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SARC016. Phase 2 study of the mTOR inhibitor RAD001 ( everolimus ) in combination with bevacizumab ( avastin ) in patients with sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors PI: Brigitte Widemann , MD, National Cancer Institute

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Phase 2 study of the mTOR inhibitor RAD001 (everolimus) in combination with bevacizumab (avastin) in patients with sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors

PI: Brigitte Widemann, MD, National Cancer Institute

Co-PI: John Perentesis, MD, University of Cincinnati

Sarc016 background

SARC016: Background

Johannessen at al, Current Biology, 2008

  • Background

    • NF1 inactivation results in aberrant activation of mTOR

      • Sirolimus halts tumor growth and prolongs survival in a genetically engineered mouse model (Nf1 p53 cis) of MPNST

      • Resistance develops through re-vascularization

      • VEGF expression  in MPNST, correlates with poor outcome


SARC016: Objectives

  • Primary Objective:

  • Clinical benefit rate (CR, PR, SD at ≥ 4 months, WHO) of RAD001 in combination with bevacizumab

  • Toxicity and safety of RAD001 and bevacizumab

  • Secondary Objective:

    • Germline NF1 mutations in patients with NF1 MPNST

    • NF1 mutation and inactivation in available tumor samples

    • Response rate sporadic and NF1 associated MPNST

    • Pharmacodynamics: S6K1 (p70s6K), eIF4E, eIF2, VEGF, VEGFR, AKT

    • 3D-MRI analysis comparison to 1 and 2-dimensional measurements

  • Two Stage Design:

    • 1ststage – 15 patients

    • 2nd stage – > 1 of 15 pts. respond, accrual to 25 patients total

  • Sarc016 inclusion criteria

    SARC016: Inclusion Criteria

    ≥ 18 years old

    Unresectableor metastatic sporadic or NF1 associated high-grade MPNST (no central pathology confirmation)

    Progression after ≥ 1 prior cytotoxic chemotherapy regimen

    Note: Patients who refuse cytotoxic chemotherapy, or for whom treatment on SARC016 is felt to be in the best patient interest will also be eligible

    Prior therapy:

    ≥7 days since the completion of therapy with a biologic agent

    ≥ 21 days since completion of cytotoxic therapy

    Prior radiation:

    If recurrence or progression in a previously radiated field at least 4 weeks since the last dose of radiation therapy.

    Adequate organ function

    Recovered from the toxic effects of all prior to < grade 1

    ECOG performance status of 0, 1, or 2

    Willing to use a medically acceptable form of birth control

    Sarc016 exclusion criteria

    Currently receiving anticancer therapies; chronic, systemic treatment with corticosteroids or another immunosuppressive agent

    Immunization with attenuated live vaccines within one week of study entry or during study period

    Uncontrolled brain or leptomeningeal metastases

    Other malignancies within ≤ 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin

    Severe and/or uncontrolled condition that could affect study participation

    Prior treatment with an mTOR inhibitor for sarcoma

    Prior treatment with bevacizumab.

    Concurrent use of anti-coagulant drugs or history of coagulopathy, or bleeding diathesis

    Use of the following prohibited on study:

    Strong CYP3A4 inhibitors prohibited

    Seville orange, star fruit, grapefruit and their juices, and St. John’s Wort

    Enzyme inducing anticonvulsants

    SARC016: Exclusion Criteria

    Sarc016 treatment plan


    Everolimus (2.5, 5, and 10 mg tablets): 10 mg/dose once daily continuous dosing

    Bevacizumab: 10 mg/kg IV every 2 weeks (day 1 and 14)

    28- day cycles until disease progression or unacceptable toxicity (maximum 2 years)

    Dose modification for toxicity:

    Everolimus: Dose reductions to 5 and 2.5 mg for toxicity

    No dose reduction for bevacizumab

    Key supportive care:

    Patients must take some form of PCP prophylaxis while on everolimus

    Good oral hygiene – mucositis toxicity of everolimus

    Corticosteroids are permissible as premedication for blood product transfusions, or as treatment for an acute allergic reaction

    Patients with positive hepatitis treat prophylactically with antiviral

    SARC016: Treatment Plan

    Sarc016 study evaluations

    SARC016: Study Evaluations

    • Prior to each cycle:

      • PE/vitals, everolimus diary, ECOG performance status, hematology, chemistry, urinalysis, record of AEs

      • HBV-DNA or HCV RNA-PCR if prior hepatitis history or receiving prohylaxis or positive screening

    • Every other treatment cycle:

      • CT/MRI

      • Echo or MUGA scan (ONLY patients who received prior anthracylineprior)

    • Correlative studies if patient consented (Details in Operations Manual):

      • Blood sample for pro-angiogenic factors and mTOR targets:

        • Baseline and prior to cycles 3 and 5

      • Genotyping for NF1 mutation:

        • Baseline only in patients with clinical diagnosis of NF1

      • Tumor analysis for NF1 mutation:

        • All patients with frozen archival tumor sample

      • Volumetric MRI analysis of MPNST:

        • All patients with MRI scanning



    Patients with NF1 related or sporadic refractoryMPNST

    N=15 patients


    Interim Analysis

    Clinical benefit rate of ≥25%

    additional 10 patients added

    • 28 day cycles of everolimus (daily dosing) + bevacizumab (day 1 and 14)

    Ongoing tumor assessment imagingevery 2 cycles until disease progression or unacceptable toxicity for a maximum of 2 years

    Sarc016 status activated

    SARC016 Status: Activated

    • Sponsor and Coordination: SARC

    • Supporter:

      • Novartis: everolimus

      • Genentech: bevacizumab

      • DoD: Clinical Trial award - Correlatives

    • Participation:

      • SARC sites and DoD NF Consortium

    • Timeline:

      • Activated at NCI – September 2012

      • Additional sites in process of activation

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