Cabozantinib for Adults With Advanced Soft Tissue Sarcoma
Condition: Refractory Soft Tissue Sarcomas
MeSH terms: Sarcoma
Intervention: Cabozantinib
Intervention description: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: Dual Inhibitor of MET and VEGFR; XL184; Metastatic Refractory; Soft Tissue Sarcoma; Rare Heterogeneous Tumor

Summary:

      Background:

      - Cabozantinib is a cancer treatment drug that blocks the growth of new blood vessels in
      tumors. It can also block a chemical on tumor cells that allows the cells to grow. A similar
      drug, pazopanib, is used to treat types of cancer known as sarcomas. Researchers want to see
      if cabozantinib can be an effective treatment for types of soft tissue sarcoma that have not
      responded to earlier treatments.

      Objectives:

      - To test the effectiveness of cabozantinib for soft tissue sarcomas that have not responded
      to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have soft tissue sarcomas that have not responded
      to standard treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood samples
           will be collected. Imaging studies and other tests will be used to study the tumor
           before the start of treatment.

        -  Participants will take cabozantinib tablets daily for 28-day cycles of treatment. The
           tablets should be taken whole on an empty stomach.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Participants will continue to take cabozantinib for as long as the tumor does not become
           worse and the side effects are not too severe.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed soft tissue sarcoma that
             is metastatic or unresectable and for which standard treatment that prolongs survival
             does not exist or is no longer effective.

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional
             techniques or as >10 mm with spiral computed tomography (CT) scan, magnetic resonance
             imaging (MRI), or calipers by clinical exam.

          -  Patients are allowed prior vascular endothelial growth factor receptor
             (VEGFR)-tyrosine kinase inhibitors (TKI) therapy.

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of cabozantinib in patients <18 years of age, children
             are excluded from this study.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
             (Karnofsky >70%).

          -  Life expectancy > 3 months.

          -  Patients must have normal organ and marrow function as defined below:

               -  leukocytes greater than or equal to 3,000/mcL

               -  absolute neutrophil count greater than or equal to 1,500/mcL

               -  platelets greater than or equal to 100,000/mcL

               -  total bilirubin less than or equal to 1.5 times ULN

               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic
                  transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic
                  transaminase(SGPT) less than or equal to 2.5 times institutional upper limit of
                  normal creatinine within normal institutional limits

               -  creatinine within normal institutional limits OR clearance greater than or equal
                  to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional
                  normal.

               -  hemoglobin greater than or equal to 9 g/dL

               -  serum albumin greater than or equal to 2.8g/dL

               -  lipase <2.0 times upper limit of normal (ULN) and no radiologic or clinical
                  evidence of pancreatitis

               -  urine protein/creatinine ratio (UPCR) less than or equal to 1

               -  serum phosphorus calcium, magnesium and potassium greater than or equal to lower
                  limit of normal (LLN)

          -  Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg
             (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted
             prior to study entry provided that the average of three BP readings at the time of
             enrollment is less than or equal to 140/90 mmHg

          -  Patients must be able to swallow whole tablets. Tablets must not be crushed or chewed.

          -  The effects of cabozantinib on the developing human fetus are unknown. For this reason
             and because receptor tyrosine kinases are known to be teratogenic, women of
             child-bearing potential and men must agree to use adequate contraception. 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).

        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.

        -Ability to understand and the willingness to sign a written informed consent document.

        EXCLUSION CRITERIA:

          -  Patients who have had anticancer therapy, including kinase inhibitors or any
             investigational agent within 4 weeks or 5 half-lives (whichever is shorter) (6 weeks
             for nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered to baseline from adverse events (except alopecia and other non-clinically
             significant adverse events (AEs). Patients who have received prior cabozantinib or
             inhibitors of tyrosine-protein kinase mesenchymal epithelial transition factor (c-MET)
             or hepatocyte growth factor (HGF) are ineligible.

