PNOC 001: Phase II Study of Everolimus for Recurrent or Progressive Low-grade Gliomas in Children

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01734512
Recruitment Status : Recruiting
First Posted : November 27, 2012
Last Update Posted : June 20, 2018
Novartis Pharmaceuticals
Pacific Pediatric Neuro-Oncology Consortium
The Pediatric Low Grade Astrocytoma Foundation
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma.

Condition or disease Intervention/treatment Phase
Pediatric Recurrent Progressive Low-grade Gliomas Pediatric Progressive Low-grade Gliomas Drug: Everolimus Phase 2

Detailed Description:
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma. All patients will receive everolimus at a dose of 5 mg/m2/dose daily. An adaptive Simon two-stage design for phase 2 studies of targeted therapies will be used to assess the efficacy primary objective. The proposed treatment with everolimus will be deemed not worthy of further investigation in this patient population if the true PFS at 6-months (PFS6) is less than 50%. If in the first stage, with a combined sample size of 25, there is preliminary evidence to suggest efficacy of everolimus is restricted to patients with PI3K/AKT/mTOR activation as measured by p-S6 positivity, a total of 45 patients will be enrolled and the design will have 81% statistical power to detect a true disease stabilization rate ≥70%. If in the first stage there is preliminary evidence to suggest efficacy of everolimus is independent of PI3K/AKT/mTOR activation, a total of 65 patients will be enrolled and the design will have >95% statistical power to detect a true disease stabilization rate ≥70%.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PNOC 001: Phase II Study of Everolimus for Recurrent or Progressive Low-grade Gliomas in Children
Study Start Date : November 2012
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Everolimus
Everolimus tablet will be taken daily by mouth with water. Twenty-eight days will constitute one course and subsequent courses will immediately follow with no break in the administration of the drug. Dosing is based on the BSA (body surface area) calculated at the beginning of each course of therapy. Patients will also be provided with a drug diary for everolimus. The maximum time on study is 24-months, but if there is no disease progression or adverse events, the patient may speak with a doctor about continuing the treatment off-study.
Drug: Everolimus
Everolimus tablet will be taken daily by mouth with water. All patients will be given a dose of 5 mg/m2/dose daily.

Primary Outcome Measures :
  1. Evaluation of efficacy by Progression Free Survival associated with everolimus therapy [ Time Frame: up to 6 months ]
    Determined by 6-month progression free survival. Response will be determined by bi-dimensional diameters. RECIST criteria will be collected and used for secondary evaluation. Patients will have brain MRI scans with and without gadolinium performed prior to therapy, after every second course in the first year, after every third course in the second year, and at the End of Study visit (if not done within prior 3 months). Spine MRIs should be performed prior to therapy and at the same time points as standard brain MRIs if clinically indicated.

Secondary Outcome Measures :
  1. Estimation of Objective Response - Progression Free Survival [ Time Frame: Up to 6 weeks ]
    Estimate Progression Free Survival distribution along with objective response rates associated with everolimus treatment.

  2. Exploration of Associations with pS6 Positivity and Outcome [ Time Frame: Up to 6 months ]
    Explore associations between pS6 positivity and outcome as measured by the 6-month disease stabilization rates and Progression Free Survival.

  3. Estimation of Objective Response - Overall Survival [ Time Frame: Up to 6 weeks ]
    Estimate Overall Survival distributions along with objective response rates associated with everolimus treatment.

  4. Tissue Collection [ Time Frame: Up to 8 Years ]
    Collect tissue from ALL enrolled patients and prospectively analyze key molecular features including activation of the PI3K, mTOR and MAPK pathways, aberrations in PTEN, IDH1, and IDH2, and activating mutations in BRAF (KIAA1549-BRAF fusion and BRAFV600E missense BRAF mutation).

  5. Quantitative measures of cerebral blood [ Time Frame: Up to 6 weeks ]
    Explore MR quantitative measures of relative cerebral blood volume, permeability and apparent diffusion coefficient within the region of hyper-intensity on T2-weighted images as markers of disease response and/or progression in comparison to institutional evaluation of disease response and/or progression and quantitative measures of tumor response as determined by central review (based upon both area and volumetric measures.

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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

--Patients must have radiographic progressive or recurrent confirmed WHO grade I or II astrocytomas, that was confirmed histologically at initial diagnosis. Progressive or recurrent disease should be based on MRI according to the definition below.

Eligible histologies:

  • Pilocytic Astrocytoma - 90600112
  • Astrocytoma, Low Grade (Fibrillary astrocytoma, WHO Grade 2) - 10065886
  • Astrocytoma, Low Grade (Low-grade Astrocytoma, NOS, WHO Grade 2) - 10003571

    • Tissue from the initial diagnosis or recurrence must be made available for correlative testing.
    • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions on MRI.
    • Patients may have had treatment (chemotherapy and/or radiotherapy) for any number of relapses prior to this recurrence.
    • Patients must have received their last dose of myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study registration or at least six (6)weeks of nitrosourea.
    • Patients must have received their last dose of other investigational or biological agent > 7 days prior to study entry.

For agents that have known adverse events occurring beyond 7 days after administration, this period should be extended beyond the time during which adverse events are known to occur. This should be discussed with the study chair.

  • If patients received prior monoclonal antibody treatment, at least three half-lives must be elapsed by the time of treatment initiation. These patients should also be discussed with the study chair.
  • Patients must have received their last fraction of craniospinal or focal radiation to primary tumor or other sites >12 weeks (3 months) prior to registration.

    --Age ≥3 and ≤21 years.

  • Because no dosing or adverse event data are currently available on the use of everolimus in patients <3 years of age, these young children are excluded from this study.

    • Life expectancy of greater than 8 weeks.
    • Patients must be able to swallow pills.
    • Patient must have a Karnofsky (if ≥ 16 years of age) or Lansky Performance score (if ≤ 16 years of age) of ≥50 by the time of registration.
    • Patients must have adequate bone marrow function (ANC ≥ 1,000/mm3, platelet count of ≥ 100,000/mm3, and hemoglobin ≥ 9 gm/dL) before starting therapy. Eligibility level for hemoglobin may be reached by transfusion.
    • INR ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of randomization).
    • Patients must have adequate liver function (SGPT/ALT ≤ 2.5 times ULN and bilirubin ≤ 1.5 times ULN) before starting therapy.
    • Patients must have adequate renal function (serum creatinine ≤ 1.5 times institutional ULN for age or GFR ≥ 70 ml/min/1.73 m2) before starting therapy.
    • Patients must have cholesterol level <350 mg/dL and triglycerides < 400 mg/dL before starting therapy. In case one or both of these are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication and documentation of cholesterol < 350mg/dL and triglycerides < 400mg/dl before start of therapy.
    • Patients must have normal pulmonary function testing for age based on pulse oximetry.
    • The effects of everolimus on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because everolimus are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
    • Female patients of child bearing potential must not be breastfeeding or pregnant as evidenced by a negative pregnancy test.

Exclusion Criteria:

  • Patients with primary spinal cord tumors
  • Patients receiving concomitant medication that may interfere with study outcome. For example, patients cannot be on enzyme inducing anticonvulsants like phenytoin.
  • Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines
  • Hepatitis B/C blood test must be done at screening for all patients. Patients who test positive for Hepatitis C antibodies and the Hepatitis B antigen are ineligible.
  • A known history of HIV seropositivity. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
  • Patients may not have therapy for this recurrence (including radiation).
  • Patients who do not have measurable disease on MRI.
  • Patients who have been previously treated with an mTOR inhibitor.
  • Patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus).
  • Patients receiving any other concurrent anticancer or investigational therapy.
  • Patients with any clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate protocol therapy.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection.
  • Patients with inability to return for follow-up visits to assess toxicity to therapy.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years.

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01734512

Contact: Sabine Mueller, MD 877-827-3222
Contact: PNOC Regulatory 415-502-1600

United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Ghirish Dhall, MD    323-361-8147   
Contact: Ashley Margol, MD   
Principal Investigator: Ghirish Dhall, MD         
Sub-Investigator: Ashley Margol, MD         
University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Tom B Davidson, MD    310-825-6708   
Contact: Anthony Wang   
Principal Investigator: Tom B Davidson, MD         
Sub-Investigator: Anthony Wang, MD         
Children's Hospital Oakland Recruiting
Oakland, California, United States, 94609
Contact: Joseph Torkildson, MD    510-428-3272   
Contact: Caroline Hastings, MD    (510) 428-3272   
Principal Investigator: Joseph Torkildson, MD         
Sub-Investigator: Caroline Hastings, MD         
University of California, San Diego Rady Children's Hospital Recruiting
San Diego, California, United States, 92123
Contact: John Crawford, MD,MS    858-966-4930   
Contact: Jennifer Elster, MD   
Principal Investigator: John Crawford, MD,MS         
Sub-Investigator: Janet Elster, MD         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Sabine Mueller, MD    877-827-3222   
Contact: Anu Banerjee, MD   
Principal Investigator: Sabine Mueller, MD         
Sub-Investigator: Anu Banerjee, MD         
United States, District of Columbia
Children's National Medical Center Not yet recruiting
Washington, District of Columbia, United States, 20010
Contact: Lindsay Kilburn, MD    202-476-3854   
Contact: Roger Packard, MD   
Principal Investigator: Lindsay Kilburn, MD         
Sub-Investigator: Roger Packard, MD         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32611
Contact: Sridharan Gururangan, FRCP    352-294-8347   
Contact: Duane Mitchell, MD, PhD    352-294-5232   
Principal Investigator: Sridharan Gururangan, FRCP         
Sub-Investigator: Duane Mitchell, MD, PhD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Stewart Goldman, MD    312-227-4873   
Contact: Rishi Lulla, MD    (312) 227-4873   
Principal Investigator: Stewart Goldman, MD         
Sub-Investigator: Rishi Lulla, MD         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21218
Contact: Kenneth Cohen, M.D.   
Contact: Eric Raabe, M.D., PhD.   
Principal Investigator: Kenneth Cohen, M.D.         
Sub-Investigator: Eric Raabe, M.D., PhD.         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Susan Chi, MD    617-632-2291   
Contact: Daphne Haas-Kogan, MD   
Principal Investigator: Susan Chi, MD         
Sub-Investigator: Daphne Haas-Kogan, MD         
United States, Minnesota
Children's Hospitals and Clinics of Minneapolis Recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Christopher Moertel, M.D.    612-626-2778   
Contact: Anne Bendel, M.D.    612-813-5940   
Principal Investigator: Christopher Moertel, M.D.         
Sub-Investigator: Anne Bendel, M.D.         
United States, Missouri
St. Louis Children's Hospital, Washington University Recruiting
Saint Louis, Missouri, United States, 63130
Contact: Karen Gauvain, MD    314-286-2790   
Contact: Josh Rubin, MD   
Principal Investigator: Karen Gauvain, MD         
Sub-Investigator: Josh Rubin, MD         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Jonathan Finlay, MD    614-722-4087   
Contact: Mohamed AbdelBaki, MD   
Principal Investigator: Jonathan Finlay, MD         
Sub-Investigator: Mohamed AbdelBaki, MD         
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Kellie Nazemi, MD    503-494-1543   
Contact: Rebecca Loret De Mola, DO,MCR   
Principal Investigator: Kellie Nazemi, MD         
Sub-Investigator: Rebecca Loret De Moya, DO,MCR         
United States, Pennsylvania
The Children's Hospital Of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Jane Minturn, MD, PhD    267-426-5026   
Contact: Angela Waanders, MD, MPH   
Principal Investigator: Jane Minturn, MD, PhD         
Sub-Investigator: Angela Waanders, MD, MPH         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Amar Gajjar, MD    901-595-2615    Amar.Gajjar@STJUDE.ORG   
Contact: Ibrahim Qaddoumi, MD    901-595-2365   
Principal Investigator: Amar Gajjar, MD         
Sub-Investigator: Ibrahim Qaddoumi, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Nicholas Whipple, MD,MPH    801-662-4700   
Contact: Carol Bruggers, MD    801-662-4700   
Principal Investigator: Nicholas Whipple, MD,MPH         
Sub-Investigator: Carol Bruggers, MD         
United States, Washington
University of Washington, Seattle Recruiting
Seattle, Washington, United States, 98195
Contact: Sarah Leary, MD    206-667-7955   
Contact: Nick Vitanza, MD    206-667-7955   
Principal Investigator: Sarah Leary, MD         
Sub-Investigator: Nick Vitanza, MD         
Sponsors and Collaborators
University of California, San Francisco
Novartis Pharmaceuticals
Pacific Pediatric Neuro-Oncology Consortium
The Pediatric Low Grade Astrocytoma Foundation
Study Chair: Daphne Haas-Kogan, MD Harvard University Dana-Farber Institute
Principal Investigator: Sabine Mueller, MD University of California, San Francisco

Responsible Party: University of California, San Francisco Identifier: NCT01734512     History of Changes
Other Study ID Numbers: CC#120817
First Posted: November 27, 2012    Key Record Dates
Last Update Posted: June 20, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of California, San Francisco:
pediatric recurrent progressive low-grade gliomas
pediatric progressive low-grade gliomas
mTOR inhibition

Additional relevant MeSH terms:
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents