Panobinostat in Treating Younger Patients with Diffuse Intrinsic Pontine Glioma

Status: Active

Description

This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma. Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patient must be able to swallow capsules whole
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients must have had their last fraction of: * Craniospinal 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Absolute neutrophil count >= 1,000/mm^3
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Hemoglobin >= 8 g/dl (may receive transfusions)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Albumin >= 3 g/dl
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Potassium >= lower limit of normal (LLN)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Serum total calcium (correct for serum albumin) or ionized calcium >= LLN
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Female patients of childbearing potential must have a negative serum or urine pregnancy test
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • NON-PROGRESSED DIPG (STRATUM 2): Patients with DIPG who have not yet progressed by clinical or radiographic criteria * 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
  • NON-PROGRESSED DIPG (STRATUM 2): 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 10mg/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
  • NON-PROGRESSED DIPG (STRATUM 2): Patient must be able to swallow capsules whole
  • NON-PROGRESSED DIPG (STRATUM 2): 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
  • NON-PROGRESSED DIPG (STRATUM 2): Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment; patients must not have received any other prior therapy for treatment of their central nervous system (CNS) malignancy besides standard radiation therapy
  • NON-PROGRESSED DIPG (STRATUM 2): Patients must have recovered from the acute treatment-related toxicities (defined as =< grade 1) of radiotherapy prior to entering this study
  • NON-PROGRESSED DIPG (STRATUM 2): Patients must have had their last fraction of focal irradiation to the primary site > 14 days prior to enrollment; patients must not have received local palliative irradiation or craniospinal irradiation
  • NON-PROGRESSED DIPG (STRATUM 2): Absolute neutrophil count >= 1,000/mm^3
  • NON-PROGRESSED DIPG (STRATUM 2): Platelets >= 100,000/ mm^3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir)
  • NON-PROGRESSED DIPG (STRATUM 2): Hemoglobin >= 8 g/dl (may receive transfusions)
  • NON-PROGRESSED DIPG (STRATUM 2): Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
  • NON-PROGRESSED DIPG (STRATUM 2): ALT(SGPT) =< 3 x institutional upper limit of normal
  • NON-PROGRESSED DIPG (STRATUM 2): Albumin >= 3 g/dl
  • NON-PROGRESSED DIPG (STRATUM 2): Potassium >= LLN
  • NON-PROGRESSED DIPG (STRATUM 2): Serum total calcium (correct for serum albumin) or ionized calcium >= LLN
  • NON-PROGRESSED DIPG (STRATUM 2): 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)
  • NON-PROGRESSED DIPG (STRATUM 2): Left ventricular ejection fraction >= 50 by gated radionuclide study OR shortening fraction of >= 27% by echocardiogram
  • NON-PROGRESSED DIPG (STRATUM 2): Patient has no ventricular arrhythmias except for benign premature ventricular contractions
  • NON-PROGRESSED DIPG (STRATUM 2): Patient has a QTc interval < 450 ms
  • NON-PROGRESSED DIPG (STRATUM 2): 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 PEG formulations
  • NON-PROGRESSED DIPG (STRATUM 2): Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study
  • NON-PROGRESSED DIPG (STRATUM 2): Female patients of childbearing potential must have a negative serum or urine pregnancy test
  • NON-PROGRESSED DIPG (STRATUM 2): 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
  • NON-PROGRESSED DIPG (STRATUM 2): 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

  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation)
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have had prior histone deacetylase (HDAC), deacetylase (DAC), heat shock protein 90 (HSP90) inhibitors for the treatment of their DIPG
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have had valproic acid within 28 days prior to enrollment
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have had prior bone marrow transplant
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have any other significant concurrent illness
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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 ability of the patient to tolerate protocol therapy or put them at additional risk for toxicity or would interfere with the study procedures or results
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have a history of any other malignancy
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients are known to be refractory to red blood cell or platelet transfusions
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients who are receiving any other anticancer or investigational drug therapy
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients who are required to receive any medication which can prolong the QTc interval
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Female patient is breastfeeding
  • RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
  • NON-PROGRESSED DIPG (STRATUM 2): Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation
  • NON-PROGRESSED DIPG (STRATUM 2): Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician
  • NON-PROGRESSED DIPG (STRATUM 2): Patients have impairment of GI function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease
  • NON-PROGRESSED DIPG (STRATUM 2): Patients have diarrhea > CTCAE grade 2
  • NON-PROGRESSED DIPG (STRATUM 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 ability of the patient to tolerate protocol therapy or put them at additional risk for toxicity or would interfere with the study procedures or results
  • NON-PROGRESSED DIPG (STRATUM 2): Patients have a history of any other malignancy
  • NON-PROGRESSED DIPG (STRATUM 2): Patients are known to be refractory to red blood cell or platelet transfusions
  • NON-PROGRESSED DIPG (STRATUM 2): Patients who are receiving any other anticancer or investigational drug therapy
  • NON-PROGRESSED DIPG (STRATUM 2): Patients who are required to receive any medication which can prolong the QTc interval
  • NON-PROGRESSED DIPG (STRATUM 2): Female patient is breastfeeding
  • NON-PROGRESSED DIPG (STRATUM 2): 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

Locations & Contacts

California

Los Angeles
Children's Hospital Los Angeles
Status: Active
Contact: Site Public Contact
Phone: 323-361-4110
Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: Active
Contact: Site Public Contact
Phone: 800-694-0012
Email: ccto-office@stanford.edu

District of Columbia

Washington
Children's National Medical Center
Status: Active
Contact: Site Public Contact
Phone: 202-884-2549

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: Active
Contact: Site Public Contact
Phone: 773-880-4562

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 800-411-1222

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592

Ohio

Cincinnati
Cincinnati Children's Hospital Medical Center
Status: Active
Contact: Site Public Contact
Phone: 513-636-2799
Email: cancer@cchmc.org

Pennsylvania

Pittsburgh
Children's Hospital of Pittsburgh of UPMC
Status: Active
Contact: Site Public Contact
Phone: 412-692-8570
Email: jean.tersak@chp.edu

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 866-278-5833
Email: info@stjude.org

Texas

Houston
Texas Children's Hospital
Status: Active
Contact: Site Public Contact
Phone: 888-823-5923
Email: ctsucontact@westat.com

Trial Objectives and Outline

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). (Recurrent/progressive DIPG [Stratum 1])

II. To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of panobinostat in children with recurrent/progressive DIPG. (Recurrent/progressive DIPG [Stratum 1])

III. To evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG. (Recurrent/progressive DIPG [Stratum 1])

IV. To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with non-progressed DIPG treated with 3 times/week, every other week. (Non-progressed DIPG [Stratum 2])

V. To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of panobinostat administered 3 times/week, every other week in children with non-progressed DIPG. (Non-progressed DIPG [Stratum 2])

VI. To evaluate and characterize the plasma pharmacokinetics of panobinostat administered 3 times/week, every other week in children with non-progressed DIPG. (Non-progressed DIPG [Stratum 2])

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. (Recurrent/progressive DIPG [Stratum 1])

II. To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment. (Recurrent/progressive DIPG [Stratum 1])

III. To describe the progression-free survival (PFS) and overall survival (OS) of children with non-progressed DIPG who are treated with panobinostat. (Non-progressed DIPG [Stratum 2])

IV. To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment. (Non-progressed DIPG [Stratum 2])

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.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Pediatric Brain Tumor Consortium

Principal Investigator
Michelle Monje

Trial IDs

Primary ID PBTC-047
Secondary IDs NCI-2015-01919, NCT02899715
Clinicaltrials.gov ID NCT02717455