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

Study Description

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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 Design

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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

Arms and Interventions

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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.

Outcome Measures

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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.

Eligibility Criteria

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

Criteria

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 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.

Contacts and Locations

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Contacts

Contact: Sabine Mueller, MD	415-476-3831	sabine.mueller@ucsf.edu
Contact: PNOC Regulatory	415-502-1600	PNOC_Regulatory@ucsf.edu

Locations

United States, California
Children's Hospital Los Angeles	Recruiting
Los Angeles, California, United States, 90027
Contact: Ghirish Dhall, MD 323-361-8147 GDhall@chla.usc.edu
Contact: Ashley Margol, MD amargol@chla.usc.edu
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 tdavidson@mednet.ucla.edu
Contact: Anthony Wang acwang@mednet.ucla.edu
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 jtorkildson@mail.cho.org
Contact: Caroline Hastings, MD (510) 428-3272 chastings@mail.cho.org
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 858-966-4930 jrcrawford@rchsd.org
Contact: Janet Yoon, MD jyoon@rchsd.org
Principal Investigator: John Crawford, MD
Sub-Investigator: Janet Yoon, MD
University of California, San Francisco	Recruiting
San Francisco, California, United States, 94158
Contact: Sabine Mueller, MD 415-476-3831 sabine.mueller@ucsf.edu
Contact: Anu Banerjee, MD anu.banerjee@ucsf.edu
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 lkilburn@cnmc.org
Contact: Roger Packard, MD rpackard@nmc.org
Principal Investigator: Lindsay Kilburn, MD
Sub-Investigator: Roger Packard, MD
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 sgoldman@luriechildrens.org
Contact: Jason Fangusaro, MD jfangusaro@luriechildrens.org
Principal Investigator: Stewart Goldman, MD
Sub-Investigator: Jason Fangusaro, MD
United States, Massachusetts
Dana-Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02215
Contact: Susan Chi, MD 617-632-2291 susan_chi@dfci.harvard.edu
Contact: Daphne Haas-Kogan, MD dhaas-kogan@lroc.harvard.edu
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, MD 612-626-2778 moert001@umn.edu
Contact: Anne Bendel, MD 612-813-5940 anne.bendel@childrensmn.org
United States, Missouri
St. Louis Children's Hospital, Washington University	Recruiting
Saint Louis, Missouri, United States, 63130
Contact: Karen Gauvain, MD 314-286-2790 gauvain_k@kids.wustl.edu
Contact: Josh Rubin, MD rubin_j@kids.wustl.edu
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 jonathan.finlay@nationwidechildrens.org
Contact: Mohamed AbdelBaki, MD mohamed.abdelbaki@NationwideChildrens.org
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 nazemik@ohsu.edu
Principal Investigator: Kellie Nazemi, MD
United States, Pennsylvania
The Children's Hospital Of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Jane Minturn, MD, PhD 267-426-5026 MINTURN@email.chop.edu
Contact: Michael Fisher, MD FISHERM@email.chop.edu
Principal Investigator: Jane Minturn, MD, PhD
Sub-Investigator: Michael Fisher, MD
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 ibrahim.qaddoumi@stjude.org
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: Richard Lemons, MD 801-662-4700 richard.lemons@intermountainmail.org
Contact: Carol Bruggers, MD 801-662-4700 carol.bruggers@imail.org
Principal Investigator: Richard Lemons, MD
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 sarah.leary@seattlechildrens.org
Contact: Russ Geyer, MD 206-667-7955 russ.geyer@seattlechildrens.org
Principal Investigator: Sarah Leary, MD
Sub-Investigator: Russ Geyer, MD

Sponsors and Collaborators

University of California, San Francisco

Novartis Pharmaceuticals

Pacific Pediatric Neuro-Oncology Consortium

The Pediatric Low Grade Astrocytoma Foundation

Investigators

Study Chair:	Daphne Haas-Kogan, MD	Harvard University Dana-Farber Institute
Principal Investigator:	Sabine Mueller, MD	University of California, San Francisco

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT01734512 History of Changes
Other Study ID Numbers:	CC#120817
First Posted:	November 27, 2012
Last Update Posted:	April 13, 2018
Last Verified:	April 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; everolimus; mTOR inhibition

Additional relevant MeSH terms:

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Everolimus	Sirolimus; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents