PRIMARY OBJECTIVES:
I. To determine the feasibility of adding cabozantinib S-malate (cabozantinib) to standard MAP (high dose methotrexate, doxorubicin hydrochloride \[doxorubicin\], and cisplatin) chemotherapy in patients with newly diagnosed metastatic osteosarcoma with a resectable primary tumor.
II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma.
III. To determine whether MAP chemotherapy plus cabozantinib results in more favorable event-free survival (EFS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma.
SECONDARY OBJECTIVES:
I. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with localized, resectable osteosarcoma.
II. To determine whether MAP chemotherapy plus cabozantinib results in more favorable overall survival (OS) than MAP chemotherapy alone in patients with metastatic, pelvic and unresectable osteosarcoma.
EXPLORATORY OBJECTIVES:
I. To determine the rate of good histologic response (\> 90%) of resected primary tumor specimens following neoadjuvant chemotherapy with MAP plus cabozantinib and compare with response rates for MAP chemotherapy alone.
II. To describe the toxicities of the addition of cabozantinib to MAP chemotherapy in patients with newly diagnosed osteosarcoma.
III. To describe frequency of application of local control methods (surgery, hypofractionated stereotactic body radiotherapy, or radiofrequency ablation) for extrapulmonary metastatic osteosarcoma.
IV. To compare total cumulative delivered doses of MAP chemotherapy agents between standard and experimental arms across multiple phases of therapy.
V. To assess the pharmacokinetics of cabozantinib when administered concomitantly with standard chemotherapy agents during feasibility.
VI. To collect pulmonary metastatic lesions, paired primary tumor tissue, and serial blood samples for tumor profiling, liquid biopsies, and future testing of correlative biology studies.
OUTLINE: This is a dose-escalation study of cabozantinib (Feasibility Phase) followed by a randomized phase II/III study (Efficacy Phase).
FEASIBILITY PHASE: Patients receive cabozantinib orally (PO), methotrexate intravenously (IV), doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles. Patients are then considered for appropriate local control. Then they receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
EFFICACY PHASE: Patients with standard risk osteosarcoma are randomized to Arm A or Arm B. Patients with high risk osteosarcoma are randomized to Arm C or Arm D.
ARM A: Standard risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles.
ARM B: Standard risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "consolidation" cycles, and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
ARM C: High risk patients receive methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day cycles and methotrexate IV and doxorubicin IV for two additional 35-day cycles.
ARM D: High risk patients receive cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for two 35-day "induction" cycles, followed by appropriate local control. Patients then receive "consolidation" with methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle, followed by cabozantinib PO, methotrexate IV, doxorubicin IV, and cisplatin IV for one 35-day cycle and cabozantinib PO, methotrexate IV, and doxorubicin IV for two additional 35-day cycles. Patients then receive cabozantinib PO for six 28-day "maintenance" cycles.
All patients also undergo X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) or bone scintigraphy at diagnosis and additonal time points throughout the trial. All patients also undergo collection of blood samples during screening and on study.
Inclusion Criteria:
- Patients must be < 40 years of age at the time of enrollment.
- Patients must have a body surface area of >= 0.8 m^2 at the time of enrollment.
- Patients must have histologic diagnosis (by institutional pathologist) of newly
diagnosed high grade osteosarcoma. Primary tumors of all extremity and axial sites are
eligible as long as diagnosis of high-grade osteosarcoma is established. Osteosarcoma
as a second malignancy is eligible if no prior exposure to systemic chemotherapies.
- Feasibility Phase:
Patients must have metastatic disease and a resectable primary tumor. Designation of a
primary tumor as resectable will be determined at the time of diagnosis by the
institutional multidisciplinary team.
For this study, metastatic disease is defined as one or more of the following:
- Lesions which are discontinuous from the primary tumor, are not regional lymph nodes,
and do not share a bone or body cavity with the primary tumor. Skip lesions in the
same bone as the primary tumor do not constitute metastatic disease. Skip lesions in
an adjacent bone are considered bone metastases.
- Lung metastases: defined as biopsy-proven metastasis or the presence of one or more
pulmonary lesions >= 5 mm, OR multiple pulmonary lesions >= 3 mm or greater in size.
- Bone metastases: Areas suspicious for bone metastasis based on fludeoxyglucose F-18
(18F-FDG)-positron emission tomography (PET) scan (or whole body technetium-99 bone
scan if 18F-FDG-PET is unavailable at the treating institution) require confirmatory
biopsy or supportive anatomic imaging of at least one suspicious site with either
magnetic resonance imaging (MRI) or computed tomography (CT) (whole body
18F-FDG-PET/CT or 18F-FDG-PET/MR scans are acceptable).
- Efficacy Phases (Phase 2/3)
Patients with both localized and metastatic disease are eligible for the efficacy phase,
regardless of resectability. Patients will be enrolled to two separate cohorts:
- Cohort 1 (Standard Risk): Patients with non-pelvic primary osteosarcoma deemed to be
resectable at the time of diagnosis by the institutional multidisciplinary team,
without evidence of metastatic lesions.
- Cohort 2 (High-Risk): Patients with a primary pelvic tumor, a primary tumor designated
as unresectable by the institutional multidisciplinary team, AND/OR radiographic
evidence of metastatic lesions.
