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Patients with each of the below pediatric tumor types, having achieved a "best response |
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(BR) defined as |
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Absence of measurable disease by CT or MRI 4 weeks off any antineoplastic therapy OR |
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Absence of evaluable disease by 18-FDG PET-CT or PET-MRI on two scans at least 4 weeks |
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apart, while off therapy, despite the presence of measurable disease by conventional |
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CT or MRI (e.g., after irradiation of target lesions) OR |
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Stable measurable disease with <10% change in size of any target lesion, as measured |
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by CT or MRI, after 4 weeks without any antineoplastic therapy, independent of MIBG or |
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PET avidity |
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Stratum 1: Neuroblastoma (target enrollment 35 patients) |
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Neuroblastoma in best response 2 (i.e., re-induced to best response after prior |
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relapse) or greater (BR2+); this includes patients who had refractory disease or |
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progressed during upfront therapy and attained a stable best response with salvage |
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therapy; this does NOT include patients who received additional treatment for partial |
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response to induction therapy; specific cases may be discussed with the study chair |
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for clarification |
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Neuroblastoma in BR1 in patient >5 years of age and stage M at diagnosis without a |
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complete response at the end of induction therapy |
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Neuroblastoma in BR1 at the end of frontline therapy but with residual stable disease |
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(including MIBG-avid stable disease as per section 3.1.1 or >5% bone marrow |
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involvement) |
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Patients with neuroblastoma must also have stable (≤20% variance) or falling urine |
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HVA/Cr and VMA/Cr over two labs obtained 4 weeks apart |
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Stratum 2: Central nervous system (CNS) tumors (target enrollment 29 patients) |
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Atypical teratoid rhabdoid tumors (ATRT), BR1+ |
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Diffuse intrinsic pontine glioma (DIPG), BR1+ having completed upfront radiation |
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therapy |
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High grade gliomas (HGG, WHO Grade 3 or 4 astrocytomas) in BR1+ |
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Medulloblastoma, Molecular Group 3 (with MYC/MYCN expression/amplification) or Group 4 |
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in BR1+ |
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Medulloblastoma in any molecular group in BR2+ |
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Germ Cell tumor of the CNS, BR2+ |
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Stratum 3: Sarcomas and other solid tumors (target enrollment 36 patients) |
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Malignant rhabdoid Tumor, BR1+ |
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Osteosarcoma, any BR2+ |
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Ewing sarcoma with metastases not undergoing metastatectomy, BR1+ |
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Ewing sarcoma, any BR2+ |
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Rhabdomyosarcoma, BR1 with irradiated positive margins |
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Rhabdomyosarcoma, BR2+, alveolar subtype or fusion-positive subtype |
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Rhabdomyosarcoma, BR2+, embryonal subtype, Group 4 at original diagnosis |
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Desmoplastic small round blue cell tumor, BR1+ |
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Any other soft tissue sarcoma, BR2+ |
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Germ cell tumors outside the CNS, BR2+ |
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Wilms tumor, diffuse anaplasia histology, any stage, BR2+ |
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Wilms tumor, relapse <12 months, prior treatment with doxorubicin, and intraabdominal |
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recurrence, any histology, BR2+ |
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Other solid tumors in which patients had refractory or progressive disease to initial |
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therapy, excluding cases of surgery alone, and were then able to attain a stable best |
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response with a salvage regimen |
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Other solid tumors not arising from the head with <25% 1-year EFS, per discussion with |
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the principal investigator |
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Other Inclusion Criteria |
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Age: ≥ 18 months of age and <40 years of age at time of study entry |
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Performance level: Patients must have a Lansky or Karnofsky performance status score |
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of ≥ 50, corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients > 16 |
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years of age and Lansky for patients ≤ 16 years of age. Patients who are unable to |
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walk because of paralysis, but who are up in a wheelchair, will be considered |
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ambulatory for the purpose of assessing the performance score. Patients should also |
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have recovery to baseline or ≤ Grade 1 CTCAE v4.03 from toxicities related to any |
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prior treatments, unless AE(s) are clinically nonsignificant and/or stable on |
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supportive therapy (as further clarified below) |
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Patient Body Surface Area (BSA): Patients must be ≥0.35 m2 in BSA at time of diagnosis |
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Prior therapy: patients must have recovered from the acute toxic effects of prior |
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therapy, with the following time specifications |
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Myelosuppressive chemotherapy: Patients must not have received myelosuppressive |
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chemotherapy within 3 weeks of enrollment on study (6 weeks if prior therapy |
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included nitrosourea) |
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Other medicinal anti-cancer agents: Patients must not have received |
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nonmyelosuppressive anticancer agents, including any type of small molecule |
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kinase inhibitor, within 14 days of enrollment on study |
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Biological anticancer therapy (including antibody therapy) Patients must not have |
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received biological anticancer therapy within 21 days of enrollment on study |
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Radiation therapy: Patients (except in stratum 4) must not have received external |
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beam radiation therapy to sites outside of the lungs within 2 weeks of study |
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enrollment, external beam radiation therapy to sites within the lungs within 4 |
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weeks of study enrollment, or MIBG therapy within 6 weeks of study enrollment |
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Subjects with clinically relevant ongoing complications from prior radiation |
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therapy are not eligible |
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Myeloablative therapy: Patients must not have received myeloablative therapy |
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within 2 months of study enrollment and must not have received a blood stem |
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cell/marrow infusion within 3 weeks of study enrollment and must have attained |
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blood count recovery as defined below. Patient must not have been on agents for |
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control of graft versus host disease for at least 4 weeks prior to study |
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enrollment |
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Bone Marrow Function: Patients must have adequate bone marrow function at time of |
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study enrollment, as defined as |
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Absolute neutrophil count (ANC) ≥1000/mcL; patients cannot have received filgrastim |
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pegfilgrastim or equivalent biosimilar within 14 days of study enrollment |
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Platelet count ≥ 100,000/mcL; patients can receive no more than 15 mL/kg of platelet |
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transfusions per week at time of enrollment to meet the parameters; patients can |
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receive a TPO agonist (e.g., eltrombopag or romiplostim) at time of enrollment but |
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must be on a stable dose for at least 14 days prior to enrollment |
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Hemoglobin ≥ 8.0 g/dL; patients can receive no more than 10 mL/kg of packed red blood |
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cells (PRBCs)/week transfused at time of enrollment on therapy to meet the parameters |
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patients may receive erythropoietin or biosimilar equivalent but must have been on a |
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stable dose and not require PRBC transfusions for at least 14 days prior to study |
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enrollment |
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Patients should also have <5% bone marrow involvement by tumor if bone marrows have |
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been evaluated as part of clinical standard of care |
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Renal Function: Patients must have a creatinine clearance, as defined by the modified |
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Schwartz formula or by radioisotope GFR, of ≥70 mL/min/1.72 m2, and must have urine |
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protein ≤ 30 mg/dL or ≤+1 of dipstick or quantitative protein <1000 mg in a 24 hr |
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urine sample |
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Hepatic function: patients must have adequate hepatic function, defined as |
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total bilirubin <2x upper limit of normal for age |
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ALT<5x ULN |
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Serum albumin >2.7 g/dL |
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Cardiovascular Function: Patients must have adequate cardiovascular function as |
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defined as |
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No significant arrhythmias, strokes, or myocardial infarction within 6 months of |
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study enrollment |
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QTc ≤ 480 msec at time of study enrollment |
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Blood pressure ≤ 95th percentile for age, height, and gender for patients <18 |
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years of age (78), or BP ≤140/90 for patients ≥18 years of age. At time of |
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enrollment, patients may be on one antihypertensive agent at a stable dose for at |
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least 4 weeks prior to enrollment |
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Pancreatic function: Patient must have adequate pancreatic function, as defined by a |
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serum lipase <2x ULN |
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Neurologic function: Patients with defined seizures who are on a stable anti- |
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convulsant regimen using drugs that do not induce hepatic metabolizing enzymes for at |
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least 4 weeks are eligible for enrollment |
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Lung integrity: Patients must not have had any invasive pulmonary procedure (including |
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bronchoalveolar lavage, lung biopsy, transbronchial biopsy, or thoracotomy) or |
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pneumothorax within 4 weeks of enrollment on study |
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Surgeries or trauma: Patients must not have had any major surgical procedure |
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laparoscopic procedure, sepsis, shock, or trauma within 4 weeks of the start of |
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therapy. Patients must not have had a central line or subcutaneous port placement |
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revision, or removal (excluding a peripherally inserted central catheter (PICC)) |
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within 7 days of the start of therapy. Patients must not have had a core or fine |
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needle biopsy within 7 days of the start of therapy. The primary surgeon of any major |
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surgical procedures must authorize antineoplastic treatment before enrollment on |
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study. Any wounds or incisions must be healed prior to enrollment on study. Bone |
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marrow aspiration and/or biopsy are not considered surgical procedures for the purpose |
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of this study |
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Patients must be able to swallow tablets intact. Tablets cannot be cut or crushed |
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Sexually active fertile subjects and their partners must agree to use medically |
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accepted methods of contraception (eg, barrier methods, including male condom, female |
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condom, or diaphragm with spermicidal gel) during the course of the study and for 4 |
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months after the last dose of study treatment |
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Patient or legal guardian must be capable of understanding and complying with the |
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protocol requirements and must have signed the informed consent document |
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Prior treatment with cabozantinib
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Women who are pregnant or breastfeeding will not be enrolled on this study due to
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potential teratogenic or development toxicities. Post-menarchal females must be
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confirmed to not be pregnant at time of enrollment and each month of treatment. Males
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and females of reproductive age and potential must agree to two forms of birth control
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between themselves and their partner(s) throughout the treatment period and for four
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months after the final dose of cabozantinib
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Patients requiring corticosteroids who have not been on a stable or decreasing dose of
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corticosteroid for the 7 days prior to enrollment are not eligible. If used to modify
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immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last
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dose of corticosteroid. Patients may not be on other chronic immunosuppressive agents
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for at least 14 days prior to enrollment on study
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Patients with active graft versus host disease
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Patients on other anticancer agents, either as experimental therapies, standard of
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care or off-label are not eligible for enrollment
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Patients must not have taken a strong CYP3A4 inhibitor or inducer within 14 days of
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the first dose of cabozantinib. It is encouraged for patients taking other inducers or
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inhibitors of CYP3A4 be changed to another appropriate drug during the period of
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cabozantinib administration
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Patients on anticoagulation treatment are not eligible for enrollment. Patients on
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anticoagulation prophylaxis for a history of thrombosis (diagnosed >6 weeks prior and
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no longer on treatment dosing) can remain on anticoagulation during study with
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standard of care agents, but not on experimental agents. Patients cannot receive
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betrixaban or dabigatran for anticoagulation
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The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
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3 x the laboratory ULN within 7 days before the first dose of study treatment
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Patients with an uncontrolled infection are ineligible for enrollment
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Patients who, in the opinion of the investigator, are not able to comply with safety
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monitoring requirements are not eligible for enrollment
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Patients with radiation-related mucocutaneous injury, either primary or related to
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radiation recall or false photosensitivity, are not eligible for enrollment until
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toxicities have resolved for at least 7 days
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Cardiovascular disorders
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Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
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pectoris, serious cardiac arrhythmias
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Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
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systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
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Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI)
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or other ischemic event, or thromboembolic event (eg, deep venous thrombosis
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pulmonary embolism) within 6 months before first dose, excluding uncomplicated
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central venous catheter-associated thrombus that is not expanding, with or
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without stable use of anticoagulation
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Gastrointestinal (GI) disorders including those associated with a high risk of
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perforation or fistula formation
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The subject has evidence of tumor invading the GI tract, active peptic ulcer disease
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inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis
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symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the
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pancreatic duct or common bile duct, or gastric outlet obstruction
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Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
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|
within 6 months before first dose
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Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
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ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage)
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within 12 weeks before first dose
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Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
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manifestation
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Lesions invading or encasing any major blood vessels
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Other clinically significant disorders that would preclude safe study participation
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Serious non-healing wound/ulcer/bone fracture
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Uncompensated/symptomatic hypothyroidism; patients with controlled hypothyroidism with
|
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the use of thyroid replacement therapy are eligible for inclusion
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Moderate to severe hepatic impairment (Child-Pugh B or C)
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Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
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before first dose of study treatment. Complete wound healing from major surgery must
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have occurred 1 month before first dose and from minor surgery (eg, simple excision
|
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tooth extraction) at least 10 days before first dose. Subjects with clinically
|
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|
relevant ongoing complications from prior surgery are not eligible
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|
Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per
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|
|
electrocardiogram (ECG) within 28 days before first dose of study treatment [add
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|
|
reference for Fridericia formula]
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|
Previously identified allergy or hypersensitivity to components of the study treatment
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|
formulations
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Diagnosis of another malignancy within 2 years before first dose of study treatment
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|
except for superficial skin cancers, or localized, low grade tumors deemed cured and
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|
not treated with systemic therapy
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|