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Cabozantinib-s-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma

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ClinicalTrials.gov Identifier: NCT02243605
Recruitment Status : Recruiting
First Posted : September 18, 2014
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well cabozantinib-s-malate works in treating patients with osteosarcoma or Ewing sarcoma that has grown or returned (come back) after a period of improvement. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and may also prevent the growth of new blood vessels that tumors need to grow.

Condition or disease Intervention/treatment Phase
Metastatic Ewing Sarcoma Metastatic Osteosarcoma Recurrent Ewing Sarcoma Recurrent Osteosarcoma Stage III Osteosarcoma AJCC v7 Stage IV Osteosarcoma AJCC v7 Stage IVA Osteosarcoma AJCC v7 Stage IVB Osteosarcoma AJCC v7 Unresectable Ewing Sarcoma Unresectable Osteosarcoma Drug: Cabozantinib S-malate Other: Laboratory Biomarker Analysis Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the antitumor activity of cabozantinib-s-malate (cabozantinib) for Ewing sarcomas, in terms of 6-month objectives response as per the Response Evaluation Criteria in Solid Tumors, Revised (RECIST version [v]1.1).

II. To evaluate the antitumor activity of cabozantinib for osteosarcoma, in terms of 6-month objective response (complete response, partial response) and 6-month non-progression (complete response, partial response and stable disease), as per RECIST v1.1.

SECONDARY OBJECTIVES:

I. 6-month objective response. (Ewing sarcoma only) II. Best overall response (as per the revised RECIST v1.1). (Ewing sarcoma and osteosarcoma) III. 1- and 2-year progression-free survival. (Ewing sarcoma and osteosarcoma) IV. 1- and 2-year overall survival. (Ewing sarcoma and osteosarcoma) V. Cabozantinib safety. (Ewing sarcoma and osteosarcoma) VI. To assess the ability of metabolic tumor response as measured by fludeoxyglucose (FDG)-positron emission tomography (PET) at the end of one cycle of treatment to predict progression-free survival (PFS). (Ewing sarcoma and osteosarcoma) VII. Translational research: to determine and compare tumor expression of MET, phosphorylated (phosphor)-MET and circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble VEGF receptor 2 (VEGFR2) (sVEGFR2) prior to and following administration of cabozantinib. (Ewing sarcoma and osteosarcoma)

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of XL184 (Cabozantinib) in Treating Patients With Relapsed Osteosarcomas and Ewing Sarcomas
Actual Study Start Date : December 19, 2014
Estimated Primary Completion Date : June 30, 2019


Arm Intervention/treatment
Experimental: Treatment (cabozantinib-s-malate)
Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL184

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Non-progression, defined as complete response (CR), partial response (PR), or stable disease (osteosarcoma) [ Time Frame: At 6 months ]
  2. Objective response, defined as CR or PR (osteosarcoma) [ Time Frame: At 6 months ]
  3. Objective response, defined as CR or PR (Ewing sarcoma) [ Time Frame: At 6 months ]

Secondary Outcome Measures :
  1. Best overall response [ Time Frame: From the start of the treatment until disease progression/recurrence, assessed up to 2 years ]
    Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). Will be described using frequency, percentage, and 95% confidence interval (binomial law).

  2. PFS [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
    Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). PFS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.

  3. Overall survival (OS) [ Time Frame: Time from start of treatment to the time of death, assessed up to 2 years ]
    Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). OS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.

  4. Incidence of adverse events, assessed using the CTCAE version 4 [ Time Frame: Up to 2 years ]
    Quantitative variables will be described using mean and standard errors if the normality assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be used. Qualitative variables will be described using frequency, percentage, and 95% confidence interval.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Young patient age between 12 - 15 could be included in only 6 centers (Bordeaux, Lyon, Villejuif, Lille, Marseille and Paris)
  • Patients must have histologically confirmed diagnosis of osteosarcoma or Ewing sarcoma by central review, except if the diagnosis was already confirmed by the RRePS (Réseau de Référence en Pathologie des Sarcomes et des Tissus Mous et des Viscères) network
  • Relapsed disease after standard chemotherapy
  • Patients must have measurable disease (lesion in previously irradiated field could be considered as measurable if progressive at inclusion) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with spiral computed tomography (CT) scan
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count >= 1,500/mcL
  • Lymphocyte count > 1,000/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
  • Creatinine =< 1.5 x ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (Cockcroft formula)
  • Hemoglobin >= 9 g/dL
  • Serum albumin >= 2.8 g/dL
  • Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis
  • Urine protein/creatinine ratio (UPCR) =< 1
  • Serum phosphorus >= lower limit of normal (LLN)
  • Serum calcium >= LLN
  • Serum magnesium >= LLN
  • Serum potassium >= LLN
  • Female subjects of childbearing potential must not be pregnant at screening; females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy); however, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons
  • Women of child-bearing potential and men must agree to use adequate contraception (see below) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of cabozantinib administration

    • Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)
  • Metastatic or unresectable locally advanced
  • Documented disease progression (as per RECIST v1.1) before study entry; for patients with osteosarcoma, this progression will be confirmed by central review on the basis of two CT scan or magnetic resonance imaging (MRI) obtained at less than 6 months in the period of 12 months prior to inclusion
  • Ability to understand and the willingness to sign a written informed consent document
  • In accordance with French Regulatory Authorities: Patients with French Social Security in compliance with the French law relating to biomedical research (Huriet Law 88-1138 and related decrees)

Exclusion Criteria:

  • The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
  • Prior treatment with cabozantinib
  • Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the first dose of study treatment; systemic treatment with radionuclides within 6 weeks before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
  • Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before the first dose of study treatment; note: subjects with prostate cancer currently receiving luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be maintained on these agents
  • The subject has received any other type of investigational agent within 28 days before the first dose of study treatment
  • The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
  • The subject has a primary brain tumor
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
  • The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
  • The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
  • The subject requires chronic concomitant treatment of strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

    • it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • The subject has experienced any of the following:

    • Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
    • Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
    • Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  • The subject has radiographic evidence of cavitating pulmonary lesion(s)
  • The subject has tumor in contact with, invading or encasing any major blood vessels
  • The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
  • The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    • Cardiovascular disorders including:

      • Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening
      • Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
      • Any history of congenital long QT syndrome
      • Any of the following within 6 months before the first dose of study treatment:

        • Unstable angina pectoris
        • Clinically-significant cardiac arrhythmias
        • Stroke (including transient ischemic attack [TIA], or other ischemic event)
        • Myocardial infarction
        • Thromboembolic event requiring therapeutic anticoagulation (note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)
    • Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

      • Any of the following within 28 days before the first dose of study treatment

        • Intra-abdominal tumor/metastases invading GI mucosa
        • Any evidence of active peptic ulcer disease, patients must be completely recovered
        • Any evidence of inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, patients must be completely recovered from these conditions
        • Malabsorption syndrome
      • Any of the following within 6 months before the first dose of study treatment:

        • Abdominal fistula
        • Gastrointestinal perforation
        • Bowel obstruction or gastric outlet obstruction
        • Intra-abdominal abscess; note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment
    • Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
    • Other clinically significant disorders such as:

      • Active infection requiring systemic treatment within 28 days before the first dose of study treatment
      • Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
      • History of organ transplant
      • Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
      • History of major surgery as follows:

        • Major surgery within 12 weeks before the first dose of study treatment; complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment
        • Minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior surgery are not eligible
  • The subject is unable to swallow tablets
  • The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before treatment; note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
  • The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
  • The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cabozantinib
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Participation to a study involving a medical or therapeutic intervention in the last 30 days
  • Prior participation in this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02243605


Locations
France
Institut Bergonie Cancer Center Recruiting
Bordeaux, France, 33076
Contact: Antoine Italiano       b.lortal@bordeaux.unicancer.fr   
Principal Investigator: Antoine Italiano         
Centre Georges-Francois Leclerc Recruiting
Dijon, France, 21079
Contact: Nicolas Isambert    33-3-80-73-75-06    nisambert@cgfl.fr   
Principal Investigator: Nicolas Isambert         
Centre Oscar Lambert Recruiting
Lille, France, 59020
Contact: Nicolas P. Penel    33-3-20-29-59-20    n-penel@o-lambret.fr   
Principal Investigator: Nicolas P. Penel         
Centre Leon Berard Recruiting
Lyon, France, 69373
Contact: Jean-Yves Blay    33-4-78-78-28-28    jean-yves.blay@lyon.unicancer.fr   
Principal Investigator: Jean-Yves Blay         
Hopital De La Timone Recruiting
Marseille, France, 13385
Contact: Florence Duffaud    33-4-91-38-74-14    Florence.duffaud@ap-hm.fr   
Principal Investigator: Florence Duffaud         
Centre Antoine Lacassagne Recruiting
Nice, France, 06189
Contact: Antoine Thyss    33-4-92-03-14-97    antoine.thyss@nice.unicancer.fr   
Principal Investigator: Antoine Thyss         
Institut Curie Paris Recruiting
Paris, France, 75005
Contact: Sophie Piperno-Neumann    33-1-44-32-46-80    sophie.piperno-neumann@curie.net   
Principal Investigator: Sophie Piperno-Neumann         
Institut de Cancerologie de l'Ouest-Rene Gauducheau Recruiting
Saint Herblain, France, 44805
Contact: Emmanuelle Bompas    33-2-40-67-99-39    emmanuelle.bompas@ico.unicancer.fr   
Principal Investigator: Emmanuelle Bompas         
CHRU Strasbourg - Hospital Civil Recruiting
Strasbourg, France, 67091
Contact: Natacha Entz-Werle    33-3-88-12-80-97    Natacha.entz-werle@chru-strasbourg.fr   
Principal Investigator: Natacha Entz-Werle         
Center Claudius Regaud Recruiting
Toulouse, France, 31052
Contact: Christine Chevreau    33-5-61-42-42-42    chevreau.christine@iuct-oncopole.fr   
Principal Investigator: Christine Chevreau         
Gustave Roussy Recruiting
Villejuif, France, 94805
Contact: Olivier Mir    33-1-42-11-43-16    olivier.mir@gustaveroussy.fr   
Principal Investigator: Olivier Mir         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Antoine Italiano Institut Bergonie Cancer Center

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02243605     History of Changes
Other Study ID Numbers: NCI-2014-01927
NCI-2014-01927 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CABONE
9620 ( Other Identifier: Institut Bergonie Cancer Center )
9620 ( Other Identifier: CTEP )
First Posted: September 18, 2014    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: December 2018

Additional relevant MeSH terms:
Sarcoma
Osteosarcoma
Sarcoma, Ewing
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue