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

NCT03433183 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: SARC031CDMRP-NF150092
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 5

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.

Conditions

Malignant Peripheral Nerve Sheath Tumors; Neurofibromatosis 1

Outcome Measures

Primary Outcomes (1)

• Clinical benefit rate of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 associated or sporadic MPNST.

  An evaluable patient will be classified as a responder if the patient achieves a partial response (PR), complete response (CR) or stable disease (SD) ≥ 4 cycles.

  Up to 6 months

Secondary Outcomes (4)

• Progression free and overall survival

  Progression-Free Survival (PFS) is defined as the duration of time from the start of treatment to the time of objective progression or death. [Time Frame: Up to 4 years]

• Define and describe the toxicities of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 associated or sporadic MPNST.

  Up to 6 months

• Assess the impact on pain interference

  Up to 6 months

• Assess the impact on pain severity

  Up to 6 months

Study Arms (1)

Selumetinib and Sirolimus

EXPERIMENTAL

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.

Drug: Selumetinib; Drug: Sirolimus

Interventions

Selumetinib 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.

Also known as: AZD6244

Selumetinib and Sirolimus

Sirolimus 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.

Also known as: Rapamycin

Selumetinib and Sirolimus

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Sarcoma Alliance for Research through Collaboration: lead
• United States Department of Defense: collaborator
• AstraZeneca: collaborator

Study Sites (5)

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

National Cancer Institute

Bethesda, Maryland, 20892, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Neurofibrosarcoma; Neurofibromatosis 1

Interventions

AZD 6244; Sirolimus

Condition Hierarchy (Ancestors)

Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neurofibromatoses; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• AeRang Kim, MD, PhD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

• Brigitte Widemann, MD

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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 MPNST

Study Record Dates

• First Submitted: January 29, 2018
• First Posted: February 14, 2018
• Study Start: October 2, 2019
• Primary Completion: June 22, 2022
• Study Completion: October 1, 2023
• Last Updated: December 26, 2023

Record last verified: 2023-03

Locations

US (5)