Cabozantinib-S-Malate in Treating Patients with Refractory Soft Tissue Sarcoma That Is Metastatic or Cannot Be Removed by Surgery

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 and over13-C-0044
NCI-2012-03124, 09-25-0099, 121088, 130044, P121088, P9284_A07PAMDREVW01, 9284, NCT01755195

Trial Description

Summary

This phase II trial studies how well cabozantinib-s-malate works in treating patients with soft tissue sarcoma that does not respond to treatment and has spread to other places in the body or cannot be removed by surgery. Cabozantinib-s-malate may stop the growth of tumor cells by blocking certain proteins needed for cell growth and by preventing the growth of new blood vessels that tumors need to grow.

Further Study Information

PRIMARY OBJECTIVES:

I. Assess the response rate (complete response [CR] + partial response [PR]) of cabozantinib (cabozantinib-s-malate) in patients with soft tissue sarcomas.

II. Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue sarcomas.

SECONDARY OBJECTIVES:

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

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 for 30 days.

Eligibility Criteria

Inclusion Criteria:

Patients are allowed prior VEGFR-tyrosine kinase inhibitor (TKI); patients will be stratified based on prior VEGFR-TKI therapy

Prothrombin time (PT) < 1.3 x the laboratory ULN

Partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN

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 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

Life expectancy > 3 months

Leukocytes >= 3,000/mcL

Absolute neutrophil count >= 1,500/mcL

Platelets >= 100,000/mcL

Total bilirubin =< 1.5 times upper limit of normal (ULN)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

Hemoglobin >= 9 g/dL

Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky > 70%)

Urine protein/creatinine ratio (UPCR) =< 1

Serum phosphorus calcium, magnesium and potassium >= lower limit of normal (LLN)

International normalized ratio (INR) < 1.3 x the laboratory ULN

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 =< 140/90 mmHg

Patients must be able to swallow whole tablets; tablets must not be crushed or chewed

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

Serum albumin >= 2.8 g/dL

Exclusion Criteria:

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

Strong inhibitors and inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) 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

Patients who have had anticancer therapy, including kinase inhibitors, within 4 weeks (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]) due to agents administered more than 4 weeks earlier; patients who have received prior cabozantinib or inhibitors of c-MET or HGF are ineligible

Patients who are receiving any other investigational agents within 28 days before the first dose of the study treatment

The subject has radiographic evidence of cavitating pulmonary lesion(s)

The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment

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

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; breastfeeding should be discontinued if the mother is treated with cabozantinib

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

The subject has PT/INR or PTT test >= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment

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 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 to swallow tablets

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; patients with a history of infection within 28 days prior to enrollment should have completed their course of systemic therapy

The subject has evidence of tumor invading the 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 received radiation therapy:

To the thoracic cavity, abdomen, or pelvis within 1 month before the first dose of study treatment, or has ongoing complications, or is without complete recovery and healing from prior radiation therapy

To bone or brain metastasis within 14 days before the first dose of study treatment

To any other site(s) within 28 days before the first dose of study treatment

The subject has tumor invading, or encasing any major blood vessels

The subject has experienced any of the following

Clinically-significant gastrointestinal bleeding within 3 months before the first dose of study treatment; the participant must be maintained on a prophylactic regimen for management of an upper gastrointestinal (GI) bleeding event with no evidence of recurrence and/or endoscopic confirmation of resolution of the source of a lower GI bleed

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

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

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 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:

  • 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 month 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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
A P Chen, Principal Investigator

Trial Sites

U.S.A.

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

A P Chen
Ph: 301-496-4291
Email: chenali@mail.nih.gov

A P Chen
Principal Investigator

National Cancer Institute Developmental Therapeutics Clinic

A P Chen
Ph: 301-496-4291
Email: chenali@mail.nih.gov

A P Chen
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01755195

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.