Clinical trial NCT03641326: Sunitinib in Sarcomas of the Central Nervous System
Official title: Phase II Clinical Trial of Sunitinib in Sarcomas of the Central Nervous System
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Gliosarcoma
Central Nervous System Sarcoma
Keywords: Gliosarcoma
Brain Tumor
MDASI
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-08-22
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Number of Participants With Greater Than 50% Reduction in Objective Response
timeFrame: From enrollment to off study, approximately 3 Months, 1 Week, 4 Days
Secondary outcomes:
measure: Number of Participants With 6-month Progression Free Survival (PFS)
timeFrame: 6 months
measure: Number of Participants That Have Progressive Disease After 18 Months
timeFrame: After 18 months
measure: Number of Adverse Events Related to Drug
timeFrame: Baseline to off study, approximately 3 months and 12 days
measure: Evaluation of Tumor Tissue for Biomarkers
timeFrame: end of study, approximately 25 months and 12 days.
measure: Number of Responders and Non-responders With Tumor Markers of Activation
timeFrame: From baseline to end of treatment, approximately 25 months and 12 days.
measure: Number of Responders and Non-responders With a Change in Perfusion Blood Volume Before and After Treatment With Sunitinib.
timeFrame: Pre-treatment and post treatment, approximately 25 months and 12 days.
measure: Number of Responders and Non-responders With Dynamic Contrast Enhanced Magnetic Resonance Imaging (MRI) Performed Before and During Treatment With Sunitinib.
timeFrame: Before (baseline) and during treatment with Sunitinib every 6 weeks, up to approximately 25 months and 12 days.
measure: Mean Symptom Severity and Interference From Baseline Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT)
timeFrame: Baseline and off treatment, approximately 25 months and 12 days
Other outcomes:
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
timeFrame: Baseline to off study, approximately 3 months and 12 days
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark R Gilbert, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.