A Study of Cabozantinib as a Maintenance Agent to Prevent Progression or Recurrence in High-Risk Pediatric Solid Tumors

Introduction

• Org Study ID: CaboMain
• NCT ID: NCT05135975
• Lead Sponsor Name: Nationwide Children's Hospital
• Status: RECRUITING

Conditions

• Wilms Tumor

Brief Summary

This study will expand the types of pediatric cancers being evaluated for response to cabozantinib. The current COG study is restricted to Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, and a handful of uncommon tumors. The proposed study will extend this evaluation to tumors that have been shown to either express known targets of cabozantinib or with preclinical evidence of efficacy, including specifically neuroblastomas. These tumors have high morbidity and mortality, particularly in the relapse setting, and few or no proven therapeutic options. As such, evaluation of cabozantinib in these studies is warranted.

The study hypothesizes that use of cabozantinib in patients with ultra-high-risk pediatric solid tumors with minimal disease burden, as defined in the inclusion criteria below, can prevent and/or slow recurrent tumor formation in pediatric solid tumors and thereby significantly extend the period of disease control and/or induce a durable cure.

Eligibility Criteria

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 A: Solid tumors with 1-year PFS ≤25% (target enrollment 36 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.
3. Osteosarcoma, BR2 or later
4. Ewing sarcoma, BR2 or later
5. Rhabdomyosarcoma, with positive surgical margins OR with primary extremity tumor with >2 metastases at diagnosis, BR1 or later
6. Rhabdomyosarcoma, alveolar subtype or fusion-positive subtype, BR2 or later
7. Rhabdomyosarcoma, embryonal subtype, Group 4 at original diagnosis, BR2 or later
8. Desmoplastic small round blue cell tumor, BR2 or later
9. Any other soft tissue sarcoma, BR2 or later
10. Wilms tumor, diffuse anaplasia histology, any stage, BR2 or later
11. Wilms tumor, any histology with relapse within 12 months of diagnosis, who have received prior treatment with doxorubicin, and intraabdominal recurrence, BR2 or later
12. Wilms tumor, BR3 or later
13. Other solid tumor with 1-year PFS ≤ 20% can be discussed with study chair for eligibility
2. Stratum B: Metastatic Ewing sarcoma with metastases not undergoing complete metastatectomy, BR1 (target enrollment 20 patients)
3. Stratum C: Metastatic osteosarcoma after frontline therapy, BR1 (target enrollment 20 patients)
4. Stratum D: Metastatic fusion-positive rhabdomyosarcoma after frontline therapy, BR1 (target enrollment 10 patients)

3.2.3 Inclusion Criteria for Eligibility:

1. Age: ≥ 18 months of age and 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 30 mg/dL urine protein (or > 1+ on dipstick), 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. ALT2.7 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