Clinical Trials /

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

NCT03433183

Description:

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.

Related Conditions:
  • Malignant Peripheral Nerve Sheath Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: SARC031: MEK Inhibitor Selumetinib (AZD6244) in Combination With the mTOR Inhibitor Sirolimus for Patients With Malignant Peripheral Nerve Sheath Tumors
  • Official Title: SARC031: A Phase 2 Trial of the MEK Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Combination With the mTOR Inhibitor Sirolimus for Patients With Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors

Clinical Trial IDs

  • ORG STUDY ID: SARC031
  • SECONDARY ID: CDMRP-NF150092
  • NCT ID: NCT03433183

Conditions

  • Malignant Peripheral Nerve Sheath Tumors
  • Neurofibromatosis 1

Interventions

DrugSynonymsArms
SelumetinibAZD6244Selumetinib and Sirolimus
SirolimusRapamycinSelumetinib and Sirolimus

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Selumetinib and SirolimusExperimentalA 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.
  • Selumetinib
  • Sirolimus

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit rate of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 associated or sporadic MPNST.
Time Frame:Up to 6 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression free and overall survival
Time Frame: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]
Safety Issue:
Description:Determined using the Kaplan-Meier method with PFS at important time points reported along with 95% two sided confidence intervals.
Measure:Define and describe the toxicities of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 associated or sporadic MPNST.
Time Frame:Up to 6 months
Safety Issue:
Description:This study will use CTEP Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 for toxicity and adverse event reporting. The toxicities will be graded and summarized descriptively and tabulations on the type, severity and relationship to study treatment will be performed.
Measure:Assess the impact on pain interference
Time Frame:Up to 6 months
Safety Issue:
Description:Pain interference metrics will be assessed using the Patient Reported Outcomes Measurements Information System (PROMIS) scale to assess the impact of pain on daily activities. This is a self-report measure that assesses the degree to which pain has interfered with the ability to complete daily activities over the past 7 days. Items are rated on a 5-point Likert scale and the measures yield standardized T-scores.
Measure:Assess the impact on pain severity
Time Frame:Up to 6 months
Safety Issue:
Description:Pain metrics will be assessed using the Numerical Rating Scale-11 (NRS-11) scale to assess pain severity. The scale consists of a horizontal line with 0 representing "no pain" and 10 representing "worst pain you can imagine." Patients will circle one number from 0 to 10 that best describes how much their tumor pain hurt during the past week.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sarcoma Alliance for Research through Collaboration

Last Updated