Panobinostat in Treating Younger Patients With Progressive Diffuse Intrinsic Pontine Glioma

Diffuse Intrinsic Pontine Glioma Clinical Trial

Official title:

Phase I Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02899715
• Other study ID #: NCI-2015-01919
• Secondary ID: NCI-2015-01919PB
• Status: Recruiting
• Phase: Phase 1
• First received: September 13, 2016
• Last updated: November 1, 2016
• Start date: April 2016

Study information

• Verified date: November 2016
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma that is growing, spreading, or getting worse (progressive). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Description:

PRIMARY OBJECTIVES:

I. To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with recurrent/progressive diffuse intrinsic pontine glioma (DIPG).

II. To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of panobinostat in children with recurrent/progressive DIPG.

III. To evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG.

SECONDARY OBJECTIVES:

I. To describe the progression-free survival (PFS) and overall survival (OS) of children with recurrent or progressive DIPG who are treated with panobinostat.

II. To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment.

OUTLINE: This is a dose-escalation study.

Patients receive panobinostat orally (PO) thrice weekly for 3 weeks. Treatment repeats every 28 days for 26 courses (2 years) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months for 3 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. primary completion date: October 2019
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 21 Years

Eligibility

Inclusion Criteria:

• Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since diagnosis, OR the appearance of a new tumor lesion since diagnosis

• Please note: patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation

• Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma World Health Organization (WHO) II-IV

• Body surface area (BSA)

• Patients must have a BSA >= 0.80 m^2 for dose 5 mg/m^2

• Patients must have a BSA >= 0.65 m^2 for doses of 10 mg/m^2-22 mg/m^2

• Patients must have a BSA >= 0.50 m^2 for doses of 28 mg/m^2-36 mg/m^2

• Patient must be able to swallow capsules whole

• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within 7 days of enrollment must be >= 50%; patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

• Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment; patients must have recovered from the acute treatment-related toxicities (defined as =< grade 1) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Patients must have received their last dose of known myelosuppressive anticancer therapy or immunotherapy at least 21 days prior to enrollment (42 days if prior nitrosourea)

• Biologic or investigational agent (anti-neoplastic): patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment

• For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur, and discussed with the principal investigator

• Monoclonal antibody treatment and agents with known prolonged half-lives: at least three half-lives must have elapsed prior to enrollment

• Note: A list of the half-lives of commonly used monoclonal antibodies is available on the Pediatric Brain Tumor Consortium (PBTC) webpage under Generic Forms and Templates

• Patients must have had their last fraction of:

• Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment

• Focal irradiation to the primary site > 42 days prior to enrollment

• Local palliative irradiation other than previously irradiated primary site (small port) >= 14 days

• Absolute neutrophil count >= 1,000/mm^3

• Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir)

• Hemoglobin >= 8 g/dl (may receive transfusions)

• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)

• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal

• Albumin >= 3 g/dl

• Potassium >= lower limit of normal (LLN)

• Serum total calcium (correct for serum albumin) or ionized calcium >= LLN

• Serum creatinine based on age/gender as noted below; patients that do not meet the criteria below but have a 24-hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible

• 2 to < 6 years: 0.8 mg/dL

• 6 to < 10 years: 1 mg/dL

• 10 to < 13 years: 1.2 mg/dL

• 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)

• >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)

• Cardiac function:

• Left ventricular ejection fraction >= 50 by gated radionuclide study OR shortening fraction of >= 27% by echocardiogram

• Patient has no ventricular arrhythmias except for benign premature ventricular contractions

• Patient has a corrected QT (QTc) interval =< 450 ms

• Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin); 14 days must have elapsed if patients received poly(ethylene glycol) (PEG) formulations

• Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study

• Female patients of childbearing potential must have a negative serum or urine pregnancy test

• Female patients with an infant must agree not to breastfeed their infants while on this study

• Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 3 months after the last dose of panobinostat

• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

Exclusion Criteria:

• Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation)

• Patients have had prior histone deacetylase (HDAC), deacetylase (DAC), heat shock protein 90 (HSP90) inhibitors for the treatment of their DIPG

• Patients have had valproic acid within 28 days prior to enrollment

• Patients have had prior bone marrow transplant

• Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician

• Patients have any other significant concurrent illness

• Patients have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease

• Patients have diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 2

• Patients have any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures, assessments, or results

• Patients have a history of any other malignancy

• Patients are known to be refractory to red blood cell or platelet transfusions

• Patients who are receiving any other anticancer or investigational drug therapy

• Patients who are required to receive any medication which can prolong the QTc interval

• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Glioma

Intervention

Other:
• Laboratory Biomarker Analysis
Optional correlative studies

Drug:
• Panobinostat
Given PO

Other:
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Texas Children's Hospital	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Pediatric Brain Tumor Consortium	Memphis	Tennessee
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of panobinostat, defined as the dose level at which at least 6 patients have been treated and the algorithm does not recommend escalation or de-escalation		28 days	Yes
Secondary	Changes in histone 3 K27M mutations in peripheral blood and urine samples	For cell-free deoxyribonucleic acid based assays where the intent is to determine whether K27 mutations can be detected in patients' blood or urine, the percentage of patients in whom this mutation is detected within each stratum and at each time point will be estimated. Changes across time within a patient will be numerically summarized.	Baseline to up to day 1 of course 12	No
Secondary	Duration of response	Duration of response as well as dose levels at which such responses were observed will be reported.	Up to 3 years	No
Secondary	Objective response	Any objective responses that have been observed along as well as dose levels at which such responses were observed will be reported.	Up to 3 years	No
Secondary	Overall survival (OS)	OS will be estimated. Various PK parameters will be correlated with OS, as feasible.	Up to 3 years	No
Secondary	Pharmacokinetic (PK) parameters of panobinostat (apparent volume of the central compartment [Vc/F], elimination rate constant [Ke], half-life [t1/2], apparent oral clearance [CL/F], and area under the plasma concentration time curve [AUC])	Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as apparent Vc/F, Ke, t1/2, CL/F, and AUC will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will also be investigated. As feasible, the associations between PK parameters and clinical and demographic variables such as disease status and number of prior treatment, age, body surface area, steroid use or concomitant medications will be investigated. In addition to estimating individual pharmacokineti	Day 1: pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours after dose; day 3: pre-dose	No
Secondary	Progression free survival	PFS will be estimated. Various PK parameters will be correlated with PFS, as feasible.	Time of treatment initiation until the time of progressive disease or death from any cause in patients with an event and until the time of last follow-up for patients who are progression free at the time of analysis, assessed up to 3 years	No