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Refractory Soft Tissue SarcomasPhase 2NCT01755195

Cabozantinib for Adults With Advanced Soft Tissue Sarcoma

A Phase 2 study testing Cabozantinib in people with Refractory Soft Tissue Sarcomas, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 120 years
Conditions the study is for
Refractory Soft Tissue Sarcomas
What is being tested?
Cabozantinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
55 participants
Where
1 siteUnited States
Study dates
15 Jan 2013to 11 Sep 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • Both men and women of all races and ethnic groups are eligible for this trial.

Who cannot join

  • 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.
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  • 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:
  • 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 BP > 140 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
  • active peptic ulcer disease,
  • inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
  • 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 that 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:
  • serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
  • history of organ transplant, including allogeneic bone marrow 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 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
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and VEGFR, in Patients With Metastatic Refractory Soft Tissue Sarcoma

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.
Read more

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.
Read the detailed description

Background:

  • Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that constitute about 1% of adult cancers.
  • The mainstay of treatment for advanced disease has been palliative chemotherapy with a median overall survival of approximately 12 months. This has not changed considerably in the past years and there is an unmet need for newer targeted therapies.
  • Vascular endothelial growth factor (VEGF) levels are elevated in patients with STS and various sarcoma cell lines express high levels of activated c-Met receptor.
  • We hypothesize that dual targeting of the VEGF and mesenchymal-epithelial transition factor (c-MET) pathways with cabozantinib would result in clinical benefit in patients with soft tissue sarcoma.

Objectives:

Primary:

  • Assess the response rate (Complete Response (CR)+Partial Response (PR) of cabozantinib in patients with soft tissue sarcomas.
  • Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue sarcomas.

Secondary:

-Determine and compare circulating levels of hepatocyte growth factor (HGF), soluble MET (sMET), VEGF-A, and soluble vascular endothelial growth factor receptor 2 (VEGFR2) (sVEGFR2) prior to and following administration of cabozantinib.

Eligibility:

  • Patients must have had disease progression following one line of standard therapy
  • Age greater than or equal to 18 years.
  • Adequate organ function.

Design:

  • All patients will receive cabozantinib at 60 mg by mouth (PO) daily in 4 week cycles.
  • Tumor response evaluations by imaging will be done every 2 cycles (less frequently for patients on study more than one year).
  • The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective tumor response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and 6-month PFS rate of 65% against an unacceptably low rate of 45% (corresponding to median PFS of 9.6 vs. 5.2 months).
  • The trial will accrue up to 55 patients.
Being tested
Cabozantinib
Keywords
Dual Inhibitor of MET and VEGFR, XL184, Metastatic Refractory, Soft Tissue Sarcoma, Rare Heterogeneous Tumor
Medical subject headings
Sarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CabozantinibDrug

    Also called Cometriq

    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).

Study groups in NCT01755195
Study groupRoleWhat they receive
CabozantinibExperimental60 mg tablets orally once a day in a 28-day cycle.
Receives: Drug: Cabozantinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective Response (Complete Response (CR)+Partial Response (PR) of Cabozantinib in Patients With Soft Tissue Sarcomas

    Objective response was assessed by the Response Evaluation Criteria in Solid Tumors RECIST) v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

    Measured: Date treatment consent signed to date off study, approximately 86 months and 3 days.

  2. Percentage of Participants With 6 Month Progression Free Survival (PFS)

    Progression in participants with soft tissue sarcomas treated with cabozantinib was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

    Measured: 6 months

Secondary outcomes (4)

  1. Mean Change From Baseline in Levels of Circulating Hepatocyte Growth Factor (HGF)

    Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of HGF. HGF protein content (in picograms; pg) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.

    Measured: Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

  2. Mean Change From Baseline in Levels of Circulating Soluble Mesenchymal Epithelial Transition Factor (sMET)

    Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of soluble MET (sMET). sMET protein content (in nanograms; ng) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.

    Measured: Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

  3. Mean Change From Baseline in Levels of Circulating Vascular Endothelial Growth Factor A (VEGF-A)

    Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of VEGF-A. VEGF-A protein content (in picograms; pg) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.

    Measured: Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

  4. Mean Change From Baseline in Levels of Circulating Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR-2)

    Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of soluble VEGFR2 (sVEGFR-2). sVEGFR-2 protein content (in nanograms; ng) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome..

    Measured: Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Dec 2012 (estimated)
  2. Study start15 Jan 2013
  3. Primary completion30 Sep 2020
  4. Study completion11 Sep 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
55 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01755195
Sponsor's protocol ID
130044
Other IDs
13-C-0044
Status last verified
Dec 2023
First submitted
18 Dec 2012
Last updated
3 Jan 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Coindre JM, Terrier P, Guillou L, Le Doussal V, Collin F, Ranchere D, Sastre X, Vilain MO, Bonichon F, N'Guyen Bui B. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001 May 15;91(10):1914-26. doi: 10.1002/1097-0142(20010515)91:103.0.co;2-3.

    PubMed 11346874

  • Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, Parkinson DR. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993 Jul;11(7):1269-75. doi: 10.1200/JCO.1993.11.7.1269.

    PubMed 8315424

  • Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989 Sep;7(9):1208-16. doi: 10.1200/JCO.1989.7.9.1208.

    PubMed 2504890

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cabozantinib in people with Refractory Soft Tissue Sarcomas, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 55 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Sep 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response (Complete Response (CR)+Partial Response (PR) of Cabozantinib in Patients With Soft Tissue Sarcomas (time frame: Date treatment consent signed to date off study, approximately 86 months and 3 days.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01755195, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jan 2024.

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