This study is NOT currently recruiting participants.
Number
19-C-0061
Sponsoring Institute
National Cancer Institute (NCI)
Recruitment Detail
Type: Completed Study; data analyses ongoing Gender: Male & Female Min Age: 12 Years Max Age: N/A
Referral Letter Required
No
Population Exclusion(s)
Fetuses;Neonates;Pregnant Women
Keywords
Fibrosarcoma; Neurofibromatosis 1; Soft Tissue Sarcoma; Neuroendocrine Tumor; Schwannoma
Recruitment Keyword(s)
None
Condition(s)
Malignant Peripheral Nerve Sheath Tumors; Neurofibromatosis 1; Neuroepithelioma
Investigational Drug(s)
Selumetinib sirolimus
Investigational Device(s)
Intervention(s)
Drug: Selumetinib Drug: sirolimus
Supporting Site
National Cancer Institute
Neurofibromatosis type 1 (NF1) is a genetic disorder. It affects the skin and can cause nervous system tumors. Malignant peripheral nerve sheath tumors (MPNST) are the leading cause of death for people with NF1. They arise from nerves in the body and can spread. Researchers want to see if a combination of two drugs can help. The drugs, selumetinib and vistusertib, both affect tumor growth.
Objective:
To study the effects of selumetinib plus sirolimus on people with NF1 and MPNST.
Eligibility:
People ages 12 years and older with MPNST
Design:
Participants will be screened with:
-Medical history
-Physical exam
-Tests of pain and everyday activities
-Blood, urine, and heart tests
-Pregnancy test
-Eye exam
-Scans
Participants will take both study drugs 2 times a day in 28-day cycles. They will take selumetinib every day and vistusertib the first 2 days of each week.
Participants will learn about taking the drug capsules and food and medicines to avoid. They will learn about skin and mouth care and treating diarrhea.
Participants will keep a drug diary. They may get medicine for side effects.
Participants will have 6 visits during cycle 1, and 1 visit every other cycle. During visits, participants may repeat the screening tests and:
-Review their medicine diaries
-Discuss symptoms
-Have a tumor sample taken
Participants will be asked to allow their samples and test results to be stored confidentially.
When they stop taking the study drugs, participants will repeat most screening tests. They will be contacted every few months to check on their disease.
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Patients must have baseline evaluation performed prior to the first dose of study drugs and must meet all inclusion/exclusion criteria. Results of all baseline evaluations, which assure that all inclusion/exclusion criteria have been satisfied must be reviewed by the Principal Investigator or his/her designee prior to enrollment of the patient. In addition, the patient must be thoroughly informed about all aspects of the study, including study visit schedule and required evaluations and all regulatory requirements for informed consent. The written informed consent must be obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified. All clinical and laboratory studies must be performed within 14 days prior to enrollment unless otherwise indicated. Imaging studies for baseline scans must be obtained within 4 weeks prior to enrollment. Patients must start therapy no later than 7 calendar days after the date of study enrollment. INFORMED CONSENT: All patients or guardians must sign a document of informed consent indicating their understanding of the investigational nature and the risks of this study before any protocol related studies are performed. Patients under 18 years of age will sign an assent document prior to treatment. DURABLE POWER OF ATTORNEY (DPA): Patients will be offered the opportunity to assign a DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired. -Age: greater than or equal to 12 years of age -Diagnosis: Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated MPNST -Measureable Disease : Patients must have measureable disease by RECIST -Therapeutic Options: 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. -Prior Therapy: --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. --Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry. --Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry. --Biologic (anti-cancer agent): 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. --Radiation therapy: 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. --Stem Cell Transplantation. 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. --Growth Factors. 