Atezolizumab and Cabozantinib for the Treatment of Adolescents and Young Adults With Recurrent or Metastatic Osteosarcoma, TACOS Study
NCT05019703 · Phase 2 · Boston, Massachusetts, United States
- Condition
- Sarcoma
- Disease stage
- Stage I-IV
- Phase
- Phase 2
- Study type
- BIOLOGICAL, DRUG
- Intervention
- Cabozantinib
- Age
- 12 Years to
- Gender
- All
- Sponsor
- M.D. Anderson Cancer Center
- Research institution
- M.D. Anderson Cancer Center
- Facility
- Dana-Farber Cancer Institute
- Research center
- Dana-Farber Cancer Institute
Summary
This phase II trial studies the effect of atezolizumab and cabozantinib in treating adolescents and young adults with osteosarcoma that has come back (recurrent) or has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab and cabozantinib may help to control the osteosarcoma.
Detailed description
PRIMARY OBJECTIVE: I. To assess the efficacy of cabozantinib in combination with atezolizumab in recurrent/metastatic osteosarcoma as determined by the progression-free survival (PFS) defined as the time from treatment onset to either disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) or death from any cause, whichever occurs first. SECONDARY OBJECTIVES: I. To estimate the objective response rate (ORR) by RECIST 1.1 criteria, immune-based (i)RECIST, and immune-modified (im)RECIST. II. To estimate the progression-free survival (PFS) rates at 4 months and 6 months. III. To estimate the overall survival (OS) in patients with recurrent/metastatic osteosarcoma receiving cabozantinib + atezolizumab. IV. To evaluate the safety and tolerability of the combination as assessed by toxicity rates according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. EXPLORATORY OBJECTIVES: I. To determine the expression of selected biomarkers including PD-1/PD-L1, MET, and VEGFR in pre-treatment and on-treatment tumor biopsy specimens. II. To assess the immunologic response by change in immune infiltrate in tumors from baseline and on-treatment biopsy specimens and correlate findings with clinical benefit/response to therapy. III. To characterize and quantify immunologic changes in peripheral blood and correlate with clinical benefit/treatment response. OUTLINE: Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1 and cabozantinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 30 days, then every 3 months for 2 years.
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
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 a
Primary outcomes
Progression-free survival (PFS)
Secondary outcomes
Objective response rate; PFS; Overall survival (OS)