- A serum creatinine based on age/gender as follows (within 7 days prior to
enrollment unless otherwise indicated):
- (Age: Maximum Serum Creatinine [mg/dL]; Gender)
- 1 month to < 6 months: 0.4 (male); 0.4 (female)
- 6 months to < 1 year: 0.5 (male); 0.5 (female)
- 1 to < 2 years: 0.6 (male); 0.6 (female)
- 2 to < 6 years: 0.8 (male); 0.8 (female)
- 6 to < 10 years: 1 (male); 1 (female)
- 10 to < 13 years: 1.2 (male); 1.2 (female)
- 13 to < 16 years: 1.5 (male); 1.4 (female)
- >= 16 years: 1.7 (male); 1.4 (female)
- OR - a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2
- OR - a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed
using direct measurement with a nuclear blood sampling method OR direct small molecule
clearance method (iothalamate or other molecule per institutional standard).
- Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility.
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days
prior to enrollment unless otherwise indicated)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase
[ALT]) =< 135 U/L (within 7 days prior to enrollment unless otherwise
indicated)
- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value
of 45 U/L
- No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart
Association (NYHA) Class III or IV congestive heart failure, unstable angina
pectoris, serious cardiac arrhythmias or
- Shortening fraction of >= 27%, or
- Ejection fraction of >= 50%, or
- Corrected QT interval by Fridericia (QTcF) < 480 msec on electrocardiogram. Patients
with Grade 1 prolonged QTc (450-480 msec) at time of study enrollment should have
correctable causes of prolonged QTc addressed if possible (i.e., electrolytes,
medications).
- Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment unless otherwise indicated)
- Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions within a 7-day period prior to enrollment) (within 7 days
prior to enrollment unless otherwise indicated)
- Hemoglobin >= 8.0 g/dL (within 7 days prior to enrollment unless otherwise
indicated)
- International normalized ratio (INR) =< 1.5 (within 7 days prior to enrollment
unless otherwise indicated)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible as long as they
are NOT receiving anti-retroviral agents that are strong inhibitors or inducers
of CYP3A4, CYP2D6, and/or MRP2 transporter protein.
- All patients and/or their parents or legal guardians must sign a written informed
consent.
- All institutional, Food and Drug Administration (FDA), and National Cancer
Institute (NCI) requirements for human studies must be met.
Exclusion Criteria:
- Patients who have received previous systemic therapy for osteosarcoma or a prior
oncologic diagnosis.
- Patients who have central nervous system metastases.
- Patients with central cavitating pulmonary lesions invading or encasing any major
blood vessels in the lung.
- Patients who are unable to swallow tablets. Tablets cannot be crushed or chewed.
- Patients with gastrointestinal disorders including active disorders associated with a
high risk of perforation or fistula formation. Specifically, no clinically significant
gastrointestinal (GI) bleeding, GI perforation, bowel obstruction, intra-abdominal
abscess or fistula for 6 months prior to enrollment, no hemoptysis or other signs of
pulmonary hemorrhage for 3 months prior to enrollment.
- Patients with active bleeding or bleeding diathesis. No clinically significant
hematuria, hematemesis, or hemoptysis or other history of significant bleeding within
3 months prior to enrollment.
- Patients with uncompensated or symptomatic hypothyroidism. Patients who have
hypothyroidism controlled with thyroid replacement hormone are eligible.
- Patients with moderate to severe hepatic impairment (Child-Pugh B or C).
- Patients who have had primary tumor resection or attempted curative resection of
metastases prior to enrollment.
- Patients who have undergone other major surgical procedure (eg, laparotomy) within 14
days prior to enrollment. Thoracoscopic procedures for diagnostic purposes (biopsy of
lung nodule) and central access such as port-a-cath placement are allowed.
- Patients with a history of serious or non-healing wound or bone fracture (pathologic
fracture of primary tumor is not considered exclusion).
- Patients with any medical or surgical conditions that would interfere with
gastrointestinal absorption of cabozantinib.
- Patients with previously identify allergy or hypersensitivity to components of the
study treatment formulations.
- Patients who are receiving any other investigational agent not defined within this
protocol 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.
- Patients who received enzyme-inducing anticonvulsants within 14 days prior to
enrollment.
- Patients with a prior history of hypertension (> 95th percentile for age, height, and
gender for patients < 18 years and > 140/90 mmHg for patients >= 18 years requiring
medication for blood pressure control.
- Patients who are receiving drugs that prolong QTc.
- Patients receiving anticoagulation with oral coumarin agents (eg warfarin), direct
thrombin inhibitors (eg dabigatran), direct factor Xa inhibitor betrixaban, or
platelet inhibitors (eg, clopidogrel). Low dose aspirin for cardioprotection (per
local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are
permitted. Anticoagulation with therapeutic doses of LMWH and direct factor Xa
inhibitors rivaroxaban or apixaban are allowed in subjects who are on a stable dose
for at least 6 weeks before the first dose of study treatment, and who have had no
complications from a thromboembolic event or the anticoagulation regimen.
- Patients receiving strong CYP3A4 inducers or strong CYP3A4 inhibitors.
- Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential.
- Lactating females who plan to breastfeed their infants.
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of protocol therapy.