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. -Concurrent Therapies: No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted -Performance Status: --Lansky/Karnofsky performance level greater than or equal to 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. -Hematologic Function: --Peripheral absolute neutrophil count (ANC) of greater than or equal to 1,000/uL --Platelet count greater than or equal to 75,000/uL (transfusion independent (no transfusion within at least 7 days prior to enrollment) -Hepatic Function --Total bilirubin must be less than or equal to 1.5 times the upper limit of normal (ULN) --SGPT (ALT) must be less than or equal to 3.0 times ULN -Renal Function: Serum creatinine less than or equal to ULN or creatinine clearance >60 ml/min/1.73 m2 -Serum triglyceride level less than or equal to 300mg/dL and serum cholesterol less than or equal to 300mg/dL (Patient may be on lipid-lowering medicine). -Cardiac Function: -- Normal ejection fraction by ECHO or cardiac MRI >55% --QTcF less than or equal to 450ms - Fertile men and women of childbearing potential must agree to use an effective method of birth control. Female patients of child bearing potential must be willing to use 2 forms of contraception (per institutional standards) from the time of screening until 4 weeks after discontinuing the study (1 highly effective and 1 barrier method, see below). They must not be breastfeeding and must have negative pregnancy test prior to start of dosing. -For a female patient to be considered as of not child bearing potential, she should fulfil one of the following: -- Post menopausal women, defined as either women aged more than 50 years and have amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years who have amenorrhea for at least 12 months following cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution. OR -- Have documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy (but not tubal ligation) -- Have medically confirmed, irreversible premature ovarian failure. -Highly effective methods of contraception are: -- Use of medroxyprogesterone acetate depot injection (DepoproveraTM).(Please note: use of any other oral, injected, or implanted effective as it is currently unknown whether selumetinib/vistusertib may reduce their effectiveness) -- Placement of a copper-banded intrauterine device (IUD) or intrauterine system (IUS) -- True abstinence -- Bilateral tubal ligation -- Vasectomized partner -Barrier Methods Include: --Condom -- Occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide Male patients should either be surgically sterile or willing to use an effective barrier method of contraception during the study and for 16 weeks following the last dose of study treatment if sexually active with a female of child bearing potential. If not done, storage of sperm prior to receiving study treatment will be advised to male patients with a desire to have children - 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 orother 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 greater than or equal to 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 vistusertib or selumetinib or drugs with similar chemical structures or class to vistusertib 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 Inclusion of Children, Women and Minorities: Men, women, children (as applicable) and members of all ethnic and racial groups are eligible for this trial. Subjects of both genders and from all racial and ethnic groups are eligible for this trial if they meet the eligibility criteria outlined in Section 3.1. No groups are being excluded from participation in the trial. Approximately 50% of MPNST develop in individuals with NF1, and we expect that approximately 50% of individuals enrolled will have NF1 associated MPNST and 50% will have sporadic MPNST. The treatment approach to MPNST is similar for children and adults. Approved adult and adolescent drug dosing was determined to be equivalent in approximately 95% of all products with an adolescent indication studied under the FDA amendments act of 2007. Whereas sporadic MPNST are typically diagnosed in late adulthood, MPNST diagnosis peaks at a younger age in patients with NF1, generally in early adulthood (20-50 years) with 10-20% of cases reported at event younger ages (1-19 years). Thus, treating patients with greater than or equal to 12 years of age will allow for the majority of patients with MPNST without affecting safety and dosing per FDA findings.
All clinical and laboratory studies must be performed within 14 days prior to enrollment unless otherwise indicated. Imaging studies for baseline scans must be obtained within 4 weeks prior to enrollment. Patients must start therapy no later than 7 calendar days after the date of study enrollment.
INFORMED CONSENT: All patients or guardians must sign a document of informed consent indicating their understanding of the investigational nature and the risks of this study before any protocol related studies are performed. Patients under 18 years of age will sign an assent document prior to treatment.
DURABLE POWER OF ATTORNEY (DPA): Patients will be offered the opportunity to assign a DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.
-Age: greater than or equal to 12 years of age
-Diagnosis: Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated MPNST
-Measureable Disease : Patients must have measureable disease by RECIST
-Therapeutic Options: 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.
