SARC031: MEK Inhibitor Selumetinib (AZD6244) in Combination With the mTOR Inhibitor Sirolimus for Patients With Malignant Peripheral Nerve Sheath Tumors

NCT ID: NCT03433183

Last Updated: 2023-12-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-02
• Study Completion Date: 2023-10-01

Brief Summary

To determine the clinical benefit rate of selumetinib in combination with sirolimus in patients with unresectable or metastatic neurofibromatosis type 1 (NF1) associated or sporadic MPNST.

Detailed Description

I. Primary Objective

• To determine the clinical benefit rate of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 associated or sporadic MPNST

II. Secondary Objective(s)

• To define and describe the toxicities of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 associated or sporadic MPNST.
• To assess the impact on intensity and pain interference and correlate to changes in clinical, imaging response and progression
• To assess progression free and overall survival

Selumetinib will be given orally 50mg twice daily continuously and sirolimus will be given orally 4mg once daily with a cycle 1 day 1 loading dose of 12mg. One cycle will be 28 days. Patients will be able to remain on treatment as long as they do not experience progressive disease or unacceptable toxicity. Stage 1 will require 7 patients, with no further accrual if 0 of 7 respond. If 1 or greater of the 7 patients respond, accrual will continue until 21 patients have been enrolled.

Conditions

Malignant Peripheral Nerve Sheath Tumors; Neurofibromatosis 1

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Selumetinib and Sirolimus

A Simon's two-stage phase 2 trial of MEK inhibitor selumetinib in combination with the mTOR inhibitor sirolimus to determine the safety and clinical benefit in patients with unresectable or metastatic MPNSTs. Both agents will be given orally on an empty stomach. Selumetinib will be given orally at a dose of 50mg twice daily continuously. Sirolimus will be given orally at a dose of 4mg once daily with a cycle 1 day 1 loading dose of 12mg. Each cycle will be considered 28 days.

Group Type: EXPERIMENTAL

Selumetinib

Intervention Type: DRUG

Selumetinib (AZD6244) is an oral selective inhibitor of the mitogen-activated protein kinase (MEK) 1/2 currently in development for adult malignancies, pediatric low-grade gliomas and NF1 plexiform neurofibromas. MEK is a critical kinase in the mitogen activated protein (MAP) kinase signal transduction pathway for many growth factor receptors that provide growth signals to cancer cells.

Sirolimus

Intervention Type: DRUG

Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus and inhibitor of mammalian Target of Rapamycin (mTOR) serine threonine kinase, which plays a critical role in regulating cellular energy sensing, growth and metabolism.

Interventions

Selumetinib

Selumetinib (AZD6244) is an oral selective inhibitor of the mitogen-activated protein kinase (MEK) 1/2 currently in development for adult malignancies, pediatric low-grade gliomas and NF1 plexiform neurofibromas. MEK is a critical kinase in the mitogen activated protein (MAP) kinase signal transduction pathway for many growth factor receptors that provide growth signals to cancer cells.

Intervention Type: DRUG

Sirolimus

Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus and inhibitor of mammalian Target of Rapamycin (mTOR) serine threonine kinase, which plays a critical role in regulating cellular energy sensing, growth and metabolism.

Intervention Type: DRUG

Other Intervention Names

AZD6244; Rapamycin

Eligibility Criteria

Inclusion Criteria

• Age ≥ 12 years of age
• Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated MPNST.
• Patients must have measureable disease by RECIST.
• Patients must have experienced progression after one or more prior regimens of cytotoxic chemotherapy. Patients who have refused cytotoxic chemotherapy or for whom treatment on this protocol prior to receiving cytotoxic chemotherapy is felt to be in the best interest for the patient by the local investigator will also be eligible.
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study.
• No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study entry.
• The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry.
• The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry.
• The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 7 days prior to study entry.
• The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry.
• At least 2 months post-autologous stem cell transplant or at least 3 months post-allogeneic transplant and recovered from toxicities without evidence of graft versus host disease and on stable doses of immunosuppressive medications if required.
• The last dose of colony stimulating factors, such as filgrastim, sargramostim, and erythropoietin, must be at least 1 week prior to study entry, the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at least 2 weeks prior to study entry.
• No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted.
• Karnofsky performance level ≥ 50%.
• Patients who are unable to walk because of paralysis or motor weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
• Peripheral absolute neutrophil count (ANC) of ≥1000/μL
• Platelet count ≥75,000/μL (transfusion independent (no transfusion within at least 7 days prior to enrollment)
• Total bilirubin must be ≤ 1.5 times the upper limit of normal (ULN)
• SGPT (ALT) must be ≤ 3.0 times ULN
• Serum creatinine ≤ ULN or creatinine clearance >60 ml/min/1.73 m2
• Serum triglyceride level ≤300 mg/dL and serum cholesterol level ≤ 300 mg/dL (Patient may be on lipid-lowering medicine)
• Normal ejection fraction by ECHO or cardiac MRI >55%
• QTcF ≤ 450ms
• Fertile men and women of childbearing potential must agree to use an effective method of birth control.
• Patients with central nervous system disease are eligible for enrollment if they have received prior radiotherapy or surgery to sites of CNS metastatic disease and are without evidence of clinical progression or stable disease at 4 weeks.

Exclusion Criteria

• Patients receiving other anti-cancer agents are not eligible.
• Patients who cannot swallow whole pills.
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent (for example cyclosporine). Topical or inhaled corticosteroids are allowed.
• Patients should not receive immunizations with attenuated live vaccines within four weeks of study entry or during study period.
• Any recent major surgery within a minimum of 4 weeks, with the exception of surgical placement for vascular access, or minor surgery (excluding tumor biopsies) within 14 days.
• Patients who any known severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• Severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value corrected for hemoglobin and alveolar volume and/or O2 saturation that is 88% or less at rest on room air. For patients who do NOT have respiratory symptoms (e.g. dyspnea at rest, known requirement for supplemental oxygen), pulmonary function test is not required.
• Cardiac conditions as follows:

• Uncontrolled hypertension (blood pressure ≥150/95 mmHg despite medical therapy).
• Acute coronary syndrome within 6 months prior to starting treatment
• Uncontrolled angina despite medical therapy
• Symptomatic heart failure NYHA Class II-IV prior or current cardiomyopathy, or severe valvular disease
• Prior or current cardiomyopathy
• Uncontrolled Type 1 or 2 diabetes as defined by fasting serum glucose >1.5 x ULN
• Uncontrolled infection
• Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome, or renal tubular acidosis.
• Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of small bowel, symptomatic inflammatory bowel disease, or ulcerative colitis, or partial or complete bowel obstruction.
• Ophthalmological conditions as follows:

• Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion
• Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
• Supplementation with vitamin E greater than 100% of the daily recommended dose.
• Hypersensitivity to active or inactive excipients of rapamycins (sirolimus, temsirolimus or everolimus) or selumetinib or drugs with similar chemical structures or class to sirolimus or selumetinib.
• Patients unwilling or unable to comply with the protocol.
• Seville orange, star fruit, grapefruit and their juices, and St. John's Wort use are not allowed while on study.
• Exposure to strong or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP if taken within the stated washout periods before the first dose of study treatment.
• Exposure to specific substrates of drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K within the appropriate washout periods (a minimum of 5 x reported elimination half-life) before the first dose of study treatment.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Sarcoma Alliance for Research through Collaboration

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

AeRang Kim, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Brigitte Widemann, MD

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

Children's National Medical Center

Washington D.C., District of Columbia, United States

Johns Hopkins University

Baltimore, Maryland, United States

National Cancer Institute

Bethesda, Maryland, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Washington University

St Louis, Missouri, United States

Countries

United States

Other Identifiers

CDMRP-NF150092

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

SARC031

Identifier Type: -

Identifier Source: org_study_id