A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas

NCT00634270 | Completed Phase 2 Results DMC

• 3 other identifiers: F071019012DOD: W81XWH-05-615.UAB: 251558.
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 9

Brief Summary

Treatment Overview This phase II study will evaluate the activity of sirolimus in children and adults with NF1 and inoperable plexiform neurofibromas that have the potential to cause significant morbidity. The following disease strata will be studied: Stratum 1: Progressive plexiform neurofibroma(s) that have the potential to cause significant morbidity. The endpoint will be time to tumor progression based on volumetric tumor measurements. Stratum 2: Plexiform neurofibromas without documented radiographic progression at trial entry. The endpoint will be radiographic response. As of May 2009, Stratum 2 was closed to enrollment. Stratum 1 is active.

Conditions

Neurofibromatosis Type 1

Keywords

Plexiform, Neurofibromatosis Type 1, Sirolimus, Phase II

Outcome Measures

Primary Outcomes (9)

• Time to Disease Progression Based on Volumetric MRI

  Median time to progression in Stratum 1 as defined as an increase of at least 20% of the volume of the primary lesion. Note: Since Stratum 2 looked at response rate only, median time to progression was not reviewed for this outcome.

  24 Months Stratum 1

• Results in Objective Radiographic Responses Based on Volumetric MRI Measurements in Children and Adults With NF1 and Inoperable PN in the Absence of Documented Radiographic Progression at Trial Entry

  Stratum 2 outcome - Response

  48 weeks Stratum 2

• Toxicity

  Number of participants experiencing adverse events

  24 weeks Stratum 1 / 48 weeks Stratum 2

• To Characterize the Pharmacokinetic Profile of Sirolimus Administered to This Patient Population (Clearance Liters/Hour (L/h))

  An iterative 2-stage Bayesian method was used for the PK parameter analyses

  Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours

• To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population Using Liters/Hour Per Population Median Weight of 70kg (L/h70kg)

  An iterative 2-stage Bayesian method was used for the PK parameter analyses

  Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours

• To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - (Clearance (L/h Per 1.85 m^2)

  An iterative 2-stage Bayesian Method was used for the PK parameter analyses

  Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours

• To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population- Therapeutic Dose (mg/m^2 Per Dose)

  An iterative 2-stage Bayesian Method was used for the PK parameter analyses

  Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours

• To Characterize the Pharmacokinetic Profile of Sirolimus in When Administered to This Patient Population - Therapeutic Dose (mg/kg Per Dose)

  An iterative 2-stage Bayesian Method was used for the PK parameter analyses

  Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours

• To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - Therapeutic Dose (mg/kg)^0.75

  An iterative 2-stage Bayesian method was used for the PK parameter analyses

  Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours

Secondary Outcomes (6)

• To Evaluate the Quality of Life During Treatment With Sirolimus by Assessing Preliminary Correlations of Response With Quality-of-life Outcomes

  24 weeks Stratum 1 / 48 weeks Stratum 2

• To Assess the Value of Three-dimensional MRI (3-D MRI) in the Evaluation of Plexiform Neurofibromas and Paraspinal Neurofibromas, and to Compare 3-D MRI to Conventional Two-dimensional MRI (2-D MRI) and One Dimensional MRI (1-D MRI) Data Analysis

  24 weeks Stratum 1 / 48 weeks Stratum 2

• To Asses Preliminary Correlations of Radiographic Response With Changes in Pharmacodynamics Parameters Including p70s6 Kinase Activity in Peripheral Blood Mononuclear Cells.

  24 weeks Stratum 1 / 48 weeks Stratum 2

• To Evaluate the Effect of Sirolimus on Clinical Response by Reduction in Pain, or Improvement in Function or Performance Scale.

  24 weeks Stratum 1 / 48 weeks Stratum 2

• To Evaluate Pharmacogenetic Polymorphisms of Cytochrome P450 3A4 & 3A5 Alleles and P-glycoprotein/MDR for Their Influence on the Metabolism of Sirolimus in This Patient Population.

  24 weeks Stratum 1 Only

Study Arms (1)

Sirolimus

EXPERIMENTAL

Design * Sirolimus oral solution will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment course) with pharmacokinetically-guided dosing. * Disease status will be evaluated using volumetric MRI analysis at regular intervals. * The plasma pharmacokinetics and pharmacodynamics of sirolimus will be evaluated, as will pharmacogenetic polymorphisms and their influence on the metabolism of sirolimus in this patient population. * Pain reduction and quality of life outcomes will also be assessed. * Toxicity of chronic sirolimus administered will be evaluated using physical and laboratory evaluations.

Drug: Sirolimus

Interventions

Sirolimus DRUG

This phase II study will evaluate children and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with sirolimus. It is divided in two strata. The first stratum will evaluate time to progression (TTP) in children and adults with NF1 and progressive plexiform neurofibromas with the potential to cause significant morbidity treated with sirolimus. The second stratum will evaluate objective radiographic response to sirolimus in children and adults with NF1 and inoperable plexiform neurofibromas with the potential to cause significant morbidity that do not have documented progression of the PN at time of trial entry.

Also known as: Rapamune, Rapamycin

Sirolimus

Eligibility Criteria

• Age: 3 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients must have the clinical diagnosis of NF1 using the NIH Consensus Conference criteria.
• Six or more café-au-lait spots (greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 1.5 cm in postpubertal subjects).
• Freckling in the axilla or groin.
• Optic glioma.
• Two or more Lisch nodules.
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex).
• A first-degree relative with NF1.
• Patients must have plexiform neurofibroma(s) that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Patients with paraspinal plexiform neurofibromas will be eligible for this trial. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected.
• Age: Patients must be greater than or equal to 3 years of age at the time of study entry.
• Durable Power of Attorney: Adults evaluated for this study will be offered a durable power of attorney. Adults who are unable to provide informed consent will have to have a durable power of attorney in order to participate in this trial.
• Disease status: Measurable disease: Patients must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. For the purpose of this study, a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension.
• Performance Level: Karnofsky greater than or equal to 50% for patients \> 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age (Appendix IV). Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior Therapy: Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable. Patients are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a patient with surgical option refuses surgery. Patients may have been previously treated for a plexiform neurofibroma but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study.
• a. Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto this study.
• b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function.

You may not qualify if:

• Chronic treatment with systemic steroids or another immunosuppressive agent.
• Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
• Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy. Patients not requiring treatment are eligible for this protocol.
• Dental braces or prosthesis that interfere with volumetric analysis of the neurofibroma(s).
• Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
• A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube) is allowed.
• Women who are pregnant or breast feeding.
• Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. Women of childbearing potential will be given a pregnancy test within 7 days prior to administration of sirolimus and must have a negative urine or serum pregnancy test.
• Patients who have received prior treatment with an mTOR inhibitor.
• History of noncompliance to medical regimens.
• Patients unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
• Patients who have an uncontrolled infection.

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Boston Children's Hospital: collaborator
• Children's Hospital of Philadelphia: collaborator
• Children's National Research Institute: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• National Cancer Institute (NCI): collaborator
• University of Chicago: collaborator
• University of Utah: collaborator
• Washington University School of Medicine: collaborator

Study Sites (9)

The University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Children's National Medical Center

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

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

National Cancer Institute (NCI)

Bethesda, Maryland, 20892, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-4006, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19096, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

MeSH Terms

Conditions

Neurofibromatosis 1

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Bruce Korf, MD, PhD
• Organization: The Univ of Alabama at Birmingham

kcole@uab.edu

205.934.5140

Study Officials

• Bruce Korf, MD

  The University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

• Brian Weiss, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

• Roger Packer, MD

  Children's National Medical Center - Chairman of the NF Consortium

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 20, 2008
• First Posted: March 13, 2008
• Study Start: April 1, 2008
• Primary Completion: November 1, 2014
• Study Completion: December 1, 2015
• Last Updated: November 17, 2017
• Results First Posted: February 14, 2017

Record last verified: 2017-10

Locations

US (9)