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Radiopharmaceuticals

Tyrosine

Participants with intracranial neoplasms (glial or metastatic disease) with concern for recurrence or progression on conventional imaging (e.g., MRI) will receive F-18 fluoroethyltyrosine (FET) injected intravenously over approximately 1 minute and receive a single PET image lasting up to 40 minutes. Repeat FET PET will be offered to adult patients.

Participants with suspected glial neoplasms (Grade 2-4) planning to undergo a non-investigational biopsy or surgery prior to non-investigational, primary treatment (radiation therapy and/or surgery) will receive F-18 fluoroethyltyrosine (FET) injected intravenously over approximately 1 minute and receive a single PET image lasting up to 40 minutes. Repeat FET PET will be offered to adult patients.

Patients given an injected dose of 4 to 7 millicurie (mCi) of FET per scan. The radiopharmaceutical will be administered while the patient is in the PET scanner

F-18 Fluoroethyltyrosine (FET)

All patients receive single PET imaging lasting for 40 minutes. Acquired PET data will be reconstructed so that three time points are created: (1) Perfusion: 60-second acquisition that starts immediately when activity is noted in the field of view, (2) Equilibrium: 10-minute acquisition acquired between 10 and 20 minutes after injection, and (3) Washout: 10-minute acquisition acquired between 30 and 40 minutes after injection. A repeat PET image will be offered to adult patients.

Positron Emission Tomography (PET)

Thomas A Hope, MD

This phase II trial studies how well F-18 fluoroethyltyrosine (fluoroethyltyrosine) works in detecting tumors in participants with intracranial tumors that have come back. FET accumulates in malignant cells within intracranial neoplasms and can be used to detect recurrent disease and characterize the grade of glial neoplasms. Imaging agents such as FET can help oncologist to see the tumor better during a positron emission tomography (PET) scan.

PRIMARY OBJECTIVES:

I. To determine if F-18 fluoroethyltyrosine (FET) PET can differentiate between benign treatment-related changes and recurrence in comparison to pathology in population 1 with recurrent metastatic disease and high-grade gliomas.

II. To determine if FET PET can accurately differentiate between low-grade and high-grade gliomas in population 2.

SECONDARY OBJECTIVES:

I. To determine if FET PET can differentiate between benign treatment-related changes and recurrence in comparison to pathology or imaging follow-up in population 1.

II. To determine if FET PET can differentiate between benign treatment-related changes and recurrence in comparison to pathology in population 1 with recurrent low-grade gliomas.

OUTLINE:

Participants receive F-18 fluoroethyltyrosine intravenously (IV) over approximately 1 minute and undergo PET over 40 minutes. After completion of study treatment, participants are followed up periodically.

Fluoroethyltyrosine for Evaluation of Intracranial Neoplasms

Fluoroethyltyrosine for the Evaluation of Intracranial Neoplasm

Radiologists will classify lesions as having recurrent disease or not having recurrent disease. True Positives (TP) are defined as an FET PET read positive for tumor and pathology/follow-up demonstrates tumor recurrence in at least one biopsy sample, False positives (FP) are defined as an FET PET read positive for tumor and pathology/follow-up demonstrates negative tumor recurrence in all of the biopsy samples, True negatives (TN) are defined as an FET PET read as negative for tumor and pathology/follow-up also negative tumor recurrence in all of the biopsy samples and a false negative (FN) is defined as an FET PET read as negative for tumor and pathology/follow-up demonstrates tumor recurrence in at least one biopsy sample. Misclassification rate = \[FP+FN)\]/\[FP+FN+TP+TN\]

Readers will have access only to FET PET images for participants with suspected glial neoplasms (Grade 2-4) planning to undergo biopsy or surgery prior to primary treatment during evaluation and will grade the lesions in a binary fashion as having Grade II glial neoplasms or having Grade III/IV glial neoplasms. True positive (TP2): FET PET read as positive for Grade III/IV neoplasm, pathology demonstrates Grade III/IV neoplasm. False positive (FP2): FET PET read as positive for Grade III/IV neoplasm, pathology demonstrates Grade II neoplasm. True negative (TN2): FET PET read as positive for Grade II neoplasm, pathology demonstrates Grade II neoplasm. False negative (FN2): FET PET read as positive for Grade II neoplasm, pathology demonstrates Grade III/IV neoplasm. Misclassification rate = \[FP2+FN2\]/\[FP2+FN2+TP2+TN2\]

Participants with available histology (performed within 4 weeks of FET scans) or follow-up imaging (performed within 6 months of FET scan) will be included and a composite truth standard for recurrence or treatment-related changes will be evaluated for each case. In the absence of pathology, the composite truth standard will use available clinical information to make a determination. Positive for tumor recurrence on follow-up imaging will be based on Response assessment in neuro-oncology criteria (RANO) criteria reads. Follow-up imaging has to be performed within six months of the FET PET imaging study to be considered for evaluation. Additionally, the composite truth standard may consider tumor board notes and subsequent management of the patient to make a determination.

Low-grade glioma is defined by low uptake of FET. Radiologists will classify lesions based on imaging as either having recurrent disease or not having recurrent disease. True Positives (TP1L) are defined as an FET PET read positive for low-grade tumor and pathology/follow-up demonstrates low-grade tumor recurrence in at least one biopsy sample, False positives (FP1L) are defined as an FET PET read positive for low grade tumor recurrence and pathology/follow-up demonstrates negative low-grade tumor recurrence in all of the biopsy samples, True negatives (TN1L) are defined as an FET PET read as negative for low-grade tumor recurrence and pathology/follow-up also negative for low grade tumor recurrence in all of the biopsy samples and a false negative (FN1L) is defined as an FET PET read as negative for low grade tumor recurrence and pathology/follow-up demonstrates low grade tumor recurrence in at least one biopsy sample. Misclassification rate = \[FP1L+FN1L)\]/\[FP1L+FN1L+TP1L+TN1L\]

Fleiss' kappa statistic will be used to determine the agreement between the assessment of FET-PET tumor targeting (tracer uptake in target lesion: yes/ no), as assessed by three independent blinded readers. Scores range from 0 to 1 with higher scores indicating a great degree of agreement

Cohen's kappa statistics will be used to determine the reproducibility of the assessment by individual readers when analyzing the same data repeatedly and measures the agreement between two raters who each classify items into mutually exclusive categories.

Thomas Hope

Assistant Professor

Antineoplastic Agents

Anti-Infective Agents

Everolimus

Sirolimus

Mitogens

Trametinib

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Patients receive dosing per their assigned dose level. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Aubrie Dreschler

Sabine Mueller, MD, PhD, MAS

Girish Dhall, MD

Gregory Friedman, MD

Ashley Margol, MD

Tom Davidson, MD

Jennifer Elster, MD

Aubrie Drechsler

Sabine Mueller, MD, MPH

Lindsay Kilburn, MD

Roger Packer, MD

Elias Sayour, MD, PhD

Angela Waanders, MD, MPH

Scott Coven, DO, MPH

Daniel Runco, MD, MS

Kenneth Cohen, MD, MBA

Eric Raabe, MD, PhD

Susan Chi

Tabitha Cooney

Anne Bendel, MD

Maggie Skrypek, MD

Mohamad AbdelBaki, MD

Josh Rubin, MD, PhD

Derek Hanson, MD

Katharine Offer, MD

Sharon Gardner, MD

Matthew Miller, MD

Christopher Park, MD

Cassie Kline, MD, MAS

Jane Mintrum, MD, PhD

Daniela Westerhold

Faryal Dina

Patricia Baxter, MD

Donald W Parsons, MD, PHD

Sabine Mueller

This phase I trial studies the side effects and best dose of trametinib and everolimus in treating pediatric and young adult patients with gliomas that have come back (recurrent). Trametinib acts by targeting a protein in cells called MEK and disrupting tumor growth. Everolimus is a drug that may block another pathway in tumor cells that can help tumors grow. Giving trametinib and everolimus may work better to treat low and high grade gliomas compared to trametinib or everolimus alone.

PRIMARY OBJECTIVES:

I. To estimate the recommended phase 2 dose (RP2D) of trametinib given orally in combination with everolimus in pediatric and young adult patients with gliomas.

II. To describe the toxicity profile and define the dose limiting toxicities (DLTs) of the combination of trametinib and everolimus in pediatric and young adult patients with recurrent low-grade gliomas (LGG) or high grade glioma (HGG).

III. To characterize the pharmacokinetic profile of trametinib and everolimus when given in combination.

EXPLORATORY OBJECTIVES:

I. To describe the objective response rate and the 2-year progression-free survival (PFS) of LGGs to this therapy in the context of a phase I study.

II. To assess quality of life (QOL) and cognitive measures in pediatric and young adult patients with LGG or HGG.

III. To identify potential predictive biomarkers to targeted therapy in pediatric and young adult patients with LGGs.

IV. To assess endocrine outcomes in pediatric and young adult patients with LGGs.

V. To explore magnetic resonance (MR) quantitative measures of relative cerebral blood volume, permeability and apparent diffusion coefficient within the region of hyperintensity 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).

OUTLINE: This is a dose-escalation study.

Patients receive a combination of trametinib orally (PO) and everolimus in either of two dosing scheduled (continuous and intermittent). Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, then every 6 months for 5 years from the start of therapy.

Trametinib and Everolimus for Treatment of Pediatric and Young Adult Patients With Recurrent Gliomas (PNOC021)

PNOC021: A Phase I Trial Evaluating the Combination of Trametinib and Everolimus in Pediatric and Young Adult Patients With Recurrent Low-Grade Gliomas and High Grade Gliomas

We will employ the Bayesian optimal interval (BOIN) design to find the MTD for both continuous and intermittent dosing schedules. The BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model-based designs, such as the continual reassessment method (CRM).

Toxicities will be graded based on Common Terminology Criteria for Adverse Events (CTCAE) V5 .0 and followed for 30 days after last treatment or until resolution or returned to baseline values.

Any treatment related adverse event during the first cycle of therapy that leads to a dose reduction or results in delay of treatment \> 7 days or which results in the permanent cessation of therapy will be considered dose limiting.

The RP2D rate is selected based on isotonic regression as specified in Liu and Yuan (2015). This computation is implemented by the shiny app "BOIN" available at http://www.trialdesign.org. Specifically, select as the RP2D the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.

Plasma trametinib and everolimus concentration-time data will be analyzed using a classic non-compartmental approach and/or population-based compartmental methods using non-linear mixed effects modeling. Individual pharmacokinetic parameters of interest after single and repeated doses (i.e., maximum plasma concentration Cmax from 0 to 24h will be calculated from the pharmacokinetic model. Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.

Plasma trametinib and everolimus concentration-time data will be analyzed using a classic non-compartmental approach and/or population-based compartmental methods using non-linear mixed effects modeling. Individual pharmacokinetic parameters of interest after single and repeated doses (i.e., area under the curve from 0 to 24h will be calculated from the pharmacokinetic model. Trametinib and everolimus pharmacokinetics after single dose will be compared to trametinib and everolimus pharmacokinetics after repeated doses.

Novartis Pharmaceuticals

Pediatric Brain Tumor Foundation

The Lilabean Foundation for Pediatric Brain Cancer Research

University of California, San Francisco

Principal Investigator

Other Dietary Supplements

Pyruvate

Patients undergo MRI and MRSI scans over 1 hour at baseline. Patients then continue to undergo MRSI scans that follow the clinical MRI schedule set by doctors to monitor patients' care. Participants enrolled in cohort 1 may later enroll in cohort 2 of study once eligibility has been reviewed and approved by neuro-oncologist

Patients undergo MRI scan at baseline. Patients then receive hyperpolarized carbon C 13 pyruvate IV over less than 1 minute and undergo MRSI scan at baseline. Patients then continue to undergo MRSI scans that follow the clinical MRI schedule set by doctors to monitor patients' care.

Hyperpolarized Carbon C 13 Pyruvate

Magnetic Resonance Imaging

Magnetic Resonance Spectroscopic Imaging

Wendy Ma

Susan M. Chang, MD

Susan M Chang, MD

This trial studies how well serial magnetic resonance (MR) imaging and MR spectroscopic imaging work in characterizing lower grade glioma. Diagnostic procedures, such as MR imaging and MR spectroscopic imaging, may detect serial changes in lower grade glioma. This study may help researchers learn more about practical ways of evaluating and standardizing treatment in patients with brain tumors.

PRIMARY OBJECTIVES:

I. To assess the safety and feasibility of hyperpolarized 13C MR metabolic imaging as a new and unique tool for making an early assessment of progression and evaluation of response to therapy in patients with lower grade glioma II. To determine whether changes in levels of hyperpolarized 13C pyruvate, lactate and bicarbonate may provide early evidence of tumor progression in patients with lower grade glioma who are being followed with surveillance scans.

III. To determine whether patients with lower grade glioma who are receiving treatment exhibit a reduction in levels of hyperpolarized 13C lactate/pyruvate at follow-up compared to their baseline scan.

OUTLINE: Patients will be enrolled into Cohort 2. Participants previously enrolled in Cohort 1 may enroll in Cohort 2 of study upon re-review of eligibility.

COHORT 1 (CLOSED TO ENROLLMENT): Patients undergo MR imaging (MRI) and MR spectroscopic imaging (MRSI) scans over 1 hour at baseline. Patients then continue to undergo MRSI scans that follow the clinical MRI schedule set by doctors to monitor patients' care.

COHORT 2: Patients undergo MRI scan at baseline. Patients then receive hyperpolarized carbon C 13 pyruvate intravenously (IV) over less than 1 minute and undergo MRSI scan at baseline. Patients then continue to undergo MRSI scans that follow the clinical MRI schedule set by doctors to monitor patients' care.

Serial MR Imaging and MR Spectroscopic Imaging for the Characterization of Lower Grade Glioma

Metabolic Imaging of Patients With Lower Grade Glioma Using Hyperpolarized 13C Pyruvate

Safety evaluation for endpoint will include monitoring for the occurrence of treatment-emergent adverse events (AEs). Reported toxicities will be graded using the National Cancer Institute (NCI) Common Terminology (Toxicity) Criteria for Adverse Events (CTCAE) version 4.0. All available safety data will be used and will be analyzed using descriptive statistics.

The peak lactate/pyruvate in tumor and normal appearing brain tissue will be reported.

The peak bicarbonate/pyruvate in tumor and normal appearing brain tissue will be reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Fluoroethyltyrosine for Evaluation of Intracranial Neoplasms	NCT04044937	Intracranial Ne... Low Grade Gliom... Recurrent Gliob... Recurrent World... Recurrent WHO G...	F-18 Fluoroethy... Positron Emissi...	3 Years -	University of California, San Francisco
Trametinib and Everolimus for Treatment of Pediatric and Young Adult Patients With Recurrent Gliomas (PNOC021)	NCT04485559	Recurrent World... Low-grade Gliom... High Grade Glio...	Everolimus Trametinib	1 Year - 25 Years	University of California, San Francisco
Serial MR Imaging and MR Spectroscopic Imaging for the Characterization of Lower Grade Glioma	NCT04540107	Recurrent World... Recurrent WHO G... WHO Grade II Gl... WHO Grade III G...	Hyperpolarized ... Magnetic Resona... Magnetic Resona...	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for recurrent world health organization (who) grade ii glioma