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

  • STATUS
    Recruiting
  • End date
    Dec 12, 2029
  • participants needed
    100
  • sponsor
    Nationwide Children's Hospital
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Updated on 12 March 2022
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platelet count
renal function
cancer
filgrastim
nitrosoureas
measurable disease
small molecule
karnofsky performance status
bone marrow procedure
doxorubicin
kidney function tests
neutrophil count
cancer chemotherapy
avid
sarcoma
medulloblastoma
desmoplastic
soft tissue sarcoma
mycn protein

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. These include neuroblastoma, high-grade gliomas, diffuse intrinsic pontine gliomas and other high-grade brain tumors, and germ cell tumors. 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.

Description

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.

The investigators propose to evaluate the efficacy of up to one year of treatment with cabozantinib in pediatric solid tumors with a minimal disease burden. There are multiple reasons for this approach, as opposed to continual therapy until toxicity or disease progression alone. First, for most of these ultra-high-risk diseases, the greatest risk of recurrence has historically been within 12 months after last therapy, and often times considerably sooner (18, 44-49). As such, the investigators should be able to evaluate a meaningful difference within 12 months. Second, the goal of this study is to evaluate if, during a critical period of disease control, use of cabozantinib can induce a durable remission. There are active Phase 2 and 3 studies of cabozantinib, including with the Children's Oncology Group, evaluating the efficacy of cabozantinib in controlling pediatric cancers with measurable burden of disease. However, we know that in patients with minimal, immeasurable disease burden there is still active disease with high risk of growth. This study seeks to augment ongoing work in pediatric cancers by testing the hypothesis that cabozantinib can durably silence cancer cell viability in a minimal residual disease state. Third, this work would mark a fundamental change in the indication for use of cabozantinib in pediatric cancers, broadening its utility from a "rescue" agent to a maintenance therapy that may be critical for disease control, during either primary or secondary remission.

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. These include neuroblastoma, high-grade gliomas, diffuse intrinsic pontine gliomas and other high-grade brain tumors, and germ cell tumors. 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.

Details
Condition Neuroblastoma, CNS Tumor, Sarcoma
Treatment Cabozantinib
Clinical Study IdentifierNCT05135975
SponsorNationwide Children's Hospital
Last Modified on12 March 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Patients with each of the below pediatric tumor types, having achieved a "best response
(BR) defined as
Absence of measurable disease by CT or MRI 4 weeks off any antineoplastic therapy OR
Absence of evaluable disease by 18-FDG PET-CT or PET-MRI on two scans at least 4 weeks
apart, while off therapy, despite the presence of measurable disease by conventional
CT or MRI (e.g., after irradiation of target lesions) OR
Stable measurable disease with <10% change in size of any target lesion, as measured
by CT or MRI, after 4 weeks without any antineoplastic therapy, independent of MIBG or
PET avidity
Stratum 1: Neuroblastoma (target enrollment 35 patients)
Neuroblastoma in best response 2 (i.e., re-induced to best response after prior
relapse) or greater (BR2+); this includes patients who had refractory disease or
progressed during upfront therapy and attained a stable best response with salvage
therapy; this does NOT include patients who received additional treatment for partial
response to induction therapy; specific cases may be discussed with the study chair
for clarification
Neuroblastoma in BR1 in patient >5 years of age and stage M at diagnosis without a
complete response at the end of induction therapy
Neuroblastoma in BR1 at the end of frontline therapy but with residual stable disease
(including MIBG-avid stable disease as per section 3.1.1 or >5% bone marrow
involvement)
Patients with neuroblastoma must also have stable (≤20% variance) or falling urine
HVA/Cr and VMA/Cr over two labs obtained 4 weeks apart
Stratum 2: Central nervous system (CNS) tumors (target enrollment 29 patients)
Atypical teratoid rhabdoid tumors (ATRT), BR1+
Diffuse intrinsic pontine glioma (DIPG), BR1+ having completed upfront radiation
therapy
High grade gliomas (HGG, WHO Grade 3 or 4 astrocytomas) in BR1+
Medulloblastoma, Molecular Group 3 (with MYC/MYCN expression/amplification) or Group 4
in BR1+
Medulloblastoma in any molecular group in BR2+
Germ Cell tumor of the CNS, BR2+
Stratum 3: Sarcomas and other solid tumors (target enrollment 36 patients)
Malignant rhabdoid Tumor, BR1+
Osteosarcoma, any BR2+
Ewing sarcoma with metastases not undergoing metastatectomy, BR1+
Ewing sarcoma, any BR2+
Rhabdomyosarcoma, BR1 with irradiated positive margins
Rhabdomyosarcoma, BR2+, alveolar subtype or fusion-positive subtype
Rhabdomyosarcoma, BR2+, embryonal subtype, Group 4 at original diagnosis
Desmoplastic small round blue cell tumor, BR1+
Any other soft tissue sarcoma, BR2+
Germ cell tumors outside the CNS, BR2+
Wilms tumor, diffuse anaplasia histology, any stage, BR2+
Wilms tumor, relapse <12 months, prior treatment with doxorubicin, and intraabdominal
recurrence, any histology, BR2+
Other solid tumors in which patients had refractory or progressive disease to initial
therapy, excluding cases of surgery alone, and were then able to attain a stable best
response with a salvage regimen
Other solid tumors not arising from the head with <25% 1-year EFS, per discussion with
the principal investigator
Other Inclusion Criteria
Age: ≥ 18 months of age and <40 years of age at time of study entry
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 up 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 (as further clarified below)
Patient Body Surface Area (BSA): Patients must be ≥0.35 m2 in BSA at time of diagnosis
Prior therapy: 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
nonmyelosuppressive anticancer agents, including any type of small molecule
kinase inhibitor, within 14 days of enrollment on study
Biological anticancer therapy (including antibody therapy) Patients must not have
received biological anticancer therapy within 21 days of enrollment on study
Radiation therapy: Patients (except in stratum 4) 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 MIBG therapy within 6 weeks of study enrollment
Subjects with clinically relevant ongoing complications from prior radiation
therapy are not eligible
Myeloablative therapy: Patients must not have received myeloablative therapy
within 2 months of study enrollment and must not have received a blood stem
cell/marrow infusion within 3 weeks of study enrollment and must have attained
blood count recovery as defined below. Patient must not have been on agents for
control of graft versus host disease for at least 4 weeks prior to study
enrollment
Bone Marrow Function: Patients must have adequate bone marrow function at time of
study enrollment, as defined as
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 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 should also have <5% bone marrow involvement by tumor if bone marrows have
been evaluated as part of clinical standard of care
Renal Function: Patients must have a creatinine clearance, as defined by the modified
Schwartz formula or by radioisotope GFR, of ≥70 mL/min/1.72 m2, and must have urine
protein ≤ 30 mg/dL or ≤+1 of dipstick or quantitative protein <1000 mg in a 24 hr
urine sample
Hepatic function: patients must have adequate hepatic function, defined as
total bilirubin <2x upper limit of normal for age
ALT<5x ULN
Serum albumin >2.7 g/dL
Cardiovascular Function: Patients must have adequate cardiovascular function as
defined as
No significant arrhythmias, strokes, or myocardial infarction within 6 months of
study enrollment
QTc ≤ 480 msec at time of study enrollment
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 4 weeks prior to enrollment
Pancreatic function: Patient must have adequate pancreatic function, as defined by a
serum lipase <2x ULN
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
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
Surgeries or trauma: Patients must not have had any major surgical procedure
laparoscopic procedure, sepsis, shock, or trauma within 4 weeks of the start of
therapy. 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 the start of therapy. Patients must not have had a core or fine
needle biopsy within 7 days of the start of therapy. The primary surgeon of any major
surgical procedures must authorize antineoplastic treatment before enrollment on
study. Any wounds or incisions must be healed 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
Patient or legal guardian must be capable of understanding and complying with the
protocol requirements and must have signed the informed consent document

