Patients must not have taken a strong CYP3A4 inhibitor or inducer within 14 days of enrollment. It is encouraged for patients taking other inducers or inhibitors of CYP3A4 be changed to another appropriate drug during the period of cabozantinib administration. Please review all concurrent medications upon receipt of screening information, and at time of enrollment with the patient. Review of medications with institutional pharmacy staff is recommended for any such interactions as new medications are introduced to the market frequently
• Patients who have started therapeutic anticoagulation for an identified thrombus or pulmonary embolism within 6 weeks of study enrollment are not eligible for enrollment. Patients on anticoagulation treatment or prophylaxis for a prior thrombosis (diagnosed > 6 weeks prior to enrollment) can remain on anticoagulation during study with standard of care agents, but not on experimental agents. Patients cannot receive betrixaban or dabigatran for anticoagulation
• Patients with a prolonged prothrombin time ≥ 1.5 times ULN within 7 days of enrollment are not eligible for enrollment (unless on anticoagulation prophylaxis with a direct oral anticoagulant). If the lab value normalizes to < 1.5 times ULN, the patient is eligible for enrollment if all other criteria are met. If the patient is on anticoagulation prophylaxis, they must have a stable PT (≤ 20% variance, ≥ 48 hours apart) without clinically significant bleeding at time of enrollment
• Patients with a prolonged activated partial thromboplastin time (aPTT) test ≥ 1.5 times ULN within 7 days of study enrollment should have an aPTT with heparinase obtained (unless on anticoagulation prophylaxis with enoxaparin or direct oral anticoagulant). If the aPTT with heparinase is < 1.5 times ULN and the patient has no clinically significant bleeding, the patient is eligible for enrollment and the lab does not need to be repeated. If the aPTT with heparinase remains ≥ 1.5 times ULN, the patient will be deemed ineligible at that time. If pursuance of potential enrollment is desired, the patient must be referred to hematology for evaluation. If aPTT value normalizes to < 1.5 times ULN, OR hematology evaluation determines a clinically insignificant cause for the prolonged aPTT (e.g., factor XII deficiency), the patient is eligible for enrollment if all other criteria are met.. If the patient is on anticoagulation prophylaxis, they must have a stable aPTT (≤ 20% variance, ≥ 48 hours apart) without clinically significant bleeding within 7 days of enrollment
• Patients with an uncontrolled infection are ineligible for enrollment
• Patients who, in the opinion of the investigator, are not able to comply with safety monitoring requirements are not eligible for enrollment
• Patients with radiation-related mucocutaneous injury, either primary or related to radiation recall or false photosensitivity, are not eligible for enrollment until toxicities have resolved for at least 7 days
• Patients with the following cardiovascular disorders are deemed ineligible: * Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, and/or grade 3 or higher cardiac arrhythmias. * Patients with persistent and sustained Grade 2 or higher hypertension uncontrolled by a single antihypertensive agent at a stable dose for at least 2 weeks prior to enrollment
• Patients with gastrointestinal (GI) disorders associated with a high risk of perforation or fistula formation within 4 weeks of enrollment are ineligible. These include: evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. Additionally, patients with abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 24 weeks of enrollment are ineligible. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
• Patients with clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of grade 3 or higher bleeding (eg, pulmonary hemorrhage) within 12 weeks before enrollment are ineligible, unless associated with chemotherapy-induced thrombocytopenia that has resolved, criteria 5, for at least 2 weeks prior enrollment
• Patients with cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation are ineligible
• Patients with primary or metastatic tumors invading or encasing any major blood vessels are ineligible, unless that tumor has been previously irradiated and determined by the study chair, or delegate, to no longer be active disease
• Patients with other clinically significant disorders that would preclude safe study participation are ineligible
• Patients with serious non-healing wound/ulcer/bone fracture are ineligible
• Patients with uncompensated/symptomatic hypothyroidism are ineligible; patients with controlled hypothyroidism with the use of thyroid replacement therapy with a stable dose for at least 2 weeks prior to enrollment are eligible for inclusion
• Patients with moderate to severe hepatic impairment (Child-Pugh B or C) are ineligible
• Patients with previously identified allergy or hypersensitivity to components of the study treatment formulations are ineligible
• Patients with diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy, are ineligible