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

• ClinicalTrials.gov Identifier: NCT01734512
• Recruitment Status: Active, not recruiting
• First Posted: November 27, 2012
• Results First Posted: February 18, 2021
• Last Update Posted: December 27, 2023
• Sponsor: University of California, San Francisco
• Collaborators: Novartis Pharmaceuticals; Pacific Pediatric Neuro-Oncology Consortium; The Pediatric Low Grade Astrocytoma (PLGA) Foundation
• Information provided by (Responsible Party): University of California, San Francisco

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Pediatric Recurrent Progressive Low-grade Gliomas; Pediatric Progressive Low-grade Gliomas
• Intervention: Drug: Everolimus
• Enrollment: 65

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Everolimus
Arm/Group Description	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 body surface area (BSA) 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. Everolimus: Everolimus tablet will be taken daily by mouth with water. All patients will be given a dose of 5 mg/m2/dose daily.
Period Title: Overall Study
Started	65
Completed	65
Not Completed	0

Baseline Characteristics

Arm/Group Title		Everolimus
Arm/Group Description		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 body surface area (BSA) 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. Everolimus: Everolimus tablet will be taken daily by mouth with water. All patients will be given a dose of 5 mg/m2/dose daily.
Overall Number of Baseline Participants		65
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	65 participants
3-9 years old		35 53.8%
10-21 years old		30 46.2%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	65 participants
	Female	29 44.6%
	Male	36 55.4%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	65 participants
	Hispanic or Latino	15 23.1%
	Not Hispanic or Latino	47 72.3%
	Unknown or Not Reported	3 4.6%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	65 participants
	American Indian or Alaska Native	0 0.0%
	Asian	2 3.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	1 1.5%
	White	47 72.3%
	More than one race	1 1.5%
	Unknown or Not Reported	14 21.5%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	65 participants
		65

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Progression Free Survival at 6 Months
Description	Response was 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.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description:	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 body surface area (BSA) 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. Everolimus: Everolimus tablet will be taken daily by mouth with water. All patients will be given a dose of 5 mg/m2/dose daily.
Overall Number of Participants Analyzed	65
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage
	67; (54 to 77)

2. Secondary Outcome

Title	Proportion of Participants With Objective Response
Description	The proportion of participants who demonstrated a complete or partial response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1 Criteria where complete Response (CR) is defined as the complete disappearance of all known disease for >=8 weeks. Complete response is dated from time all lesions have disappeared on a stable or decreasing dose of corticosteroids. A Partial Response (PR) is a reduction of at least 50% in the size of all measurable tumor as quantitated by sum of the products of the largest diameters (SLD) of measurable lesions and maintained for >=8 weeks on a stable or decreasing dose of corticosteroids. Partial response is dated from the time of first observation. Overall response also takes into account the response in both the target and non-target lesion, and the appearance of new lesions, where applicable and depend on the achievement of both measurement and confirmation criteria.
Time Frame	Up to 6 months

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	Median Progression Free Survival in Recurrent Pediatric Low-grade Glioma (LGGs)
Description	Progression free survival will be calculated from date of first treatment to the date of first observation of progressive disease, non-reversible neurological progression or increasing steroid requirements (applies to stable disease only), death due to any cause, or early discontinuation of treatment
Time Frame	Up to 5 years

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	Median Overall Survival in Recurrent Pediatric LGGs
Description	Overall survival will be calculated from date of original diagnoses to death and also from the date of study registration to death. The latter will be an endpoint for assessment of benefit of this therapy.
Time Frame	Up to 5 years

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Up to 5 years
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Everolimus
Arm/Group Description	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 body surface area (BSA) 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. Everolimus: Everolimus tablet will be taken daily by mouth with water. All patients will be given a dose of 5 mg/m2/dose daily.
All-Cause Mortality
	Everolimus
	Affected / at Risk (%)
Total	5/65 (7.69%)
Serious Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	20/65 (30.77%)
Ear and labyrinth disorders
Hearing Impaired † 1	1/65 (1.54%)	1
Gastrointestinal disorders
Vomiting † 1	1/65 (1.54%)	2
General disorders
Edema face † 1	1/65 (1.54%)	1
Fever † 1	2/65 (3.08%)	4
Infections and infestations
Sepsis † 1	1/65 (1.54%)	1
Catheter related infection † 1	1/65 (1.54%)	1
Infections and infestations - Other † 1	1/65 (1.54%)	1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other † 1	2/65 (3.08%)	5
Metabolism and nutrition disorders
Dehydration † 1	2/65 (3.08%)	2
Hypernatremia † 1	1/65 (1.54%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other † 1	3/65 (4.62%)	3
Nervous system disorders
Seizure † 1	2/65 (3.08%)	2
Cognitive disturbance † 1	1/65 (1.54%)	1
Hydrocephalus † 1	6/65 (9.23%)	11
Encephalopathy † 1	1/65 (1.54%)	1
Headache † 1	2/65 (3.08%)	4
Respiratory, thoracic and mediastinal disorders
Respiratory failure † 1	1/65 (1.54%)	1
Skin and subcutaneous tissue disorders
Skin infection † 1	2/65 (3.08%)	2
Surgical and medical procedures
Surgical and medical procedures - Other † 1	1/65 (1.54%)	1
Vascular disorders
Hypertension † 1	1/65 (1.54%)	1
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Everolimus
	Affected / at Risk (%)	# Events
Total	62/65 (95.38%)
Blood and lymphatic system disorders
Anemia † 1	18/65 (27.69%)	47
Cardiac disorders
Sinus tachycardia † 1	8/65 (12.31%)	13
Gastrointestinal disorders
Mucositis oral † 1	35/65 (53.85%)	93
Diarrhea † 1	15/65 (23.08%)	30
Nausea † 1	14/65 (21.54%)	16
Vomiting † 1	11/65 (16.92%)	13
Oral pain † 1	8/65 (12.31%)	11
Abdominal pain † 1	7/65 (10.77%)	8
Gastrointestinal disorders - Other † 1	5/65 (7.69%)	6
Stomach pain † 1	4/65 (6.15%)	7
General disorders
Fatigue † 1	25/65 (38.46%)	36
Fever † 1	9/65 (13.85%)	18
Pain † 1	4/65 (6.15%)	4
Infections and infestations
Upper respiratory infection † 1	8/65 (12.31%)	9
Investigations
Cholesterol high † 1	34/65 (52.31%)	63
Aspartate aminotransferase increased † 1	30/65 (46.15%)	62
Alanine aminotransferase increased † 1	26/65 (40.00%)	58
Neutrophil count decreased † 1	19/65 (29.23%)	38
Lymphocyte count decreased † 1	15/65 (23.08%)	25
White blood cell decreased † 1	15/65 (23.08%)	46
Platelet count decreased † 1	14/65 (21.54%)	23
Investigations - Other † 1	11/65 (16.92%)	27
Weight loss † 1	6/65 (9.23%)	8
Alkaline phosphatase increased † 1	5/65 (7.69%)	6
Creatinine increased † 1	4/65 (6.15%)	8
Metabolism and nutrition disorders
Hypertriglyceridemia † 1	34/65 (52.31%)	98
Hyperglycemia † 1	16/65 (24.62%)	27
Hypophosphatemia † 1	14/65 (21.54%)	21
Hypokalemia † 1	13/65 (20.00%)	30
Anorexia † 1	9/65 (13.85%)	12
Hypernatremia † 1	9/65 (13.85%)	19
Metabolism and nutrition disorders - Other † 1	6/65 (9.23%)	10
Hypomagnesemia † 1	5/65 (7.69%)	7
Hypercalcemia † 1	4/65 (6.15%)	4
Hyponatremia † 1	4/65 (6.15%)	11
Musculoskeletal and connective tissue disorders
Pain in extremity † 1	4/65 (6.15%)	5
Musculoskeletal and connective tissue disorder - Other † 1	4/65 (6.15%)	5
Nervous system disorders
Headache † 1	19/65 (29.23%)	36
Dizziness † 1	5/65 (7.69%)	5
Respiratory, thoracic and mediastinal disorders
Cough † 1	7/65 (10.77%)	9
Sore throat † 1	7/65 (10.77%)	10
Epistaxis † 1	6/65 (9.23%)	7
Nasal congestion † 1	5/65 (7.69%)	6
Respiratory, thoracic and mediastinal disorders - Other † 1	4/65 (6.15%)	4
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	12/65 (18.46%)	17
Dry skin † 1	5/65 (7.69%)	5
Rash acneiform † 1	4/65 (6.15%)	4
Skin and subcutaneous tissue disorders - Other † 1	4/65 (6.15%)	4
Vascular disorders
Hypertension † 1	6/65 (9.23%)	15
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Sabine Mueller, MD, PhD
• Organization: University of California, San Francisco
• Phone: (415) 502-7301
• EMail: sabine.mueller@ucsf.edu

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01734512
• Other Study ID Numbers: 120817; NCI-2012-02774 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
• First Submitted: November 21, 2012
• First Posted: November 27, 2012
• Results First Submitted: January 14, 2021
• Results First Posted: February 18, 2021
• Last Update Posted: December 27, 2023