Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors

Hepatocellular Carcinoma Clinical Trial

Official title:

Phase 2 Trial of XL184 (Cabozantinib) an Oral Small-Molecule Inhibitor of Multiple Kinases, in Children and Young Adults With Refractory Sarcomas, Wilms Tumor, and Other Rare Tumors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02867592
• Other study ID #: NCI-2016-01258
• Secondary ID: NCI-2016-01258AD
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 18, 2017
• Est. completion date: September 21, 2024

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well cabozantinib-s-malate works in treating younger patients with sarcomas, Wilms tumor, or other rare tumors that have come back, do not respond to therapy, or are newly diagnosed. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for tumor growth and tumor blood vessel growth.

Description:

PRIMARY OBJECTIVES:

I. To determine the objective response rate (complete response + partial response) of cabozantinib-s-malate (XL184) in children and young adults with Ewing sarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, and Wilms tumor.

II. To estimate whether XL184 therapy either improves the disease control rate at 4 months in patients with recurrent measurable osteosarcoma as compared to a historical Childrens Oncology Group (COG) experience or produces an objective response rate.

SECONDARY OBJECTIVES:

I. To further define XL184 related toxicities in pediatric, adolescent and young adult patients.

II. To further define XL184 pharmacokinetics in the pediatric and adolescent patients.

III. To estimate 1-year time to progression, progression free survival (PFS) and overall survival for each stratum, and if feasible to compare to historical controls.

EXPLORATORY OBJECTIVES:

I. To assess the effect of XL184 on patients' immune cell subsets. II. To obtain tumor tissue (snap frozen, formalin-fixed and paraffin-embedded [FFPE] blocks, or unstained slides) from diagnosis, recurrence, or both, for possible future studies.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) on a continuous dosing schedule using a dosing nomogram on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 6 months for 1 year and then annually for up to 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 109
• Est. completion date: September 21, 2024
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 30 Years

Eligibility

Inclusion Criteria:

• Upper age limit of =< 18 years of age for medullary thyroid carcinoma (MTC), renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) =< 30 years for all other diagnoses

• Patients must have a body surface area >= 0.35 m^2

• Patients must have recurrent or refractory disease, or newly diagnosed disease with no known curative therapy or therapy proven to prolong survival with an acceptable quality of life; patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse:

• Ewing sarcoma

• Rhabdomyosarcoma (RMS)

• Non-rhabdomyosarcoma soft tissue sarcomas (STS) including microphthalmia transcription factor associated STS (alveolar soft part sarcoma [ASPS] and clear cell sarcoma [CCS])

• Osteosarcoma

• Wilms tumor

• Rare tumors

• Medullary thyroid carcinoma (MTC)

• Renal cell carcinoma (RCC)

• Hepatocellular carcinoma (HCC)

• Hepatoblastoma

• Adrenal coertex carcinoma

• Pediatric solid tumors (including central nervous system [CNS] tumors) with known molecular alterations in the targets of XL184 (i.e., MET amplification, overexpression, activating mutation, MET translocation, MET exon skipping mutations, activating RET mutations, RET rearrangement, overexpression or activation of AXL); documentation of the alteration from a Clinical Laboratory Improvement Act (CLIA) certified laboratory will be required

• Note: Documentation of any known tumor molecular alterations and RET mutation status for patients with MTC (germline) must be uploaded via the RAVE system

• Patients must have radiographically measurable disease; measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm)

• Note: The following do NOT qualify as measurable disease:

• Malignant fluid collections (e.g., ascites, pleural effusions)

• Bone marrow infiltration

• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans)

• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)

• Previously radiated lesions that have not demonstrated clear progression post radiation

• Leptomeningeal lesions that do not meet the measurement parameters noted above

• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (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 must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)

• At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim

• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent

• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1

• >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of M-Iodobenzylguanidine (MIBG); >= 3 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total-body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given

• Subjects should not have any clinically relevant ongoing complications from prior radiation therapy (i.e., radiation esophagitis or other inflammation of the viscera)

• No evidence of active graft versus (vs.) host disease and >= 2 months must have elapsed since transplant

• Not previously received XL184 or another MET/HGF inhibitor (tivantinib or crizotinib); there are no limits on number of prior therapeutic regimens; patients who have been treated with prior VEGF pathway, or RET inhibitors (except XL184) may be eligible

• Peripheral absolute neutrophil count (ANC) >= 1000/uL for patients with solid tumors without bone marrow involvement

• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment) for patients with solid tumors without bone marrow involvement

• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) for patients with solid tumors without bone marrow involvement

• Peripheral absolute neutrophil count (ANC) >= 750/uL for patients with solid tumors and known bone marrow metastatic disease

• Platelet count >= 50,000/uL for patients with solid tumors and known bone marrow metastatic disease

• Hemoglobin >= 8.0 g/dL for patients with solid tumors and known bone marrow metastatic disease

• Transfusions are permitted to meet both the platelet and hemoglobin criteria for patients with known bone marrow metastatic disease; patients must not be known to be refractory to red blood cell or platelet transfusions

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

• 2 to < 6 years of age

• Male and female: 0.8 (maximum serum creatinine [mg/dL])

• 6 to < 10 years of age

• Male and female: 1 (maximum serum creatinine [mg/dL])

• 10 to < 13 years of age

• Male and female: 1.2 (maximum serum creatinine [mg/dL])

• 13 to < 16 years of age

• Male 1.5 (maximum serum creatinine [mg/dL])

• Female: 1.4 (maximum serum creatinine [mg/dL])

• >= 16 years of age

• Male: 1.7 (maximum serum creatinine [mg/dL])

• Female: 1.4 (maximum serum creatinine [mg/dL])

• Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour (h) urine sample

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3 x ULN) (for the purpose of this study, the ULN for SGPT is 45 U/L)

• Serum albumin >= 2.8 g/dL

• No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)

• No clinically significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment

• QTc =< 480 msec; Note: Patients with grade 1 prolonged QTc (450- 480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e., electrolytes, medications)

• Patients with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures may be enrolled

• CNS toxicity =< grade 2 with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible

• A blood pressure (BP) =< the 95th percentile for age, height, and gender for pediatric patients < 18 years old and =< 140/90 mmHg for patients >= 18 years old; patients should not be receiving medication for treatment of hypertension (except patients with Wilms tumor and RCC who may be eligible if on stable doses of no more than one anti-hypertensive medication with a baseline BP =< ULN for pediatric patients and =< 140/90 for adult patients); please note that 3 serial blood pressures should be obtained and averaged to determine baseline BP

• International normalized ratio (INR) =< 1.5

• Serum amylase =< 1.5 x ULN

• Serum lipase =< 1.5 x ULN

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control- a medically accepted barrier method of contraceptive method (e.g., male or female condom) and a second effective method of birth control-during protocol therapy and for at least 4 months after the last dose of XL184; abstinence is an acceptable method of birth control

• Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment (14 days if pegfilgrastim)

• 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

• Previous treatment with XL184 (cabozantinib) or another MET/HGF inhibitor (tivantinib, crizotinib)

• Patients who are currently receiving another investigational drug are not eligible

• Patients who are currently receiving other anti-cancer agents are not eligible

• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial

• Patients must not be receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's wort

• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin, and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel) are prohibited

• Note: 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 is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen

• Patients must not have received enzyme-inducing anticonvulsants within 14 days prior to enrollment

• Patients who are receiving drugs that prolong QTc are not eligible

• Patients who are unable to swallow intact tablets are not eligible

• Patients who have an uncontrolled infection 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 with active bleeding are not eligible; specifically, no clinically significant gastrointestinal (GI) bleeding, GI perforation, 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 evidence of an acute intracranial or intratumoral hemorrhage on CT or MRI are not eligible (patients with evidence of resolving hemorrhage will be eligible); in patients with CNS tumors, an MRI with ECHO gradient sequences would be required to exclude presence of petechial hemorrhages

• Patients who have had or are planning to have the following invasive procedures are not eligible:

• Major surgical procedure, laparoscopic procedure, or open biopsy within 28 days prior to enrollment

• Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 3 days prior to enrollment for external lines (e.g., Hickman or Broviac catheter, peripherally inserted central catheter [PICC]) and at least 7 days prior to enrollment for a subcutaneous port

• Core biopsy within 7 days prior to enrollment

• Fine needle aspirate within 7 days prior to enrollment

• Surgical or other wounds must be adequately healed prior to enrollment

• NOTE: For purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy

• Patients who have had significant traumatic injury within 28 days prior to enrollment are not eligible

• Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of the study drug are not eligible

Related Conditions & MeSH terms

• Adrenal Cortical Carcinoma
• Adrenocortical Carcinoma
• Alveolar Soft Part Sarcoma
• Carcinoma
• Carcinoma, Hepatocellular
• Carcinoma, Neuroendocrine
• Carcinoma, Renal Cell
• Central Nervous System Neoplasm
• Central Nervous System Neoplasms
• Clear Cell Sarcoma of Soft Tissue
• Ewing Sarcoma
• Hepatoblastoma
• Hepatocellular Carcinoma
• Neoplasms
• Nervous System Neoplasms
• Osteosarcoma
• Recurrence
• Recurrent Alveolar Soft Part Sarcoma
• Recurrent Ewing Sarcoma
• Recurrent Hepatoblastoma
• Recurrent Hepatocellular Carcinoma
• Recurrent Kidney Wilms Tumor
• Recurrent Malignant Solid Neoplasm
• Recurrent Osteosarcoma
• Recurrent Primary Malignant Central Nervous System Neoplasm
• Recurrent Renal Cell Carcinoma
• Recurrent Rhabdomyosarcoma
• Recurrent Soft Tissue Sarcoma
• Recurrent Thyroid Gland Medullary Carcinoma
• Refractory Ewing Sarcoma
• Refractory Hepatoblastoma
• Refractory Hepatocellular Carcinoma
• Refractory Malignant Solid Neoplasm
• Refractory Osteosarcoma
• Refractory Primary Central Nervous System Neoplasm
• Refractory Primary Malignant Central Nervous System Neoplasm
• Refractory Renal Cell Carcinoma
• Refractory Rhabdomyosarcoma
• Refractory Soft Tissue Sarcoma
• Renal Cell Carcinoma
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Alveolar Soft Part
• Sarcoma, Clear Cell
• Sarcoma, Ewing
• Soft Tissue Sarcoma
• Solid Neoplasm
• Thyroid Diseases
• Thyroid Gland Medullary Carcinoma
• Thyroid Neoplasms
• Wilms Tumor