          -  The subject has received radionuclide treatment within 6 weeks of the first dose of
             study treatment

          -  The subject has received radiation therapy within 4 weeks (greater than or equal to 2
             weeks for palliative radiation therapy)

          -  Patients with active brain metastases or carcinomatous meningitis or epidural disease
             are excluded from this clinical trial. Subjects with brain metastases previously
             treated with whole brain radiation or radiosurgery or subjects with epidural disease
             previously treated with radiation who are asymptomatic and have remained stable for 4
             weeks and do not require steroid treatment for at least 2 weeks before starting study
             treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is
             permitted if completed at least 3 months before starting study treatment. Baseline
             brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain
             metastases is required to confirm eligibility.

          -  Eligibility of subjects receiving any medications or substances known to affect or
             with the potential to affect the activity of cabozantinib will be determined following
             review of their cases by the Principal Investigator. Patients who are taking
             enzyme-inducing anticonvulsant agents are not eligible.

          -  Patients with refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,
             inflammatory bowel disease), or significant bowel resection that could interfere with
             absorption.

          -  Uncontrolled intercurrent illness including, but not limited to symptomatic congestive
             heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements.

          -  Pregnant women are excluded from this study because cabozantinib has the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             cabozantinib, breastfeeding should be discontinued if the mother is treated with
             cabozantinib.

          -  Strong inhibitors and inducers of cytochrome P450 3A4 (CYP3A4) can affect levels of
             cabozantinib and should be avoided whenever possible or switched to alternatives.
             Subjects requiring chronic concomitant treatment of strong CYP3A4 inducers (e.g.,
             dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
             phenobarbital, and St. John's Wort) are not eligible for this study. Because the lists
             of these agents are constantly changing, it is important to regularly consult a
             frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; 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.

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             cabozantinib. Appropriate studies will be undertaken in patients receiving combination
             antiretroviral therapy when indicated.

          -  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 (less than or
             equal to 81 mg/day), low-dose warfarin (less than or equal to 1 mg/day), and
             prophylactic low molecular weight heparin (LMWH) are permitted. (Please note that
             there may be cases in which patients on study require anticoagulation for deep vein
             thrombosis (DVT)/pulmonary embolism (PE) management; this does not necessitate taking

        the patient off study.)

          -  The subject has experienced any of the following

               -  clinically-significant gastrointestinal bleeding within 6 months before the first
                  dose of study treatment

               -  hemoptysis of greater than or equal to 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:

               1. Cardiovascular disorders including:

                    1. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III
                       (moderate) or Class IV (severe) at the time of screening

                    2. Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg
                       systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment
                       within 7 days of the first dose of study treatment

                    3. Any history of congenital long QT syndrome

                    4. 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)

               2. Gastrointestinal disorders particularly those associated with a high risk of
                  perforation or fistula formation including:

                    1. Any of the following within 28 days before the first dose of study treatment

                         -  intra-abdominal tumor/metastases invading GI mucosa

                         -  active peptic ulcer disease,

                         -  inflammatory bowel disease (including ulcerative colitis and Crohn's
                            disease), diverticulitis, cholecystitis, symptomatic cholangitis or
                            appendicitis

                         -  malabsorption syndrome

                    2. 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 that 6 months
                            before the first dose of study treatment.

               3. 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

               4. Other clinically significant disorders such as:

                    1. serious non-healing wound/ulcer/bone fracture within 28 days before the
                       first dose of study treatment

                    2. history of organ transplant, including allogeneic bone marrow transplant

                    3. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
                       before the first dose of study treatment

                    4. history of major surgery as follows:

                  i. Major surgery within 3 months of the first dose of cabozantinib if there were
                  no wound healing complications or within 6 months of the first dose of
                  cabozantinib if there were wound complications

                  ii. Minor surgery within 1 months of the first dose of cabozantinib if there were
                  no wound healing complications or within 3 months of the first dose of
                  cabozantinib if there were wound complications

                  In addition, complete wound healing from prior surgery must be confirmed at least
                  28 days before the first dose of cabozantinib irrespective of the time from
                  surgery

          -  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 enrollment. Note: if initial QTcF is found to be > 500
             ms, two additional EKGs separated by at least 3 minutes should be performed. If the
             average of these three consecutive results for QTcF is less than or equal to 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.

          -  Patients should not have any clinical evidence of an active infection at the time of
             enrollment.

        INCLUSION OF WOMEN AND MINORITIES:

        Both men and women of all races and ethnic groups are eligible for this trial.