Sunitinib in Sarcomas of the Central Nervous System

Phase II Clinical Trial of Sunitinib in Sarcomas of the Central Nervous System

Background:

A sarcoma is a rare cancer. It grows in the body's connective tissue. Sarcomas in the brain and central nervous system are especially rare. The drug Sunitinib has been approved in many countries for treating other types of rare or advanced cancers. These include kidney, pancreas, and bowel cancer. Researchers want to see if it can help people with sarcomas of the central nervous system.

Objective:

To study the effects of Sunitinib on gliosarcomas or sarcomas of the central nervous system.

Eligibility:

Adults ages 18 and older with a gliosarcoma or sarcoma of the central nervous system

Design:

Participants will be screened with the following tests. Some may be done as part of their regular cancer care:

Medical history

Medication review

Physical exam

Blood, heart, and pregnancy tests

Cranial scans to locate and measure their tumor

Participants will take Sunitinib by mouth every day for 2 weeks and then take none of the drug for 1 week. These 3 weeks equal 1 cycle.

Participants will have 2 study visits in cycle 1. They will have 1 visit in all other cycles. They will answer questions about quality of life and repeat some screening tests.

Participants will take their blood pressure at home weekly. They keep a diary of each dose of Sunitinib and blood pressure reading.

Participants can choose to share data about their physical activity levels and quality of sleep. These participants will wear a small, portable watch-sized accelerometer device on the wrist for 6 cycles.

About 1 month after their last study drug dose, participants will have a final study visit. They will have a physical exam, blood tests, and scans.

Study Overview

• Status: Terminated
• Conditions: Gliosarcoma; Central Nervous System Sarcoma
• Intervention / Treatment: Drug: Sunitinib; Device: wGT3x-BT

Detailed Description

Background:

• Gliosarcoma and primary central nervous system (CNS) sarcomas are malignant brain tumors uniformly associated with poor outcome.
• There are no known effective medical therapies for these cancers.
• Sunitinib is an orally administered small molecule that inhibits signaling of multiple receptor tyrosine kinases including those known to be activated in CNS sarcomas.

Objectives:

To determine the anti-tumor effect of sunitinib in recurrent gliosarcomas and primary CNS sarcomas as assessed by objective response rate (ORR).

Eligibility:

• Patients with histologically proven gliosarcoma and primary CNS sarcoma at disease relapse after failing standard therapy (surgery and irradiation).
• Tumor tissue blocks or 15 unstained slides should be available
• Subjects must be greater than or equal to 18 years old.
• Karnofsky performance status of greater than or equal to 60
• Patients must have adequate organ function.
• Patients must not have received tyrosine kinase inhibitor(s) in the past.

Design:

• This is a prospective, single institution, single arm, multi-cohort phase II study of sunitinib in subjects with recurrent gliosarcoma and primary CNS sarcoma that have failed prior surgery and irradiation (unless radiation therapy was contraindicated).
• Subjects will be classified into three cohorts: 1) Primary gliosarcoma; 2) Secondary gliosarcoma; 3) Primary CNS sarcoma. Cohort expansion will be carried out at indication of promising response.
• Sunitinib will be administered orally using a continuous schedule at 50 mg per day (with dose adjustments allowed for toxicity) for 2 weeks with 1 week off to constitute a 3-week cycle until disease progression or development of intolerable side-effects.
• Toxicity will be assessed every cycle by Common Terminology Criteria in Solid Tumors (CTCAE) version 5.0.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:
• Patients must have histologically confirmed gliosarcoma (primary or secondary) or primary central nervous system sarcoma confirmed by the Laboratory of Pathology, National Cancer Institute (NCI).
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured bi-dimensionally by MRI (or computed tomography (CT) scan if magnetic resonance imaging (MRI) is contraindicated).
• Patients must have failed standard therapy consisting of surgery, irradiation, and chemotherapy if indicated.
• Age greater than or equal to 18 years.
• Karnofsky greater than or equal to 60%.

• 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 within normal institutional limits
  • 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 OR creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with

creatinine levels above institutional normal.

• Patients must have the ability to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study.
• The effects of sunitinib on the developing human fetus are unknown. For this reason and because anti-angiogenic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Tumor tissue blocks or at least 10-15 unstained slides from the diagnosis should be available.
• At the time of registration, all subjects must be removed greater than or equal to 28 days from any investigational agents.

EXCLUSION CRITERIA:

• Patients who are receiving any other investigational agents.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Prior use of tyrosine kinase inhibitors or vascular endothelial growth factor (VEGF) inhibition.
• Patients who are receiving strong cytochromes P450 (CYP450) inducers or inhibitors are ineligible.
• Pregnant women are excluded from this study because sunitinib has 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 sunitinib, breastfeeding should be discontinued if the mother is treated with sunitinib.
• Patients with known human immunodeficiency virus (HIV) history on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with sunitinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• Uncontrolled hypertension (> 150/100 mm hemoglobin (Hg) while on antihypertensive medications.
• New York Heart Association class II or greater congestive heart failure.
• Serious cardiac arrhythmia requiring medication.
• Baseline echocardiogram with ejection fraction < 50% or greater than or equal to 20% decrease from a prior study.
• Corrected QT interval (QTc) > 500 msec on baseline electrocardiogram (EKG)
• Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin are excluded, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis. Note: Low molecular weight heparin is permitted provided the patient's international normalized ratio (INR) is less than or equal to 1.5.
• Previous exposure to anthracyclines.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participants With Primary Gliosarcoma; Sunitinib will be administered at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest. Participants will be given a small, portable pager-type and watch accelerometers to wear at the hip or non-dominant wrist. Worn daily for 6 cycles	Drug: Sunitinib; Sunitinib will be administered at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest until there is disease progression or development of intolerable side effects.; Other Names: Sutent; Device: wGT3x-BT; Participants will given a small, portable pager-type and watch accelerometers to wear at the hip or non-dominant wrist. Worn daily for 6 cycles; Other Names: Actigraph
Experimental: Participants With Secondary Gliosarcoma; Sunitinib will be administered at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest. Participants will be given a small, portable pager-type and watch accelerometers to wear at the hip or non-dominant wrist. Worn daily for 6 cycles	Drug: Sunitinib; Sunitinib will be administered at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest until there is disease progression or development of intolerable side effects.; Other Names: Sutent; Device: wGT3x-BT; Participants will given a small, portable pager-type and watch accelerometers to wear at the hip or non-dominant wrist. Worn daily for 6 cycles; Other Names: Actigraph
Experimental: Participants With Primary Central Nervous System (CNS) Sarcoma; Sunitinib will be administered at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest. Participants will be given a small, portable pager-type and watch accelerometers to wear at the hip or non-dominant wrist. Worn daily for 6 cycles	Drug: Sunitinib; Sunitinib will be administered at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest until there is disease progression or development of intolerable side effects.; Other Names: Sutent; Device: wGT3x-BT; Participants will given a small, portable pager-type and watch accelerometers to wear at the hip or non-dominant wrist. Worn daily for 6 cycles; Other Names: Actigraph

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Greater Than 50% Reduction in Objective Response	Objective Response is defined as all participants who had greater than 50% reduction in Complete Response and Partial Response assessed by the Assessment in Neuro-oncology Criteria (RANO criteria). Complete Response is no T1 gadolinium enhancing disease, no new lesions, or corticosteroids, and stable or decreasing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) or clinical status. Partial Response is ≥50% decrease in T1 gadolinium enhancing disease, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increasing clinical status.	From enrollment to off study, approximately 3 Months, 1 Week, 4 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With 6-month Progression Free Survival (PFS)	Progression is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. PFS was assessed by the Response Assessment in Neuro-oncology Criteria (RANO criteria). Progression is ≥25% increase in T1 gadolinium enhancing disease, increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR), presence of new lesions, and decrease in clinical status.	6 months
Number of Participants That Have Progressive Disease After 18 Months	Progressive disease was assessed by the Response Assessment in Neuro-oncology Criteria (RANO criteria). Progression is ≥25% increase in T1 gadolinium enhancing disease, increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR), presence of new lesions, and decrease in clinical status.	After 18 months
Number of Adverse Events Related to Drug	Adverse events was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Baseline to off study, approximately 3 months and 12 days
Evaluation of Tumor Tissue for Biomarkers	To evaluate archival tumor tissue for activation of signaling pathways targeted by sunitinib to establish potential biomarkers of response.	end of study, approximately 25 months and 12 days.
Number of Responders and Non-responders With Tumor Markers of Activation	Molecular profiling of archival tumor tissues was used to identify tumor markers of activation of response to sunitinib in responders and non-responders. A responder is a participant with a Complete Response (CR) or Partial Response (PR), and a non-responder is a participant with Stable Disease (SD) or Progressive Disease (PD) assessed by the Response Assessment in Neuro-oncology Criteria (RANO criteria). CR is no T1 gadolinium enhancing disease, no new lesions, or corticosteroids, and stable or decreasing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR). PR is ≥50% decrease in T1 gadolinium enhancing disease, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increasing clinical status. SD is <50% decrease in T1 gadolinium enhancing disease but < 25% increase, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increase in clinical status. PD is ≥25% increase in T1 gadolinium enhancing disease.	From baseline to end of treatment, approximately 25 months and 12 days.
Number of Responders and Non-responders With a Change in Perfusion Blood Volume Before and After Treatment With Sunitinib.	Perfusion was quantitated in responders and non-responders comparing pre and post treatment to determine if the treatment regimen altered vasculature and blood flow to the tumor. A responder is a participant with a Complete Response (CR) or Partial Response (PR), and a non-responder is a participant with Stable Disease (SD) or Progressive Disease (PD) assessed by the Response Assessment in Neuro-oncology Criteria (RANO criteria). CR is no T1 gadolinium enhancing disease, no new lesions, or corticosteroids, and stable or decreasing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR). PR is ≥50% decrease in T1 gadolinium enhancing disease, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increasing clinical status. SD is <50% decrease in T1 gadolinium enhancing disease but <25% increase, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increase in clinical status. PD is ≥25% increase in T1 gadolinium enhancing disease.	Pre-treatment and post treatment, approximately 25 months and 12 days.
Number of Responders and Non-responders With Dynamic Contrast Enhanced Magnetic Resonance Imaging (MRI) Performed Before and During Treatment With Sunitinib.	Dynamic contrast enhanced magnetic resonance imaging (MRI) was performed before and during treatment with sunitinib in responders and non-responders. A responder is a participant with a Complete Response (CR) or Partial Response (PR), and a non-responder is a participant with Stable Disease (SD) or Progressive Disease (PD) assessed by the Response Assessment in Neuro-oncology Criteria (RANO criteria). CR is no T1 gadolinium enhancing disease, no new lesions, or corticosteroids, and stable or decreasing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR). PR is ≥50% decrease in T1 gadolinium enhancing disease, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increasing clinical status. SD is <50% decrease in T1 gadolinium enhancing disease but < 25% increase, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increase in clinical status. PD is ≥25% increase in T1 gadolinium enhancing disease.	Before (baseline) and during treatment with Sunitinib every 6 weeks, up to approximately 25 months and 12 days.
Mean Symptom Severity and Interference From Baseline Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT)	Participants reported outcome measures using a self-reported symptom severity and interference with daily activities using the MDASI-BT. The MDASI-BT consists of symptoms rated on an 11-point scale (0 to 10) to indicate the presence and severity of the symptom, with 0 being "not present" and 10 being "as bad as you can imagine." Each symptom is rated at its worst in the last 24 hours. All patients with at least one valid questionnaire will be included in the analyses. This outcome measure was predicated on change. Differences of at least 2 points will be classified as the minimum clinically meaningful change in the symptom severity and symptom interference measures.	Baseline and off treatment, approximately 25 months and 12 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Baseline to off study, approximately 3 months and 12 days

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mark R Gilbert, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Kondo T, Takagi T, Kobayashi H, Iizuka J, Nozaki T, Hashimoto Y, Ikezawa E, Yoshida K, Omae K, Tanabe K. Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma--comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J Clin Oncol. 2014 Mar;44(3):270-7. doi: 10.1093/jjco/hyt232. Epub 2014 Jan 27.
• Cachia D, Kamiya-Matsuoka C, Mandel JJ, Olar A, Cykowski MD, Armstrong TS, Fuller GN, Gilbert MR, De Groot JF. Primary and secondary gliosarcomas: clinical, molecular and survival characteristics. J Neurooncol. 2015 Nov;125(2):401-10. doi: 10.1007/s11060-015-1930-y. Epub 2015 Sep 9.
• Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol. 2011 Jul;11(7):856-61. doi: 10.1016/j.intimp.2011.01.030. Epub 2011 Feb 11.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2019
• Primary Completion (Actual): April 2, 2021
• Study Completion (Actual): April 2, 2021

Study Registration Dates

• First Submitted: August 21, 2018
• First Submitted That Met QC Criteria: August 21, 2018
• First Posted (Actual): August 22, 2018

Study Record Updates

• Last Update Posted (Actual): April 19, 2022
• Last Update Submitted That Met QC Criteria: March 24, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Brain Tumor; Gliosarcoma; MDASI
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Sarcoma; Gliosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Sunitinib
• Other Study ID Numbers: 180137; 18-C-0137

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No