Intervention

Drug:
• Cabozantinib
Given PO
• Cabozantinib S-malate
Given PO Note: Capsule formulation (Cometriq) not used in this trial.

Other:
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	El Paso Children's Hospital	El Paso	Texas
United States	Texas Tech University Health Sciences Center-El Paso	El Paso	Texas
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Comprehensive Cancer Centers of Nevada-Horizon Ridge	Henderson	Nevada
United States	Kaiser Permanente Moanalua Medical Center	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Langone Hospital - Long Island	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Hope Cancer Care of Nevada-Pahrump	Pahrump	Nevada
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Huron Medical Center PC	Port Huron	Michigan
United States	Oregon Health and Science University	Portland	Oregon
United States	Radiation Oncology Associates	Reno	Nevada
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Barnes-Jewish Hospital	Saint Louis	Missouri
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Kaiser Permanente-San Diego Mission	San Diego	California
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaiser Permanente-Capitol Hill Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Immune Biomarkers	The association between the host immune system and response to cabozantinib-s-malate will be assessed in an exploratory manner. each biomarker will be correlated with the clinical outcomes of objective response and progression free survival.	Baseline, day 1 (prior to dose) of cycles 2 and 3
Primary	Objective Response (Non-Osteosarcoma Strata)	Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Response rates will be calculated as the percent of evaluable patients who are responders (Overall Best Response of Partial Response or Complete Response), and confidence intervals will be constructed accounting for the two-stage design.	Up to the first 6 cycles of therapy
Primary	Objective Response (Osteosarcoma Stratum)	Will be assessed by the Response Evaluation Criteria in Solid Tumors version 1.1 and Disease Control (see section 9.3.2 of the ADVL1622 Protocol). Response + Disease Control rate will be calculated as the percent of evaluable patients who are responders or who met the definition of disease control, and confidence intervals will be constructed accounting for the two-stage design.	Up to the first 6 cycles of therapy.
Secondary	Percentage of Participants With Adverse Events	Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will report the percentage of patients within each disease stratum who experienced a grade 3 or higher toxicity with attribution of possible, probable, or definite while on protocol therapy or within 30 days of the last dose of therapy	Up to 5 years (duration of protocol therapy plus 30 days after last dose of therapy)
Secondary	Pharmacokinetics (PK) Parameters of Cabozantinib S-malate: Cmax	Day 1 PK peak concentration will be summarized by the mean and the standard deviation.	Prior to dose, 2, 4, 8 and 20-28 hours after dose on day 1
Secondary	Pharmacokinetics (PK) Parameters of Cabozantinib S-malate: Tmax	Day 1 PK time to peak concentration will be summarized by the mean and the standard deviation.	Prior to dose, 2, 4, 8 and 20-28 hours after dose on day 1
Secondary	Pharmacokinetics (PK) Parameters of Cabozantinib S-malate: AUC	Day 1 PK area under the curve will be summarized by the mean and the standard deviation.	Prior to dose, 2, 4, 8 and 20-28 hours after dose on day 1
Secondary	Pharmacokinetics (PK) Parameters of Cabozantinib S-malate: Accumulation	PK accumulation will be summarized by the mean and the standard deviation.	Cycle 1, Day 1 (20-28 hours after dose) and Cycle 1, Day 22
Secondary	Pharmacokinetics (PK) Parameters of Cabozantinib S-malate: Half-life	PK half-life will be summarized by the mean and the standard deviation.	Cycle 1, Day 1 (20-28 hours after dose) and Cycle 1, Day 22
Secondary	Time to Progression (TTP)	Percent of patients not yet progressed at 1 year as estimated by the Kaplan-Meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as a >=20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Clinical progression was also counted as an event for this analysis.	Up to 1 year
Secondary	Progression Free Survival (PFS)	The 1-year Progression Free Survival will be estimated using Kaplan-Meier methodology. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as a >=20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions	Up to 1 year
Secondary	Overall Survival (OS)	The 1-year Overall Survival will be estimated using Kaplan-Meier methodology.	Up to 1 year