-Prior Therapy:
--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.
--Myelosuppressive chemotherapy: The last dose of all myelosuppressive
anticancer drugs must be at least 3 weeks prior to study entry.
--Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry.
--Biologic (anti-cancer agent): 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.
--Radiation therapy: 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.
--Stem Cell Transplantation. 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.
--Growth Factors. 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.
-Concurrent Therapies: No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted
-Performance Status:
--Lansky/Karnofsky performance level greater than or equal to 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.
-Hematologic Function:
--Peripheral absolute neutrophil count (ANC) of greater than or equal to 1,000/uL
--Platelet count greater than or equal to 75,000/uL (transfusion independent (no transfusion within at least 7 days prior to enrollment)
-Hepatic Function
--Total bilirubin must be less than or equal to 1.5 times the upper limit of normal (ULN)
--SGPT (ALT) must be less than or equal to 3.0 times ULN
-Renal Function: Serum creatinine less than or equal to ULN or creatinine clearance >60 ml/min/1.73 m2
-Serum triglyceride level less than or equal to 300mg/dL and serum cholesterol less than or equal to 300mg/dL (Patient may be on lipid-lowering medicine).
-Cardiac Function:
-- Normal ejection fraction by ECHO or cardiac MRI >55%
--QTcF less than or equal to 450ms
- Fertile men and women of childbearing potential must agree to use an effective method of birth control.
Female patients of child bearing potential must be willing to use 2 forms of contraception (per institutional standards) from the time of screening until 4 weeks after discontinuing the study (1 highly effective and 1 barrier method, see below). They must not be breastfeeding and must have negative pregnancy test prior to start of dosing.
-For a female patient to be considered as of not child bearing potential, she should
fulfil one of the following:
-- Post menopausal women, defined as either women aged more than 50 years and have amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years who have amenorrhea for at least 12 months following cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution. OR
-- Have documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy (but not tubal ligation)
-- Have medically confirmed, irreversible premature ovarian failure.
-Highly effective methods of contraception are:
-- Use of medroxyprogesterone acetate depot injection (DepoproveraTM).(Please note: use of any other oral, injected, or implanted effective as it is currently unknown whether selumetinib/vistusertib may reduce their effectiveness)
-- Placement of a copper-banded intrauterine device (IUD) or intrauterine system (IUS)
-- True abstinence
-- Bilateral tubal ligation
-- Vasectomized partner
-Barrier Methods Include:
--Condom
-- Occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide
Male patients should either be surgically sterile or willing to use an effective barrier method of contraception during the study and for 16 weeks following the last dose of study treatment if sexually active with a female of child bearing potential. If not done, storage of sperm prior to receiving study treatment will be advised to male patients with a desire to have children
- 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 orother 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 greater than or equal to 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 vistusertib or
selumetinib or drugs with similar chemical structures or class to vistusertib 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
Inclusion of Children, Women and Minorities:
Men, women, children (as applicable) and members of all ethnic and racial groups are eligible for this trial.
Subjects of both genders and from all racial and ethnic groups are eligible for this trial if they meet the eligibility criteria outlined in Section 3.1. No groups are being excluded from participation in the trial. Approximately 50% of MPNST develop in individuals with NF1, and we expect that approximately 50% of individuals enrolled will have NF1 associated MPNST and 50% will have sporadic MPNST.
The treatment approach to MPNST is similar for children and adults. Approved adult and adolescent drug dosing was determined to be equivalent in approximately 95% of all products with an adolescent indication studied under the FDA amendments act of 2007. Whereas sporadic MPNST are typically diagnosed in late adulthood, MPNST
diagnosis peaks at a younger age in patients with NF1, generally in early adulthood (20-50 years) with 10-20% of cases reported at event younger ages (1-19 years). Thus, treating patients with greater than or equal to 12 years of age will allow for the majority of patients with MPNST without affecting safety and dosing per FDA findings.
Principal Investigator
Referral Contact
For more information: