| Eligibility |
Inclusion Criteria:
- Signed informed consent form
- Age >= 12 years at time of signing informed consent form
- Ability to comply with the study protocol, in the investigator's judgment
- Histologically confirmed diagnosis of osteosarcoma
- Metastatic or unresectable locally advanced disease
- Patients must have relapsed or become refractory to conventional therapy including
some combination of cisplatin, doxorubicin, methotrexate, and/or ifosfamide
- Measurable disease per RECIST version (v)1.1 (Note: Previously irradiated lesions can
be considered as measurable disease only if progressive disease has been unequivocally
documented at that site since radiation)
- Availability of a representative tumor specimen for exploratory biomarker research.
Archival samples are permitted if the tumor samples been obtained within 6 months
prior to enrollment and the patient has not received intervening therapy
- A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block
(preferred) or at least 15 slides containing unstained, freshly cut, serial
sections should be submitted along with an associated pathology report prior to
study enrollment. If only 10-14 slides are available, the patient may still be
eligible for the study, after principal investigator confirmation has been
obtained
- If archival tumor tissue is unavailable or is determined to be unsuitable for
required testing, tumor tissue must be obtained from a biopsy performed at
screening
- Eastern Cooperative Oncology Group (ECOG) of 0, 1 or 2. Use Karnofsky >= 50 for
patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age
- Body surface area (BSA) >= 1 m^2
- Life expectancy >= 6 months
- Recovery to baseline or =< grade 1 CTCAE v5 from toxicities related to any prior
treatments, unless adverse events (AE[s]) are clinically nonsignificant and/or stable
on supportive therapy
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (1000/uL) without granulocyte
colony-stimulating factor support (obtained within 14 days prior to initiation of
study treatment)
- Lymphocyte count >= 0.5 x 10^9/L (500/uL) (obtained within 14 days prior to initiation
of study treatment)
- Platelet count >= 100 x 10^9/L (100,000/uL) without transfusion (obtained within 14
days prior to initiation of study treatment)
- Hemoglobin >= 90 g/L (9 g/dL) (obtained within 14 days prior to initiation of study
treatment)
- Patients may be transfused to meet this criterion
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of
normal (ULN) for age (obtained within 14 days prior to initiation of study treatment)
- Alkaline phosphatase (ALP) =< 3 x upper limit of normal (ULN) for age, with the
following exceptions: patients with documented bone metastases: ALP =< 5 x ULN
(obtained within 14 days prior to initiation of study treatment)
- Serum bilirubin =< 1.5 x ULN with the following exception: patients with known Gilbert
disease: serum bilirubin =< 3 x ULN (obtained within 14 days prior to initiation of
study treatment)
- Creatinine clearance >= 50 mL/min (adults > 18 years of age, calculated using the
Cockcroft-Gault formula) or >= 50 mL/min/1.73m^2 (pediatrics patients age 12 - 17,
calculated using the Bedside Schwartz equation) (obtained within 14 days prior to
initiation of study treatment)
- Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h)
urine protein =< 1 g (obtained within 14 days prior to initiation of study treatment)
- Serum albumin >= 20 g/L (2.0 g/dL) (obtained within 14 days prior to initiation of
study treatment)
- For patients not receiving therapeutic anticoagulation: international normalized ratio
(INR) or activated partial thromboplastin (aPTT) =< 1.5 x ULN (obtained within 14 days
prior to initiation of study treatment)
- Negative human immunodeficiency virus (HIV) test at screening
- Negative hepatitis B surface antigen (HBsAg) test at screening
- Women of childbearing potential must not be pregnant at screening. A woman is
considered to be of childbearing potential if she is postmenarchal, unless one of the
following criteria are met: documented permanent sterilization (hysterectomy,
bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal
status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence
of other biological or physiological causes. In addition, females < 55 years-of-age
must have a serum follicle stimulating [FSH] level > 40 mIU/mL to confirm menopause).
Note: documentation may include review of medical records, medical examinations, or
medical history interview by study site
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods as defined below:
- Women must remain abstinent or use contraceptive methods with a failure rate of <
1% per year during the treatment period and for 5 months after the final dose of
study treatment with either atezolizumab or cabozantinib
- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper
intrauterine devices
- Hormonal contraceptive methods must be supplemented by a barrier method
(including male condom, female condom, or diaphragm with spermicidal gel)
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of contraception
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
a condom, and agreement to refrain from donating sperm, as defined below:
- With a female partner of childbearing potential or pregnant female partner, men
must remain abstinent or use a condom during the treatment period and for 5
months after the final dose of cabozantinib to avoid exposing the embryo. Men
must refrain from donating sperm during this same period
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of preventing drug
exposure
Exclusion Criteria:
- Inability to swallow tablets
- Prior treatment with cabozantinib
- Prior treatment with immune checkpoint blockade therapies, including anti-CTLA-4,
anti-PD-1, and anti-PD-L1 therapeutic antibodies if given in combination with a
VEGF-targeted tyrosine kinase inhibitor (TKI). Patients receiving prior anti-PD-1,
anti-PD-L1, with or without anti-CTLA-4 antibodies will not be excluded
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment
- Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment
- Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before first dose of study treatment. Patients with
clinically relevant ongoing complications from prior radiation therapy are not
eligible
- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
first dose of study treatment after major surgery (e.g., removal or biopsy of brain
metastasis). Patients must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible patients must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment
- History of leptomeningeal disease
- Uncontrolled tumor-related pain
- Patients requiring pain medication must be on a stable regimen at study entry
- Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment. Patients should be recovered from the effects of radiation
- Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not
currently associated with spinal cord compression) should be considered for
loco-regional therapy if appropriate prior to enrollment
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently)
- Patients with indwelling catheters (e.g., PleurX) are allowed
- Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
- Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH)
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in patients without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
mg/dL or corrected serum calcium > upper limit of normal [ULN])
- Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barré syndrome,
or multiple sclerosis, with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
- Rash must cover 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
within the previous 12 months
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan
- History of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Active tuberculosis
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3
months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic (patients > 13 years of age) or stage 2 hypertension
(HTN) as defined by the American Academy of Pediatrics (AAP) as systolic and diastolic
BP >= 95th percentile+12 mmHg, or >= 140/90 mmHg (whichever is lower, patients < 13
years of age) despite optimal antihypertensive treatment
- Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or
other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary
embolism) within 6 months before first dose of study treatment
- Patients with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or
deep vein thrombosis (DVT) within 6 months are allowed if stable, asymptomatic,
and treated with a stable dose of permitted anticoagulation (see exclusion
criterion) for at least 1 week before first dose of study treatment
- Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation
- The patient has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., 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 of study treatment
- Note: Complete healing of an intra-abdominal abscess must be confirmed before
first dose of study treatment
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Uncompensated/symptomatic hypothyroidism
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
- Lesions invading or encasing any major blood vessels
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
study. Minor surgeries within 10 days before first dose of study treatment. Patients
must have complete wound healing from major surgery or minor surgery before first dose
of study treatment. Patients with clinically relevant ongoing complications from prior
surgery are not eligible
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment
- Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two
additional ECGs at intervals of approximately 3 min must be performed within 30
min after the initial ECG, and the average of these three consecutive results for
QTcF will be used to determine eligibility
- History of malign
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