Exclusion Criteria

Prior treatment with cabozantinib
Women who are pregnant or breastfeeding will not be enrolled on this study due to
potential teratogenic or development toxicities. Post-menarchal females must be
confirmed to not be pregnant at time of enrollment and each month of treatment. Males
and females of reproductive age and potential must agree to two forms of birth control
between themselves and their partner(s) throughout the treatment period and for four
months after the final dose of cabozantinib
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 active graft versus host disease
Patients on 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
the first dose of cabozantinib. It is encouraged for patients taking other inducers or
inhibitors of CYP3A4 be changed to another appropriate drug during the period of
cabozantinib administration
Patients on anticoagulation treatment are not eligible for enrollment. Patients on
anticoagulation prophylaxis for a history of thrombosis (diagnosed >6 weeks prior and
no longer on treatment dosing) can remain on anticoagulation during study with
standard of care agents, but not on experimental agents. Patients cannot receive
betrixaban or dabigatran for anticoagulation
The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
3 x the laboratory ULN within 7 days before the first dose of study treatment
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
Cardiovascular disorders
Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
pectoris, serious cardiac arrhythmias
Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI)
or other ischemic event, or thromboembolic event (eg, deep venous thrombosis
pulmonary embolism) within 6 months before first dose, excluding uncomplicated
central venous catheter-associated thrombus that is not expanding, with or
without stable use of anticoagulation
Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation
The subject has 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
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose
Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage)
within 12 weeks before first dose
Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
Lesions invading or encasing any major blood vessels
Other clinically significant disorders that would preclude safe study participation
Serious non-healing wound/ulcer/bone fracture
Uncompensated/symptomatic hypothyroidism; patients with controlled hypothyroidism with
the use of thyroid replacement therapy are eligible for inclusion
Moderate to severe hepatic impairment (Child-Pugh B or C)
Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (eg, simple excision
tooth extraction) at least 10 days before first dose. Subjects with clinically
relevant ongoing complications from prior surgery are not eligible
Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per
electrocardiogram (ECG) within 28 days before first dose of study treatment [add
reference for Fridericia formula]
Previously identified allergy or hypersensitivity to components of the study treatment
formulations
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