Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma (PBTC-047)

Study Description

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Brief Summary:

This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma (DIPG). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stratum 1 treats patients with DIPG that has returned or gotten worse (progressed). Stratum 2 treats patients with DIPG that has not yet gotten worse.

Currently, only Stratum 2 is enrolling patients.

Condition or disease	Intervention/treatment	Phase
Glioma	Drug: LBH589	Phase 1

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	40 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase 1 Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma
Actual Study Start Date :	June 28, 2016
Estimated Primary Completion Date :	October 1, 2019
Estimated Study Completion Date :	October 1, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Treatment (STRATUM 1); Patients with recurrent/progressive DIPG will be enrolled at the time of progression. All patients will take the study drug panobinostat (LBH589).	Drug: LBH589; STRATUM 1: Recurrent/progressive DIPG. Panobinostat will be given every other day, 3 times/ week, p.o. preferably on Mon/Wed/Fri, for three weeks, followed by one week off of therapy. Three weeks of therapy plus the one week rest period (4 weeks) will constitute one course. Treatment will continue for up to 26 courses (about 2 years) barring progressive disease or unacceptable toxicity. STRATUM 2: Non-progressed DIPG. Panobinostat will be given every other day, 3 times/week, every other week p.o. preferably on Mon/Wed/Fri. Four weeks will constitute one course. Treatment will continue for up to 26 courses (about 2 years) unless the patient experiences progressive disease, unacceptable toxicity or any of the off-treatment criteria.; Other Name: Panobinostat
Experimental: Treatment (STRATUM 2); Patients with non-progressed DIPG will be enrolled. All patients will take the study drug panobinostat (LBH589).	Drug: LBH589; STRATUM 1: Recurrent/progressive DIPG. Panobinostat will be given every other day, 3 times/ week, p.o. preferably on Mon/Wed/Fri, for three weeks, followed by one week off of therapy. Three weeks of therapy plus the one week rest period (4 weeks) will constitute one course. Treatment will continue for up to 26 courses (about 2 years) barring progressive disease or unacceptable toxicity. STRATUM 2: Non-progressed DIPG. Panobinostat will be given every other day, 3 times/week, every other week p.o. preferably on Mon/Wed/Fri. Four weeks will constitute one course. Treatment will continue for up to 26 courses (about 2 years) unless the patient experiences progressive disease, unacceptable toxicity or any of the off-treatment criteria.; Other Name: Panobinostat

Outcome Measures

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Primary Outcome Measures :

1. To describe the toxicity profile and the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG [ Time Frame: 26 courses (approximately 2 years) ]
   Adverse Events
2. To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of panobinostat in children with recurrent/progressive DIPG [ Time Frame: Course 1 (the first 4 weeks of treatment) ]
   Dose Finding
3. To evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG [ Time Frame: Course 1, Day 1 and Day 3 sample collections ]
   Plasma Pharmacokinetics
4. 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. [ Time Frame: 26 courses (approximately 2 years) ]
   Adverse Events
5. 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 [ Time Frame: Course 1 (the first 4 weeks of treatment) ]
   Dose Finding
6. To evaluate and characterize the plasma pharmacokinetics of panobinostat administered 3 times/week, every other week in children with non-progressed DIPG [ Time Frame: Course 1, Day 1 and Day 3 sample collections ]
   Plasma Pharmacokinetics

Secondary Outcome Measures :

1. To describe the progression-free survival (PFS) and overall survival (OS) of children with recurrent or progressive DIPG who are treated with panobinostat [ Time Frame: 26 courses (approximately 2 years) ]
   Evaluated Response per imaging or clinical progression
2. To describe the progression-free survival (PFS) and overall survival (OS) of children with non-progressed DIPG who are treated with panobinostat [ Time Frame: 26 courses (approximately 2 years) ]
   Evaluated Response per imaging or clinical progression
3. To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment. [ Time Frame: Day 1 of courses 1, 2, 4, 6, and 12 ]
   Pharmacodynamics: Cell-free DNA - Blood and Urine (Optional)

Eligibility Criteria

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Ages Eligible for Study:	2 Years to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

STRATUM 1 - INCLUSION CRITERIA

• DIAGNOSIS - 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 WHO II-IV.
• AGE - Patients must be ≥ 2 but < 22 years of age at the time of enrollment.

• BSA

  • Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2.
  • Patients must have a BSA ≥ 0.65 m2 for doses of 10mg/m2 - 22 mg/m2.
  • Patients must have a BSA ≥ 0.50 m2 for doses of 28 mg/m2 - 36 mg/m2.
• ABILITY TO SWALLOW - Patient must be able to swallow capsules whole.
• PERFORMANCE STATUS - 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.
• PRIOR THERAPY - 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.
• MYELOSUPPRESSIVE CHEMOTHERAPY - 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).

• INVESTIGATIONAL/ BIOLOGIC AGENT:

  • 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 PBTC webpage under Generic Forms and Templates.)

• RADIATION THERAPY - 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

• ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below:

  • Absolute neutrophil count ≥ 1,000/mm3
  • Platelets ≥ 100,000/ mm3 (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)
  • ALT(SGPT) < 3 x institutional upper limit of normal
  • Albumin ≥ 3 g/dl
  • Potassium ≥ 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 GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for age/gender:

    • Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
    • Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
    • Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
    • Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
    • Age ≥ 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 QTc interval < 450 ms.
• GROWTH FACTORS - 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.
• FRUIT - Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study.
• PREGNANCY STATUS - Female patients of childbearing potential must have a negative serum or urine pregnancy test.
• PREGNANCY PREVENTION - 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.
• INFORMED CONSENT - 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.

STRATUM 1 - EXCLUSION CRITERIA

• PRIOR THERAPY

  • Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation).
  • Patients have had prior HDAC, DAC, 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.
• NEUROLOGICAL STATUS - Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician.

• GASTROINTESTINAL

  • Patients have impairment of GI function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease.
  • Patients have diarrhea > CTCAE grade 2.
• SYSTEMIC ILLNESS - 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.
• OTHER MALIGNANCY - Patients have a history of any other malignancy.
• TRANSFUSIONS - Patients are known to be refractory to red blood cell or platelet transfusions.

• CONCURRENT THERAPY

  • 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. Please see Protocol Appendix B: Medications Which May Cause QTc Prolongation.
• BREASTFEEDING - Female patient IS breastfeeding.
• INABILITY TO PARTICIPATE - 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

STRATUM 2 - INCLUSION CRITERIA

• DIAGNOSIS - 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 WHO II-IV.
• AGE - Patients must be ≥ 2 but < 22 years of age at the time of enrollment.
• BSA Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2. Patients must have a BSA ≥ 0.65 m2 for doses of 10mg/m2 - 22 mg/m2. Patients must have a BSA ≥ 0.50 m2 for doses of 28 mg/m2 - 36 mg/m2.
• ABILITY TO SWALLOW - Patient must be able to swallow capsules whole.
• PERFORMANCE STATUS - 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.

• PRIOR THERAPY - 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 CNS malignancy besides standard radiation therapy.

  o Patients must have recovered from the acute treatment-related toxicities (defined as < grade 1) of radiotherapy prior to entering this study.

• RADIATION THERAPY - 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.

• ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below:

  • Absolute neutrophil count ≥ 1,000/mm3
  • Platelets ≥ 100,000/ mm3 (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)
  • ALT(SGPT) < 3 x institutional upper limit of normal
  • Albumin ≥ 3 g/dl
  • Potassium ≥ 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 in Table 9 but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible.

    • Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
    • Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
    • Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
    • Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
    • Age ≥ 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 QTc interval < 450 ms.
• GROWTH FACTORS - 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.
• FRUIT - Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study.
• PREGNANCY STATUS - Female patients of childbearing potential must have a negative serum or urine pregnancy test.
• PREGNANCY STATUS - 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.
• INFORMED CONSENT - 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.

STRATUM 2 - EXCLUSION CRITERIA

• PRIOR THERAPY - Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation)
• NEUROLOGICAL STATUS - Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician.

• GASTROINTESTINAL

  • Patients have impairment of GI function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease.
  • Patients have diarrhea > CTCAE grade 2.
• SYSTEMIC ILLNESS - 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.
• OTHER MALIGNANCY - Patients have a history of any other malignancy.
• TRANSFUSIONS - Patients are known to be refractory to red blood cell or platelet transfusions.

• CONCURRENT THERAPY

  • 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. Please see Appendix B: Medications Which May Cause QTc Prolongation.
• BREASTFEEDING - Female patient is breastfeeding.
• INABILITY TO PARTICIPATE - 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

Contacts and Locations

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

Contacts

Contact: Emily Carps, MBA, CCRA	901-595-5762	Emily.Carps@stjude.org
Contact: Stacye Richardson, MSHS, CCRP	901-595-3783	Stacye.Richardson@stjude.org

Locations

United States, California
Children's Hospital Los Angeles	Recruiting
Los Angeles, California, United States, 90026
Contact: Girish Dhall, MD 323-361-4629 gdhall@chla.usc.edu
Contact: Kelley Haley, BSN,RN,CCRP 323-361-2480 khaley@chla.usc.edu
Principal Investigator: Girish Dhall, MD
Stanford University and Lucile Packard Children's Hospital	Recruiting
Palo Alto, California, United States, 94304
Contact: Paul Graham Fisher, MD 650-721-5889 pfisher@stanford.edu
Contact: Leah White 650-725-4708 lwhite15@stanford.edu
Principal Investigator: Paul Graham Fisher, MD
United States, District of Columbia
Children's National Medical Center	Recruiting
Washington, D.C., District of Columbia, United States, 20010
Contact: Roger Packer, MD 202-884-2120 rpacker@cnmc.org
Contact: Chad Stephans 202-476-4481 CStephan@childrensnational.org
Principal Investigator: Roger Packer, MD
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago	Recruiting
Chicago, Illinois, United States, 60611
Contact: Stewart Goldman, MD 312-227-4844 sgoldman@luriechildrens.org
Contact: Emily Golbeck 312-227-4858 egolbeck@luriechildrens.org
Principal Investigator: Stewart Goldman, MD
United States, Maryland
National Cancer Institute	Recruiting
Bethesda, Maryland, United States, 20892
Contact: Kathy Warren, MD 301-435-4683 warrenk@mail.nih.gov
Contact: Sonja Crandon, RN,BSN,PMP 301-496-8009 Sonja.crandon@nih.gov
Principal Investigator: Kathy Warren, MD
United States, New York
Memorial Sloan Kettering Cancer Center	Recruiting
New York, New York, United States, 10065
Contact: Ira Dunkel, MD 212-639-2153 dunkeli@mskcc.org
Contact: Ryan Turner 646-888-5723 turnerr@mskcc.org
Principal Investigator: Ira Dunkel, MD
United States, Ohio
Cincinnati Children's Hospital Medical Center	Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maryam Fouladi, MD 513-803-0721 maryam.fouladi@cchmc.org
Contact: CCHMC Cancer Line 513-636-2799 Cancer@cchmc.org
Principal Investigator: Maryam Fouladi, MD
United States, Pennsylvania
Children's Hospital of Pittsburgh	Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Arthur 'Kim' Ritchey, MD 412-692-6794 ritcheyak@upmc.edu
Contact: Sharon DiBridge 412-692-7070 sharon.dibridge@chp.edu
Principal Investigator: Arthur 'Kim' Ritchey, MD
United States, Tennessee
St. Jude Children's Research Hospital	Recruiting
Memphis, Tennessee, United States, 38105
Contact: Alberto Broniscer, MD 901-595-4925 alberto.broniscer@stjude.org
Contact: Dillon Robinson 901-595-5922 Dillon.Robinson@stjude.org
Principal Investigator: Alberto Broniscer, MD
United States, Texas
Baylor College of Medicine	Recruiting
Houston, Texas, United States, 77030
Contact: Patricia Baxter, MD 832-824-4681 pabaxter@txch.org
Contact: Susan Burlingame, CCRP 832-824-1532 sxburlin@txch.org
Principal Investigator: Patricia Baxter, MD

Sponsors and Collaborators

Pediatric Brain Tumor Consortium

Investigators

Principal Investigator:	Michelle Monje, MD, Phd	Stanford University

More Information

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Responsible Party:	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT02717455 History of Changes
Obsolete Identifiers:	NCT02899715
Other Study ID Numbers:	PBTC-047
First Posted:	March 23, 2016
Last Update Posted:	September 25, 2017
Last Verified:	September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Pediatric Brain Tumor Consortium:

Diffuse Intrinsic Pontine Glioma

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; Panobinostat; Antineoplastic Agents; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action