Clinical trial NCT02717455
Conditions: Glioma
Keywords: Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma H3K27M DIPG DMG
Sponsor: Pediatric Brain Tumor Consortium
Start date: 2016-06-28; Completion date: 2024-03-31
Enrollment: 53 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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 or H3K27+Thalamic Diffuse Malignant Glioma (DMG) that has not yet gotten worse.

Detailed description:
Description

This is a multicenter, phase 1 trial of Panobinostat (LBH589) for children with diffuse intrinsic pontine glioma tumors.

Panobinostat is a pan-HDAC inhibitor of Class I, II and IV histone deacetylases (HDACs) involved in the deacetylation of histone and non-histone cellular proteins. Panobinostat inhibits purified total cellular histone deacetylase activity (IC50 = 0.03 uM) and activities of most HDAC isoforms (IC50 \<10nM). In addition, panobinostat induces expression of the cell-cycle control genes including CDKN1A (p21), and selectively inhibits the proliferation of a variety of tumor cells compared to normal cells. It has been extensively profiled for its in vitro and in vivo pharmacological activity on a variety of tumor cell lines and tumor xenograft mice models.

Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell cultures and orthotopic xenograft model systems, and the potentially important role of histone deacetylases and histone 3 K27M mutations in relation to pontine malignancies, the investigators are conducting a Phase 1 study of panobinostat in children with recurrent/progressive DIPG.

The primary objectives of the study are to (1) describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) taken every other week; (2) estimate the maximum tolerated dose and/or the recommended Phase 2 dose of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) taken every other week; and (3) evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) taken every other week.

Schema

STRATUM 1:

Only patients with recurrent or progressive DIPG will be enrolled initially. Panobinostat will be administered every other day, 3 times/week, p.o. preferably on a Monday/Wednesday/Friday schedule for three weeks, followed by a rest period. Three weeks of therapy plus the one week rest period (total 4 weeks) will constitute one course. Treatment will continue for up to two years (26 courses) unless the patient experiences progressive disease, unacceptable toxicity or any of the off-study criteria.

The starting dose (dose level 1) is 10 mg/m2/day. Below are the proposed dose levels to be studied:

Dose level # Panobinostat oral dose (mg) Minimum BSA Restriction

0\*: 5 mg/m2/day MWF, three weeks on, one week off (1 course = 28 days). Patients must have a BSA ≥ 0.80 m2.

1 (starting dose level): 10 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ≥ 0.65 m2.

2: 16 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ≥ 0.65 m2.

3: 22 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ≥ 0.65 m2.

4: 28 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ≥ 0.50 m2.

5: 36 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ≥ 0.50 m2.

Panobinostat will be administered as a single agent

\* Dose level 0 represents a potential treatment dose for patients requiring a dose reduction from dose level 1 and may be used as a contingency dose level if the starting dose level of panobinostat is not tolerated in the initial cohort.

STRATUM 2:

Patients with DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) who have received adequate radiation therapy but have not yet progressed will be enrolled in the currently open Stratum 2. Panobinostat will be administered every other day, 3 times/week, every other week p.o. preferably on a Monday/Wednesday/Friday schedule. Total 4 weeks will constitute one course. Treatment will continue for up to two years (26 courses) unless the patient experiences progressive disease, unacceptable toxicity or any of the off-treatment criteria.

The starting dose (dose level 1) is 16 mg/m2/day. Below are the proposed dose levels to be studied:

Dose level # Panobinostat oral dose (mg) Minimum BSA Restriction

Negative 1\*: 5 mg/m2/day MWF, every other week (1 course = 28 days). Patients must have a BSA ≥ 0.80 m2.

0\*: 10 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ≥ 0.65 m2.

1 (expected starting dose level): 16 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ≥ 0.65 m2.

2: 22 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ≥ 0.65 m2.

3: 28 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ≥ 0.50 m2.

4: 36 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ≥ 0.50 m2.

Panobinostat will be administered as a single agent

\* Dose levels 0 and -1 represent potential treatment doses for patients requiring a dose reduction from dose level 1 and may be used as a contingency dose level if the starting dose level of panobinostat is not tolerated in the initial cohort.

Arms: arm 1: Patients with recurrent/progressive DIPG will be enrolled at the time of progression. All patients will take the study drug panobinostat (LBH589). arm 2: Patients with non-progressed DIPG or H3K27M+ Thalamic DMG will be enrolled. All patients will take the study drug panobinostat (LBH589).
Interventions: intervention 1: LBH589
Intervention descriptions: intervention 1: 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 or H3K27M+ Thalamic DMG. 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.

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol # PBTC-047 
Version Date: 03/26/2021 
 
1 
 
NCI Protocol #: 
PBTC-047 
 
Local Protocol #: 
PBTC-047 
 
ClinicalTrials.gov Identifier:  NCT02717455 
 
TITLE:  Phase 1 Trial of Panobinostat in Children with Diffuse Intrinsic Pontine Glioma 
 
Coordinating Center:  
Operations, Biostatistics and Data Management Core (OBDMC) for the 
Pediatric Brain Tumor Consortium (PBTC), St. Jude Children’s Research 
Hospital 
 
*Principal Investigator: 
Michelle Monje, MD PhD 
 
 
 
 
 
 
Co-Principal Investigators: 
Kathy Warren, MD 
 
 
 
 
 
 
 
John Glod, M.D. 
 
 
 
 
 
Co-Investigators: 
Tabitha Cooney, MD 
 
 
 
 
 
 
  
 
 
 
 


NCI Protocol # PBTC-047 
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Nada Jabado MD PhD  
 
 
 
 
 
 
 
PBTC Biostatistician 
Arzu Onar-Thomas, PhD 
 
 
 
 
 
 
PBTC Biostatistician 
 Jie Huang, MS 
 
 
 
 
 
 
PBTC Protocol Coordinator 
Suresh (Rama) Ramanathan 
 
 
 
 
PBTC Neuroimaging Center 
Tina Young Poussaint, M.D. 
 
 
 
 
 
Pharmacodynamics Correlates 
Laboratory 
Michelle Monje MD PhD 
  
 
 
 
 
 
 
Pharmacodynamics  Correlates 
Laboratory 
Nada Jabado MD PhD  
 
 
 
 
 
 
Pharmacokinetics Laboratory 
William D. Figg, PharmD 
 
 
 
 
 
 
 
CRA Committee Rep 
Susan Burlingame, BS, CCRP 
 
 
 
 
 
 
 
 
NCI Supplied Agent(s): N/A 
Other Agent(s): Panobinostat (LBH589-lactate)/ Farydak®; NSC #737141; supplied by Secura 
Bio Inc. 
IND Sponsor: Center for Cancer Research, NCI/ IND#: 128437 
Protocol Type/ Version#/ Version Date: Amendment/ Version 8.0/March 26,2021  
 
This protocol is for research purposes only, and should not be copied, redistributed or used for any other purpose.  
The procedures in this protocol are intended only for use by clinical oncologists in carefully structured settings and 
may not prove to be more effective than standard treatment.  A responsible investigator associated with this clinical 
trial should be consulted before using or attempting any procedure in this protocol. Contents of this document may 
not be extracted without permission from the Study Chair. 
 


NCI Protocol # PBTC-047 
Version Date: 03/26/2021 
 
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Pediatric Brain Tumor Consortium Institutions and Principal Investigators 
Arzu Onar-Thomas, PhD* 
 
 
 
 
 
Jason Fangusaro, MD 
 
 
 
 
 
 
 
Alicia Lenzen. MD 
 
 
 
 
 
 
  
 
Kathleen Dorris, MD 
 
 
 
 
 
Nathan Robison, MD 
 
  
 
 
 
 
Ian Pollack, MD 
 
 
 
 
 
 
 
Ira Dunkel, MD 
 
 
 
 
Eugene Hwang, MD 
 
 
 
 
 
 
 
Natasha Pillay Smiley, DO 
 
 
 
 
 
 
 
 
John Glod, MD 
 
 
 
 
 
 
Giles Robinson, MD 
 
 
 
 
 
 
 
Patricia Baxter, MD 
 
 
 


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Sonia Partap, MD, MS 
 
 
 
 
 
 
 
 
 
 
*Does not have patient care responsibilities 
 
 


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SCHEMA 
 
Description 
 
This is a multicenter, phase 1 trial of Panobinostat (LBH589) for children with diffuse intrinsic 
pontine glioma tumors.  
 
Panobinostat is a pan-HDAC inhibitor of Class I, II and IV histone deacetylases (HDACs) involved 
in the deacetylation of histone and non-histone cellular proteins. Panobinostat inhibits purified 
total cellular histone deacetylase activity (IC50 = 0.03 uM) and activities of most HDAC isoforms 
(IC50 <10nM). In addition, panobinostat induces expression of the cell-cycle control genes 
including CDKN1A (p21), and selectively inhibits the proliferation of a variety of tumor cells 
compared to normal cells. It has been extensively profiled for its in vitro and in vivo 
pharmacological activity on a variety of tumor cell lines and tumor xenograft mice models. 
 
Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell 
cultures and orthotopic xenograft model systems, and the potentially important role of histone 
deacetylases and histone 3 K27M mutations in relation to pontine malignancies, we are conducting 
a Phase 1 study of panobinostat in children with recurrent/progressive DIPG followed by children 
with DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) prior to progression.  
 
The primary objectives of the study are to (1) describe the toxicity profile and define the dose- 
limiting toxicities of panobinostat in children with recurrent/progressive DIPG; (2) estimate the 
maximum tolerated dose and/or the recommended Phase 2 dose of panobinostat in children with 
recurrent/progressive DIPG; and (3) evaluate and characterize the plasma pharmacokinetics of 
panobinostat in children with recurrent/progressive DIPG. 
 
Following completion of the first primary objectives, we will pursue investigation of panobinostat 
with an alternative schedule, in children with DIPG or H3K27+ Thalamic DMG who have not yet 
progressed. The primary objectives of the amendment are to (1) describe the toxicity profile and 
define the dose-limiting toxicities of panobinostat in children with non-progressed DIPG or 
H3K27+ Thalamic DMG treated with three times/week, every other week schedule; (2) estimate 
the maximum tolerated dose and/or the recommended Phase 2 dose of panobinostat in children 
with non-progressed DIPG or H3K27+ Thalamic DMG treated with three times/week, every other 
week schedule; and (3) evaluate and characterize the plasma pharmacokinetics of panobinostat in 
children with non-progressed DIPG or H3K27+ Thalamic DMG treated with three times/week, 
every other week schedule. 
 
Schema 
 
Only patients with recurrent or progressive DIPG will be enrolled initially. Panobinostat will be 
administered every other day, 3 times/week, p.o. preferably on a Monday/Wednesday/Friday 
schedule for three weeks, followed by a rest period.  Three weeks of therapy plus the one week 
rest period (total 4 weeks) will constitute one course. Treatment will continue for up to two years 
(26 courses) unless the patient experiences progressive disease, unacceptable toxicity or any of the 
off-study criteria. 


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The starting dose (dose level 1) is 10 mg/m2/day. The table below lists the proposed dose levels to 
be studied. 
 
Table 1: Dose escalation schedule for recurrent/ progressive DIPG treated with three weeks 
on, one week off schedule (Stratum 1) 
 
Upon completion of the first primary objectives, patients with DIPG or H3K27+ Thalamic DMG 
who have received adequate radiation therapy but have not yet progressed will be enrolled in 
Stratum 2. Panobinostat will be administered every other day, 3 times/week, every other week p.o. 
preferably on a Monday/Wednesday/Friday schedule.  Total 4 weeks will constitute one course. 
Treatment will continue for up to two years (26 courses) unless the patient experiences progressive 
disease, unacceptable toxicity or any of the off-treatment criteria. 
 
The starting dose (dose level 1) for Stratum 2 will be 1 dose level above the MTD for the ‘3-weeks 
on, 1-week off’ schedule.  The current expectation is that 10mg/m2 will be the MTD for the ‘3-
weeks on, 1-week off’ schedule and thus we expect to start exploring the ‘every other week’ dosing 
schedule at 16 mg/m2/day. The table below lists the proposed dose levels to be studied: 
 
 
Dose 
level # 
panobinostat oral dose (mg) 
 
Minimum BSA Restriction 
0* 
5 mg/m2/day MWF, three weeks on, one 
week off (1 course = 28 days) 
Patients must have a BSA ≥ 0.80 m2  
 
1  
(starting 
dose 
level) 
10 mg/m2/day MWF, three weeks on, one 
week off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
2 
16 mg/m2/day MWF, three weeks on, one 
week off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
3 
22 mg/m2/day MWF, three weeks on, one 
week off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
4 
28 mg/m2/day MWF, three weeks on, one 
week off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2 
5 
36 mg/m2/day MWF, three weeks on, one 
week off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2 
 
Panobinostat will be administered as a single 
agent 
* Dose level 0 represents a potential 
treatment dose for patients requiring a 
dose reduction from dose level 1 and may 
be used as a contingency dose level if the 
starting dose level of panobinostat is not 
tolerated in the initial cohort. 
 


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Table 2: Dose escalation schedule for non-progressed DIPG or H3K27+Thalamic DMG 
treated every other week (Stratum 2) 
 
 
 
Dose level # 
panobinostat oral dose (mg) 
 
Minimum BSA Restriction 
-1* 
5 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.80 m2  
 
0* 
10 mg/m2/day MWF, every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
1  
(expected 
starting 
dose level) 
16 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
2 
22 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
3 
28 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2  
 
4 
36 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2 
 
Panobinostat will be administered as a single 
agent 
* Dose levels 0 and -1 represent potential 
treatment doses for patients requiring a dose 
reduction from dose level 1 and may be used 
as a contingency dose level if the starting dose 
level of panobinostat is not tolerated in the 
initial cohort. 
 


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TABLE OF CONTENTS 
 
Coordinating Center: ....................................................................................................................... 1 
SCHEMA ........................................................................................................................................ 5 
TABLE OF CONTENTS ................................................................................................................ 8 
1 
Objectives ............................................................................................................................. 10 
1.1 
Primary Objectives ......................................................................................................... 10 
1.2 
Secondary Objectives ..................................................................................................... 10 
2 
Background ........................................................................................................................... 11 
2.1 
Study Disease: Diffuse Intrinsic Pontine Glioma .......................................................... 11 
2.2 
Inhibition of Deacetylase ............................................................................................... 13 
2.3 
Panobinostat (LBH589) ................................................................................................. 14 
2.4 
Rationale of Proposed Pediatric Study .......................................................................... 27 
2.5 
Correlative Studies Background .................................................................................... 28 
3 
Patient Selection.................................................................................................................... 30 
3.1 
INCLUSION CRITERIA ................................................................................................. 30 
3.2 
EXCLUSION CRITERIA ................................................................................................ 32 
3.3 
Treatment at Primary Institution.................................................................................... 36 
3.4 
Criteria to Start Treatment ............................................................................................. 37 
4 
Registration Procedures ........................................................................................................ 37 
4.1 
CTEP Investigator Registration Procedures.................................................................. 37 
4.2 
General Guidelines ........................................................................................................ 40 
4.3 
Enrollment Procedures .................................................................................................. 40 
5 
Treatment Plan ...................................................................................................................... 41 
5.1 
Agent Administration...................................................................................................... 41 
5.2 
Concomitant Medications and Supportive Care Guidelines .......................................... 46 
5.3 
Duration of Therapy ....................................................................................................... 47 
6 
Dosing Delays/ Dose Modification ....................................................................................... 49 
6.1 
Notification of Study Chair ............................................................................................ 49 
6.2 
Hematologic and Non-Hematologic Adverse Events and Management ........................ 49 
6.3 
Dose Modifications for Prolonged QTc ......................................................................... 51 
7 
Adverse Events: List and Reporting Requirements .............................................................. 53 
7.1 
Adverse Events and Potential Risks for Panobinostat ................................................... 53 
7.2 
Adverse Event Characteristics ....................................................................................... 55 
7.3 
Expedited Adverse Event Reporting ............................................................................... 55 
8 
Agent Information ................................................................................................................. 60 
8.1 
Panobinostat................................................................................................................... 60 
8.2 
Agent Ordering ............................................................................................................... 60 


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8.3 
Agent Inventory Records ................................................................................................ 61 
9 
Pathology, Biomarker, Correlative, and Neuro-Imaging ...................................................... 62 
9.1 
Pathology Central Review and Biorepository ................................................................ 62 
9.2 
Pharmacokinetics – Plasma (Required) ......................................................................... 66 
9.3 
Pharmacodynamics: Cell-free DNA – Blood and Urine (Optional) .............................. 67 
9.4 
Neuroimaging Studies .................................................................................................... 69 
9.5 
Autopsy Studies .............................................................................................................. 70 
10 Study Calendar ...................................................................................................................... 72 
11 Measurement of Effect .......................................................................................................... 74 
11.1 Definitions ...................................................................................................................... 74 
11.2 Tumor Response Criteria ............................................................................................... 75 
12 Data Reporting/ Regulatory Requirements ........................................................................... 75 
12.1 Data Reporting ............................................................................................................... 75 
12.2 Method ............................................................................................................................ 76 
12.3 Responsibility for Data Submission ............................................................................... 76 
12.4 CTEP Multicenter Guidelines ........................................................................................ 76 
12.5 Collaborative Agreements Language ............................................................................. 77 
13 Statistical Considerations ...................................................................................................... 77 
13.1 Study Design/Endpoints ................................................................................................. 77 
13.2 Sample Size/Accrual Rate............................................................................................... 82 
13.3 Analysis of Secondary Endpoints ................................................................................... 83 
References ..................................................................................................................................... 85 
Appendix A: Performance Scales ................................................................................................. 90 
Appendix B: Medications Which May Cause QTc Prolongation ................................................. 91 
Appendix C: Partial List of Common Moderate and Strong Inhibitors of CYP3A4, and Common 
Sensitive CYP2D6 Substrates ....................................................................................................... 92 
Appendix D: Dosing Tables.......................................................................................................... 94 
Appendix E: Patient Diary ............................................................................................................ 96 
 
 


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1 Objectives 
1.1 
Primary Objectives: Recurrent/ Progressive DIPG (Stratum 1) 
1.1.1 To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in 
children with recurrent/progressive DIPG  
 
1.1.2 To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of 
panobinostat in children with recurrent/progressive DIPG  
 
1.1.3 To evaluate and characterize the plasma pharmacokinetics of panobinostat in children 
with recurrent/progressive DIPG  
1.2 
Secondary Objectives: Recurrent/ Progressive DIPG (Stratum 1) 
 
1.2.1 To describe the progression-free survival (PFS) and overall survival (OS) of children with 
recurrent or progressive DIPG who are treated with panobinostat 
 
1.2.2 To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes 
with treatment 
1.3 
Primary Objectives: Non-progressed DIPG  or H3K27M+ Thalamic Diffuse Midline 
Glioma (DMG) (Stratum 2) 
1.3.1 To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in 
children with non-progressed DIPG or H3K27M+ Thalamic DMG  treated with 3 
times/week, every other week.   
 
1.3.2 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 or H3K27M+ Thalamic DMG  
 
1.3.3 To evaluate and characterize the plasma pharmacokinetics of panobinostat administered 
3 times/week, every other week in children with non-progressed DIPG or H3K27M+ 
Thalamic DMG 
1.4 
Secondary Objectives: Non-progressed DIPG  or H3K27M+ Thalamic DMG (Stratum 2) 
 
1.4.1 To describe the progression-free survival (PFS) and overall survival (OS) of children with 
non-progressed DIPG or H3K27M+ Thalamic DMG who are treated with panobinostat 
 
1.4.2 To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes 
with treatment 
 
 


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2 Background 
2.1 
Study Disease: Diffuse Intrinsic Pontine Glioma 
 
Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating, aggressive brain tumor of childhood 
arising in the ventral pons. Though brainstem tumors are rare among adults, they comprise 
approximately 10-15% of pediatric brain tumors, with half of all pediatric malignant gliomas 
occurring in the brainstem1. DIPG is the most common tumor subtype in this anatomical region, 
constituting 80% of brainstem gliomas2. With an estimated 200-400 children affected by DIPG 
annually in the United States, it is the second most common malignant brain tumor of childhood 
3. The prognosis is bleak: in the absence of effective therapies, DIPG is uniformly fatal and is the 
leading cause of childhood brain tumor death. Median age at diagnosis is 6-7 years, with median 
survival of 9 months; 90% of children will die from the disease within 2 years of initial diagnosis, 
with less than 1% surviving after 5 years4. 
 
Because DIPG grows diffusely and infiltrates critical brainstem structures, surgical resection is not 
possible.  Radiation therapy has remained the mainstay of treatment for the past three decades 
since its introduction. At most treatment centers, the standard recommendation is conventionally 
fractionated local field radiotherapy with dose range of 54-60 Gy for a period of 6 weeks5. 
Radiotherapy provides temporary improvement or stabilization of symptoms and extends overall 
survival by an average of 3 months; median survival is less than 5 months without radiation6. 
Though both clinical and radiographic responses are initially observed, local recurrence invariably 
occurs.  
 
Many clinical trials of the past three decades have explored the use of various chemotherapeutic 
agents for DIPG, employing conventional and high-dose strategies as well as targeted agents. 
Chemotherapy has been attempted at time points before, during and after radiation therapy. Despite 
all efforts, no improvement in overall survival has been demonstrated7,8,9,10,11,12,13,14.   No 
chemotherapeutic agent has ever shown significant efficacy for DIPG.  However, these trials were 
performed largely without guidance by direct preclinical experimental data for DIPG; rather, they 
were designed as analogues of therapeutic strategies used for adult high-grade glioma. This 
approach is problematic: although adult and pediatric high-grade gliomas may lie on the same 
disease spectrum with certain shared histopathologic features, emerging research suggests that 
DIPG exemplifies a distinct biology from adult malignant glioma. Preclinical data for adult high-
grade glioma thus cannot be assumed to generalize to DIPG. 
 
In recent years, a rapid expansion in our understanding of the biology of DIPG has occurred 
alongside the expansion of available autopsy/biopsy tissue, development of DIPG cell lines, and 
animal models for molecular analysis. The availability of this material, paired with the advent of 
next generation sequencing tools, has enabled groundbreaking new research revealing a complex 
genomic and epigenetic landscape that characterizes DIPG as a unique entity, distinct from high-
grade gliomas that arise in adulthood, and even distinct from pediatric supratentorial malignant 
gliomas.  
 
Perhaps most revolutionary in our understanding of the molecular mechanisms of DIPG 
pathogenesis has been the discovery that most (78%) DIPG tumors contain a specific, recurrent 
mutation in one of two genes encoding histones, key chromatin components that play important 


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roles in regulating the epigenome15,16. A high fraction of diffuse midline gliomas of the thalamus 
carry the same H3K27M+ mutation, and the World Health Organization (WHO) now classifies 
diffuse midline gliomas of the pons and thalamus with the H3K27M mutation as the same disease. 
About 60-75% of these identified histone mutations occur in H3F3A (H3 histone, family 3A), a 
gene encoding histone variant H3.3, which replaces histones as necessary in the event of 
nucleosome disruption17,18. Another identified recurrent mutation, mutually exclusive of mutant 
H3F3A, is known to affect histone variant H3.1, usually via an alteration in HIST1H3B (histone 
cluster 1, H3b) and very rarely in HIST1H3C (histone cluster 1, H3c)19,20. Histone H3.1 plays a 
role in packaging newly synthesized DNA during S-phase18. In both H3.3 and H3.1, the alteration 
is a specific missense mutation resulting in the substitution of lysine with methionine at position 
27 (K27M)15,16. This position is located within the N-terminal tail of the histone; importantly, post-
translational modification of histone tails by methylation, acetylation or ubiquitylation of lysine 
residues is known to mediate the epigenetic regulation of gene expression and alter nucleosome 
structure. The addition or deletion of such modifications are facilitated by “writers” and “erasers” 
and result in altered interactions with transcription modifiers, as mediated by “readers.” While 
mutations in writers, erasers or readers have recently been implicated in other oncogenic pathways, 
it appears that in DIPG the epigenetic aberrancy directly results from mutation of the histone 
alone21,22,23,24. Indeed, DIPG represents the first identified example of the implication of a histone 
mutation in oncogenesis and disease22,25,26,27. Remarkably, the H3K27M mutation is heterozygous 
in 100% of DIPG cells, and remains so in both treatment-naïve and treatment-exposed samples, 
and within low- and high-grade tumor regions21,22,28,29,23,24. This strongly suggests clonal selection, 
emphasizing the robust selective advantage that the H3K27M mutation likely confers. 
 
H3K27M is a gain-of-function mutation that exerts broad transcriptional effects by disrupting 
lysine trimethylation at position 27. The K27 trimethylation mark (H3K27me3) is necessary for 
stimulation of methyltransferase activity of Polycomb Repressive Complex 2 (PRC2) via 
nucleosome interaction with the EZH2 subunit of PRC230. PRC2 is known to silence gene 
transcription in order to regulate stem cell differentiation in development, and mutations in 
subunits of PRC2 itself have been previously implicated in oncogenesis31. The substitution of 
lysine with methionine at position 27 interferes with PRC2 stimulation and results in the robust, 
aberrant derepression of gene transcription normally silenced by PRC2 activity30. In DIPG 
samples, this occurs in the absence of altered EZH2 expression32,33. Strikingly, while the mutant 
H3 variants represent only a fraction (~3-17%) of the total histone H3 population in DIPG cells, 
this mutation nonetheless exerts a dominant reprogramming effect and initiates a global pattern of 
hypomethylation and increased transcriptional activity, with dramatic loss of trimethylation or 
dimethylation observed across all H3 variants in human DIPG samples as well as in in vivo and in 
vitro models34,35,30,32; ectopic H3K27M expression in other cell types similarly leads to global 
reduction of H3K27me330,33. Certain trimethylation marks remain, but these were found to 
associate with certain target genes not usually under H3K27me3 control, possibly signifying 
further alteration of transcription regulation33,36. Interestingly, there is also an observed increase 
in H3K27me3 in regions simultaneously trimethylated at H3K4, a mark that usually promotes 
active gene expression36. This contradictory combination of “silent” and “active” marks signifies 
that the associated target genes are “bivalent” - i.e., uniquely primed for expression upon H3K27 
trimethylation loss—and indeed, these target genes were found to be involved in oncogenic as well 
as developmental pathways36. This evidence of broad transcription alterations occurring in such a 


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vast majority of DIPG tumors provides compelling support for an epigenetic mechanism as a key 
driver of DIPG pathogenesis. 
 
2.2 
Inhibition of Deacetylase  
 
Panobinostat (LBH589) is a deacetylase inhibitor (DACi) belonging to a structurally novel 
cinnamic hydroxamic acid class of compounds.  It is a potent class I/II pan-DAC inhibitor (pan-
DACi) that has shown anti-tumor activity in pre-clinical models and cancer patients.  Deacetylases 
(DAC) target lysine groups on chromatin and transcription factors and various non-histone 
proteins such as p53, tubulin, HSP90 and Rb.  
 
Inhibition of DAC provides a novel approach for cancer treatment.  Histones are part of the core 
proteins of nucleosomes, and acetylation and deacetylation of these proteins play a role in the 
regulation of gene expression.  Highly charged deacetylated histones bind tightly to the phosphate 
backbone of DNA, inhibiting transcription, presumably, by limiting access of transcription factors 
and RNA polymerases to DNA.  Acetylation neutralizes the charge of histones and generates a 
more open DNA conformation.  This conformation allows transcription factors and associated 
transcription apparatus access to the DNA, promoting expression of the corresponding genes.  The 
opposing activities of two groups of enzymes, histone acetyltransferase (HAT) and HDAC control 
the amount of acetylation.  In normal cells a balance exists between HAT and DAC activity that 
leads to cell specific patterns of gene expression.  Perturbation of the balance produces changes in 
gene expression. 
 
Several lines of evidence suggest that aberrant recruitment of HDAC and the resulting 
modification of chromatin structure may play a role in changing the gene expression seen in 
transformed cells. DAC inhibitors (DACi) have been shown to induce differentiation, cell cycle 
arrest or apoptosis in cultured tumor cells, and to inhibit the growth of tumors in animal models 
37,38,39, 40, 41,42,43.  In addition, DACi have been shown to induce expression of p21, a key mediator 
of cell cycle arrest in G1 phase and cellular differentiation44, 45, 46, 47. 
 
Tumor growth inhibition and apoptosis in response to DACi treatment may also be mediated 
through changes in acetylation of non-histone proteins (e.g., HSP90, p53, HIF-1α, α-tubulin).  For 
example, the chaperone protein HSP90 has been shown to be acetylated in cells treated with 
DACi48, 49, 50.  Acetylation of HSP90 inhibits its ability to bind newly synthesized client proteins, 
thus preventing proper client protein folding and function.  In the absence of HSP90 function, 
misfolded proteins are targeted for degradation in the proteasome.  Many proteins that require 
HSP90 association are critical to cancer cell growth, including ErbB1, ErbB2, AKT, Raf, KDR, 
and BCR-ABL.  Acetylation of HSP90 in cells treated with DACi inhibits the chaperone function 
of HSP90, leading to degradation of the client proteins and eventual cell death. 
 
Given the presence of histone mutations in the vast majority of DIPGs and the anti-tumor effects 
of HDAC inhibitors, there is strong rationale to evaluate the histone deacetylase inhibitor, 
Panobinostat, against DIPG. 
 


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2.3 
Panobinostat (LBH589) 
 
Panobinostat is a pan-HDAC inhibitor of Class I, II and IV histone deacetylases (HDACs) involved 
in the deacetylation of histone and non-histone cellular proteins. Panobinostat inhibits purified 
total cellular histone deacetylase activity (IC50 = 0.03 uM) and activities of most HDAC isoforms 
(IC50 < 10nM). In addition, panobinostat induces expression of the cell-cycle control genes 
including CDKNIA (p21), and selectively inhibits the proliferation of a variety of tumor cells 
compared to normal cells. It has been extensively profiled for its in vitro and in vivo 
pharmacological activity on a variety of tumor cell lines and tumor xenograft mice models. 
 
In Vitro Studies 
 
Panobinostat was profiled for antiproliferative activity in a large panel of solid and hematological 
malignancy cell lines and subsets of tumor cell types exhibiting sensitivity or relative insensitivity 
to the drug were identified. All leukemia and lymphoma cell lines tested were highly sensitive to 
panobinostat (LD50 < 50 nM). Significant antiproliferative activity was observed with 
panobinostat in combination with relevant standard of care agents in plasma cells isolated from 
patients with MM and in leukemia cell lines51, 52,53. Exposure of normal fibroblasts to low 
nanomolar concentrations of panobinostat inhibited their proliferation; however, treatment with 
up to micromolar concentrations of the compound for 72 hours did not induce significant cell 
death. Panobinostat-induced apoptosis of bronchial epithelial cells transformed by SV40 large T 
antigen/telomerase, but had little effect on normal bronchial epithelial cells, even at greater 
concentrations. These results provide the basis for a potentially favorable therapeutic window 
during anticancer therapy with panobinostat. Cultured tumor cells and/or tumors treated with 
panobinostat exhibit increased levels of acetylated histones, indicating that the anti-tumor activity 
of panobinostat is accompanied by HDAC inhibition in cell lines and in vivo. 
 
In Vivo Studies 
 
Human xenografts of tumor cell lines growing in athymic nude mice were used to profile 
panobinostat in vivo in several models. Panobinostat demonstrated single agent and/or 
combination activity in a range of xenograft models including colon, SCLC, cutaneous T-cell 
lymphoma (CTCL), multiple myeloma (MM) and other xenografted human primary tumors51. 
Single agent treatment in HCT116 xenograft tumors (colorectal) resulted in dose-related anti-
tumor activity with minimal toxicity at panobinostat concentrations which correlated with 
persistent histone acetylation. Inhibition of tumor growth and tumor regression with minimal 
toxicity, as assessed by animal body weight, was also observed in the HH CTCL xenograft model 
and the NCI-H146 SCLC xenograft model. Panobinostat also demonstrated significant anti-tumor 
activity in androgen-independent prostate cancer xenograft model, in two different types of human 
plasmacytoma murine models, in combination with trastuzumab in the HER+ BT474 breast cancer 
tumor xenograft model (data on file), in combination with docetaxel in the HID28 hormone 
independent prostate cancer model [Study RD-2010-50257]. 
 
Mechanism of Action 
 
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elucidated and may include effects on epigenetic mechanisms of gene expression as well as 
modulation of acetylation and function of histones. Panobinostat increases histone acetylation in 
preclinical models as well as in exploratory pharmacodynamic assessments on patient samples in 
clinical trials. Panobinostat treatment results in the induction of cell-cycle control genes such as 
p21, which is associated with induction of cell-cycle arrest. Treatment of tumor cells with 
panobinostat results in increased acetylation of cytoplasmic proteins, including Hsp90, a target of 
HDAC6 and a major chaperone protein required for the stabilization of many key proteins 
implicated in cancer development and growth onco-proteins. Panobinostat-induced acetylation of 
Hsp90 inhibited the protein-stabilizing function of Hsp90 and led to the destabilization and 
resulting degradation of tumor targets. As described below, in H3K27M mutant cells (such as most 
DIPGs) panobinostat-induced acetylation of histone-3 results in normalization of histone-3 
trimethylation, likely by blocking the sequestration of PRC2 by the mutant methionine in the 
oncohistone. This normalization of H3K27 trimethylation in the wild type histones results in 
sweeping normalization of the H3K27M gene expression signature54. 
 
2.3.1 DIPG Preclinical Efficacy Data 
 
DIPG research has been limited historically by a dearth of tumor tissue available for study and 
lack of experimental model systems. In recent years, however, this has begun to change. 
Employing autopsy55,58,56 and biopsy57 tissue, patient-derived DIPG cell cultures and orthotopic 
xenograft model systems have recently been established, with the first available xenograftable 
DIPG cell culture reported in 201158, 56, 57.  Armed with the tools to design clinical trials based on 
preclinical data, an international, multi-institutional collaboration formed to pool DIPG tissue 
resources and evaluate functional targets for DIPG therapy. This DIPG Preclinical Consortium 
performed a drug screen using a total of 16 DIPG cell cultures and found panobinostat to be among 
the top hits. 12/16 DIPG cell cultures exhibited sensitivity to panobinostat, with an IC50 of ~100 
nM54. Panobinostat was found to decrease DIPG cell proliferation and increase DIPG cell death 
(Figure 1a-b). Further, the increase in histone acetylation caused by panobinostat exposure 
correlated with an unexpected normalization of histone 3 K27 methylation in H3.3K27M mutant 
DIPG cells or 293T cells expressing an H3.3K27M construct54 (Figure 1c). Accordingly, a 
normalization of the “K27M” gene expression signature was observed54.  
 
Panobinostat was directly infused into the pons in a pontine orthotopic xenograft model of DIPG 
(SU-DIPG VI; H3.3K27M subtype) via convection-enhanced delivery (CED). In vivo 
bioluminescent imaging was performed immediately prior to and 7 days after panobinostat (or 
vehicle control) administration in order to measure tumor growth by quantitative assessment of 
photon emission (Figure 1d-g).  Because panobinostat affects gene expression, we confirmed that 
panobinostat expression does not down-regulate the luciferase transgene. We found a marked 
effect of panobinostat on the rate of tumor xenograft growth; in vehicle-treated control mice, the 
rate of xenograft growth was approximately 6.5 fold greater than that in mice treated with a single 
dose of panobinostat by CED (n=4 vehicle controls, 5 treated mice; P<0.05 by two-tailed t test; 
Figure 1g).  Having shown proof of principle for in vivo efficacy of panobinostat against DIPG, 
we next investigated the degree to which panobinostat penetrates the pons when administered 
systemically using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following a 
single 20 mg/kg IP dose, we found pontine panobinostat levels of 0.068ng/mg tissue, equivalent 
to ~200 nM.  As the IC50 for panobinostat was found to be ~100 nM, we reasoned that systemic 


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delivery may prove effective. Mice with brainstem orthotopic xenografts of SU-DIPG-VI cells 
were then treated with 1 mg/kg, 10 mg/kg or 20 mg/kg IP panobinostat. In vivo bioluminescent 
imaging demonstrated a significant reduction in tumor growth in panobinostat-treated animals at 
1 week in 10 mg/kg and 20 mg/kg treatment groups compared to vehicle-treated controls (n=5 per 
group and 7 per group; P<0.05 and 0.01 by two-tailed t test, respectively; Figure 1h). A second, 
patient-derived DIPG brainstem orthotopic xenograft model (IBs-w0128DIPG, derived from case 
LI-F; H3WT subtype) was also tested using panobinostat 10 mg/kg IP dosed 5 days on, 5 days off, 
for a total of 9 doses. This resulted in significantly prolonged survival in the mice treated with 
panobinostat compared to vehicle treated controls (Figure 1, n=10 per group, P < 0.05 by log-rank 
analysis). 
 


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Figure 1 
Preclinical Panobinostat activity against DIPG 
(a) FACS analysis of DIPG tumor cell proliferation and cell death: Top row: Overlapping 


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histogram plots of EdU FACS analyses are shown on the left; quantifications of EdU+ cell 
population levels from each condition are shown in bar plots on the right for DIPG cell cultures 
SU-DIPG-VI and SU-DIPG-XIII (both H3.3K27M mutant cell lines). Bottom row: Left, 
Overlapping plots of Annexin V, DAPI FACS analyses; Right, bar plots show early apoptotic 
(AV+, DAPI-) or late apoptotic (AV+, DAPI+) cell population levels from each condition for each 
cell line as above. (b) HDAC1 and HDAC2 knock-down in DIPG cells using shRNA verify 
panobinostat mechanism of action in four DIPG cell lines. Cell viability assays at each time point 
for each cell line were performed in triplicate (n = 3 wells); data are expressed relative to Day 0 
and are shown as mean ± SD. Note the varying growth rates of cell cultures result in varying y-
axes depicting relative change in cell viability. **P < 0.01; ***P < 0.001 (Two-way ANOVA).  
(c) Panobinostat increases histone-3 acetylation and restores H3K27 trimethylation. Western blot 
analyses of histone-3 acetylation and H3K27 trimethylation (H3K27me3) in H3K27M mutant 
DIPG cell lines SU-DIPG-VI and SU-DIPG-XIII (left blots) and in 293T cells expressing a mutant 
H3.3K27M-HA tagged construct (293-H3.3-K27M-FH36; right blots). Controls included total 
protein levels of H3, HDAC1, HDAC2 and EZH2.  Expression of the HA tag in the 293T cells 
confirms expression of the H3.3K27M-FH construct. (d) Schematic illustrating convection 
enhanced delivery strategy to infuse drug into brainstem. Blue illustrates approximate distribution 
of the infused solution. (e) Distribution of infusate illustrated by delivering blue dye to the 
brainstem by CED. Ventral side of a mouse brain is shown immediately following CED delivery 
of Coomassie Blue dye. Scale bar = 3 mm (f) in vivo bioluminescent imaging of DIPG xenografts 
7 days following CED delivery of panobinostat (T = treated with panobinostat) or vehicle control 
(C = control). The heat map superimposed over the mouse head represents the degree of photon 
emission by DIPG cells expressing firefly luciferase. Scale bar = 3.5 cm. (g) in vivo DIPG 
xenograft tumor growth as measured by change in bioluminescent photon emission over the seven 
days following (g) CED delivery of panobinostat.  Panobinostat = red squares (n = 5 mice) and 
vehicle control = blue circles (n = 4 mice). Data points represent the change in maximum photon 
flux (percent of baseline) between Day 0 and Day 7 for each mouse. (h) As in (g), with systemic 
administration of panobinostat. Three systemic dose levels were used, 1 mg/kg (n = 6 control, 8 
treated mice) or 10 mg/kg (n = 5 mice per group) delivered IP on M,W,F or 20 mg/kg (n = 7 mice 
per group) delivered once per week. Error bars, s.e.m. *P < 0. 0.5; **P < 0.01; N.S. indicates P > 
0.05 (two-tailed t test). (i) Systemic delivery of panobinostat prolongs survival in a histone H3 
wild type DIPG orthotopic xenograft model IBs-W0128DIPG.  Panobinostat 10 mg/kg I.P. doses 
given as indicated by arrows. n = 10 per group; P = 0.0179 (log-rank analysis). 
 
Biodistribution of Panobinostat 
 
We carefully tested brain penetration of panobinostat in rodents. Non-tumor bearing mice were 
given a dose of panobinostat (20 mg/kg IP or 10 mg/kg PO), and levels of panobinostat were 
measured in the brain parenchyma (following transcardiac perfusion of saline to avoid sample 
contamination by blood levels of the drug) 30 minutes later using liquid chromatography-tandem 
mass spectrometry (LC-MSMS).  In the pons, we measured drug level of ~.068 ng/mg (equivalent 
to ~196 nM) following 20 mg/kg IP dosing54. Because 20 mg/kg is a relatively high dose and was 
administered IP, to better model the MTD described in the TACL study we used 10 mg/kg PO 
dosing and measured at 30 min following this PO dose a concentration of ~0.053 ng/mg in 
hindbrain (brainstem plus cerebellum) tissue (unpublished results). While these brain 
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mice, they are greater than the DIPG cell IC50 for panobinostat of ~100 nM. Accordingly, when 
we treat mice bearing patient-derived DIPG orthotopic xenografts with panobinostat systemically 
3 times per week (10 mg/kg), we still measured a decrease in tumor growth and an increase in 
survival, albeit the duration of suppressed growth was less than in the mice treated with weekly 
20mg/kg systemic panobinostat54.  In summary, our preclinical data suggest that while very little 
panobinostat penetrates the brain parenchyma, DIPG cells are sufficiently sensitive to it that 
enough reaches the brain for tumor cell killing to occur. 
 
2.3.2 Animal Toxicity 
 
A complete toxicity safety evaluation program of acute, subchronic, chronic, and reproductive 
toxicology studies and genotoxicity studies was conducted to support the chronic administration 
of panobinostat to adult patients. The toxicology program was consistent with the International 
Conference on Harmonization (ICH) M3 Guideline on Non-clinical Safety Studies for the Conduct 
of Human Clinical Trials for Pharmaceuticals as well as all other relevant ICH Guidelines on 
Safety. All pivotal toxicology studies (Table 3) were performed in accordance with GLP 
guidelines and currently accepted guidelines with respect to animal numbers and dose levels used. 
 
Table 3 
 
 
Single Dose I.V. Toxicity Studies 
The maximum non-lethal dose following a single i.v. administration of panobinostat was between 


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50-75 mg/kg in mice and between 10-50 mg/kg in rats. 
 
Table 4 
 
 
Repeat Dose Toxicity Studies 
 
The primary target organs of toxicity following repeat dose i.v. and oral administration to rats and 
dogs are the hematopoietic and lymphatic systems. Decreases in red cell parameters and white 
blood cell counts (lymphocyte, neutrophil, eosinophil, monocyte, and basophil counts) were seen 
following multiple doses. Reductions in red blood cell parameters and hemoglobin were 
accompanied by marginally increased reticulocyte counts at high doses in rats and dogs. Platelet 
counts were decreased in rats but increased in dogs. Panobinostat causes a cessation of platelet 
production and maturation rather than megakaryocyte loss, and platelet generation resumes rapidly 
upon discontinuation of treatment. Recovery involves a rebound effect with increased 
megakaryocyte generation and rapid thrombopoiesis58,59. 
 
Diarrhea and necrosis of the epithelium in the small intestine was observed in dogs and rats 
following both oral and intravenous administration. In rats, GI changes were present at dose levels 
that exceeded the maximum tolerated dose. These findings are not unexpected since HDACs play 
a role in the maintenance of intestinal stem-cell proliferation, survival and differentiation and 
degenerative changes of the intestinal tract are common findings with all HDAC inhibitors. 
 
The thyroid was identified as a target organ for panobinostat based upon variable occurrences of 
thyroid weight changes, decreased colloid, follicular epithelial hypertrophy and cytoplasmic 
vacuolation. Effects on the thyroid were observed in rats and dogs following both oral and i.v. 
administration of panobinostat. A NOAEL (No-observed-adverse-effect level) was not identified. 
 
 
Hyperostosis of the femoral cavity was observed in the 13-week oral rat study. However, no 
adverse bone effects were observed in chronic studies in rats and dogs. These effects are likely to 
be pharmacologically mediated since HDAC inhibitors have been shown to promote osteoblast 
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in rats. 
 
Genotoxicity / Mutagenicity Studies 
 
Panobinostat demonstrated mutagenic potential in bacterial cells and endoreduplication effects in 
eukaryotic cells in vitro that are attributed to the pharmacological mode of action. According to 
current classification criteria for mutagenicity, panobinostat is classified as a category 4 substance. 
 
Panobinostat was tested for genotoxic activity in vitro. The AMES test and the chromosomal 
aberration (COMET) test were conducted according to GLP procedures. Study design and results 
are summarized in Table 5. 
 
Table 5 
 
 
 
The AMES and COMET screens reveal a signal for bacterial mutagenicity and DNA damaging 
potential in mammalian cells, respectively. In the 5-strain AMES test, a clear dose-dependent and 
reproducible mutagenic response was obtained. In the chromosome aberration test with human 
peripheral blood lymphocytes, a strong increase in the frequencies of polyploid cells (mainly as 
endoreduplication) was seen in the presence and in the absence of S9.  
 
In conclusion, panobinostat has a clear genotoxic potential in bacterial and eukaryotic systems 
(mutagenic and endoreduplication inducing effects). 
 
Reproductive Toxicity Studies 
 
Daily oral administration of panobinostat during gestation was associated with the development of 
embryo-fetal toxicity, including embryo-fetal lethality and an increased risk of skeletal variation 
and anomalies at maternally toxic doses ≥ 30 mg/kg/day in the rat, and doses ≥ 40 mg/kg/day in 


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the rabbit, which is approximately 0.18-0.25-fold the expected clinical exposure based upon AUC 
for a 20 mg dose. No effects on fertility were observed in male rats when panobinostat was 
administered orally for 4 weeks at doses of 10, 30 and 100 mg/kg. However, male reproductive 
effects were observed in the testes, epididymides and prostate in 4- and 13-week repeated dose 
oral toxicity studies in the dog (doses of 1.5 mg/kg and 1.5→1.0 mg/kg; approximately 0.69- and 
0.41-fold the expected clinical exposure based upon AUC for a 20 mg dose)  
 
Safety Exposure Multiples 
 
Systemic exposure based on AUC, Cmax and mg/m2 in cancer patients administered 240 mg using 
a TIW treatment regimen (20 mg TIW weekly x 4) is similar to exposure in rats and dogs at the 
maximal tolerated multiple oral doses of 75-100 and 1.5 mg/kg respectively. Safety exposure 
multiples are shown below in Table 6. 
 
Table 6 
 
 
(Panobinostat Investigator’s Brochure 2015)60 
2.3.3 Adult Clinical Trials 
 
Panobinostat is FDA-approved (in combination with bortezomib and dexamethasone) for use in 
adult patients with multiple myeloma at a dose of 20 mg p.o. 3x/week x 2 weeks of a 3 week cycle.  
Panobinostat is available as a capsule. The oral formulation has been administered across multiple 


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dosing schedules that includes days 1, 3, and 5 every week; or every other week; or days 1 and 4 
every week. (The clinical program for the IV formulation is completed with no further company-
sponsored studies currently planned.)  
 
2.3.3.1 Pharmacokinetics 
 
Absorption 
 
Following oral administration, panobinostat is rapidly absorbed with peak plasma concentration 
reached within 2 hours; systemic clearance is 33 L/hour and central volume of distribution is 25 
liters. Half-lives associated with the distribution, initial elimination and terminal elimination 
phases were 0.14, 2.3 and 37 hours, respectively. Observed drug accumulation was approximately 
1.1 fold with 3 times per week schedule with an effective half-life calculated to be approximately 
16 hours. Absolute oral bioavailability is 21%. 
 
Influence of food on panobinostat PK was evaluated in 63 patients with advanced cancer in a 
randomized 3-way cross-over design under fasting, high fat and standard breakfast conditions. The 
overall exposure and inter-patient variability in exposure (CV 59%) remained unchanged with or 
without food, whereas Cmax was reduced by up to 44% and Tmax prolonged by 1.5 hours due to 
food (i.e., under standard or high fat breakfast). Since food did not alter the overall bioavailability 
in patients, panobinostat can be administered without regard to food61, although administering in 
the fasting state to optimize Cmax may be considered. 
 
Distribution and Protein Binding 
 
Panobinostat is rapidly and extensively distributed to tissues as shown by an approximately 5- fold 
decrease of the plasma concentration observed within 15 minutes after the end of an IV infusion 
(Vss 320 L/m2). In adults, BSA, age and race are statistically significant covariates on the central 
volume of distribution. This has not yet been studied in children. 
 
The extent of panobinostat binding to human plasma protein was moderate (89.6%) in vitro 
between 0.1 ng/mL and 100 ng/mL panobinostat concentration. 
 
Metabolism and Elimination 
 
Panobinostat is extensively metabolized in patients to over 70 metabolites, all of which are inactive 
towards the target. As a result, PK was mainly characterized based on the parent compound. 
 
The hydroxamic acid containing side chain is the primary site of panobinostat metabolism, which 
involves mainly reduction, hydrolysis, and one and two-carbon chain-shortening. Unchanged 
panobinostat accounts for ≤ 2.5% of the dose in urine and < 3.5% of the dose in feces, the balance 
representing metabolites. Apparent panobinostat renal clearance (CLR/F) ranged from 2.4 to 5.5 
L/h, suggesting that the renal route is a minor elimination pathway of unchanged panobinostat. 
 


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Neither panobinostat nor any of the circulating metabolites contributed more than 10% of the total 
drug-related exposure. Of note, metabolites formed via the primary metabolic pathways were all 
inactive for DAC inhibitory activity in vitro62. 
 
2.3.3.2 Adult Phase 1 Studies 
 
Several dosing schedules using i.v. and oral panobinostat were evaluated with PK assessment. To 
date, the PK of panobinostat has been characterized in over 700 patients with cancer, of which, 
over 500 patients used the TIW dosing schedule. 
 
Single Agent Panobinostat 
 
Summary: In clinical trials of panobinostat administered as a single agent to adults with refractory 
hematologic malignancies63, Cmax and AUC increased proportionally with dose over a dose range 
of 4.8-14.0 mg/m2.    Panobinostat t1/2 was 7.8-12 hrs and plasma AUC0-24 ranged from 134.9-
372.9 h•ng/mL.  Cmax was approximately 20 ng/ml, or about 60 nM64,65.  Major toxicities included 
thrombocytopenia, neutropenia, and QTc prolongation that was dose-limiting.  Hypokalemia and 
elevated LFTs (ALT) were reported, as were mild nausea, vomiting and anorexia. 
 
In a Phase 1 trial of single agent panobinostat administered to adults with solid tumors66, patients 
received oral panobinostat 3 times per week (M-W-F) at doses ranging from 10-20 mg.  No DLT 
was observed.  Most common adverse events included thrombocytopenia, nausea and diarrhea.  
Mean elimination t1/2 was 9-14 hrs. 
 
A trial of panobinostat for refractory hematological malignancies in children is complete  (TACL, 
clinicaltrials.gov ID NCT01321346). No dose-limiting toxicities have been observed at dose levels 
up to 34 mg/m2/dose, administered 3 days/week x 4 weeks in children with leukemia68.   
 
Panobinostat in Combination  
 
Panobinostat has been evaluated in a Phase 1 trial for recurrent adult high-grade glioma (HGG) in 
combination with bevacizumab.  In adults with HGG, the combination of panobinostat with 
bevacizumab was safe and tolerated at a panobinostat dose of 30 mg PO three times per week, 
every other week and bevacizumab (10 mg/kg every other week). The main DLT was 
thrombocytopenia; (one case of grade 3 thrombocytopenia was observed at a dose of 20 mg PO 
three times per week every week, in combination with bevacizumab)67.  
 
2.3.3.3 Phase 2 Studies 
 
Panobinostat has completed or is undergoing several phase 2 trials in adults with hematological 
malignancies and solid tumors, alone and in combination with other agents. Notably, a phase 2 
trial of panobinostat (30mg PO three times per week) with bevacizumab (10mg/kg every other 
week) for recurrent adult HGG was completed (clinicaltrials.gov ID NCT00859222). Although 
well tolerated, the addition of panobinostat to bevacizumab did not significantly improve 6 month 
progression-free survival compared to bevacizumab monotherapy74. Thirty-six clinical studies, 
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studies have either been completed or are ongoing. A total of 2428 adult patients have been 
enrolled, 235 for the IV formulation and 2193 for the oral formulation, who received at least one 
dose of panobinostat either as a single agent or in combination with other agents.  
 
Patients were treated with panobinostat either 3 times per week every week (n=666) or 3 times per 
week every other week (n= 96) in single agent oral panobinostat clinical trials. These patients 
comprise the pooled safety population experiencing AEs during study treatment. The most 
frequent non-hematologic toxicities included GI events (diarrhea, nausea, vomiting), mostly of 
Grade 1-2, in both groups. Blood and lymphatic system disorders were the second most often 
reported specific system organ class involved, with dose-related thrombocytopenia being the most 
frequent AE in this category. Fatigue, mostly Grade 1-2, was also common among patients treated 
for TIW QW and TIW QOW. 
 
AEs regardless of causality for 3 times per week every week dosing were reported in 664 patients, 
99.7% of the safety population for this dosing schedule. The most commonly reported AEs across 
doses were gastrointestinal, including diarrhea (61.0%) and nausea (55.9%). Thrombocytopenia 
was the third most frequent AE (53.9%) with the highest frequency in the 40 mg dose level (137 
patients; 84%). Fatigue also was commonly seen across dose levels in 326 patients (48.9%) overall. 
Of note, hypothyroidism was reported in 12.9% of patients treated at the dose level of 40 mg, 
mostly deriving from study [CLBH589E2214] in Hodgkin Lymphoma.  (Hodgkin Lymphoma 
patients are known to have an increased risk for hypothyroidism.) 
 
In studies using a weekly schedule, Grade 3-4 AEs regardless of causality were reported in 534 
patients, 80.2% of the safety population. The most commonly reported Grade 3-4 AEs across 
doses were thrombocytopenia (40.8%), neutropenia (16.7%), anemia (15.5%), fatigue (12.3%) 
and febrile neutropenia (6.9%). Toxicity appeared dose-related, with more Grade 3-
4 hematologic AEs at higher dose levels. The highest incidence of febrile neutropenia was 
seen at the dose level of 60 mg (27.4%) compared to the other dose levels where the incidence 
was ≤ 3.7%. This could be because this dose level was only tested in   leukemia   patients, in   
whom   febrile   neutropenia   is   a   common AE.   Grade   3-4 thrombocytopenia, Grade  3-4  
neutropenia  and  Grade  3-4  anemia  accounted  for  75.7%, 82.8% and 52.8% of their 
respective all grade events. Grade 3-4 diarrhea, Grade 3-4 vomiting and Grade 3-4 nausea 
accounted for less than 10% of their respective all grades events.  For the 3 times per week 
every other week dosing schedule, AEs regardless of causality were reported in 96 patients, 
which is 100% of the safety population. The most commonly reported AEs (all grades) across 
doses were diarrhea (67.7%), nausea (62.5%), fatigue (56.3%), vomiting (43.8%), 
thrombocytopenia (42.7%), pyrexia (36.5%) and anorexia (34.4%). In the 3 times per week 
every other week schedule, Grade 3-4 AEs regardless of causality were reported in 81 
patients, 84.4% of the safety population. The most commonly reported Grade 3-4 AEs across 
doses were thrombocytopenia (36.5%), neutropenia (26.0%), fatigue (14.6%), diarrhea (11.5%), 
anemia (10.4%), and febrile neutropenia (8.3%). 
 
Overall, the most frequent Grade 3-4 AEs regardless of causality for both schedules (3 times per 
week every week, and 3 times per week every other week) were ascribed to the same SOC, namely 
blood and lymphatic system disorders. In February 2014, panobinostat was approved by the FDA 
for patients with recurrent multiple myeloma who have received at least two prior therapy 
regimens including the proteasome inhibitor, bortezomib and an immunomodulatory agent,  


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26 
 
based 
on 
a 
pre-specified 
subgroup 
analysis from 
the 
PANORAMA-1 
trial. 
 
This approval was based on a study of 193 adults with multiple myeloma who had previously 
received at least 2 treatments, including bortezomib and an immunotherapy drug. In the study, 
people were randomly assigned to receive a combination of panobinostat, bortezomib, and 
dexamethasone, or only bortezomib and dexamethasone. 
 
The pre-specified analysis looked specifically at 193 patients from the phase 3 study who were 
treated with bortezomib and dexamethasone. In this population, the median progression-free 
survival (PFS) with the panobinostat combination was 10.6 months versus 5.8 months with placebo 
(HR = 0.52; 95% CI, 0.36-0.76). Additionally, the tumor shrinkage rate with panobinostat was 
59% versus 41% with bortezomib and dexamethasone alone69.  
 
Cardiac Safety 
 
Cardiac safety data for 666 patients treated with oral panobinostat 3 times per week are presented 
in Table 7. All patients underwent intensive pre- and post-dose ECG monitoring. The most 
common finding is a post-baseline QTcF increase of > 30 and ≤ 60 msec (approximately 22%). 
No cases of torsades de pointes have been observed. QTcF abnormalities are shown in Table 7, 
for the once per week schedule.                                                     
 
Table 7 
 
QTcF changes in patients receiving oral panobinostat three-times-a-week every-week  
QTcF variable 
20 mg 
N=309 
n  (%) 
30 mg 
N=81 
n  (%) 
40 mg 
N=163 
n  (%) 
60 mg 
N=113 
n  (%) 
TOTAL 
N=666  
n  (%) 
QTcF increase from baseline > 
30 and <= 60 ms 
47 
(15.2) 
12 
(14.8) 
46 
(28.2) 
38 
(33.6) 
143 
(21.5) 
QTcF increase from baseline > 
60 ms 
7 
(2.3) 
1 
(1.2) 
16 
(3.7) 
13 
(11.5) 
27 
(4.1) 
Absolute QTcF > 450 and <= 
480 ms 
38 
(12.5) 
10 
(12.3) 
13 
(8.0) 
27 
(24.5) 
88 
(13.4) 
Absolute QTcF > 480 ms and <= 
500 ms 
5 
(1.6) 
1 
(1.2) 
4 
(2.5) 
7 
(6.2) 
17 
(2.6) 
Absolute QTcF > 500 ms 
1 
(0.3) 
0 
(0.0) 
10 
(0.0) 
5 
(4.4) 
6 
(0.9) 
N= Number of patients in the group. 
n= Number of patients at risk for a designated change with both non-missing baseline and post-baseline values. 
Patients are counted only for the worst grade observed post-baseline. 
For the every other week schedule, post-baseline increased values of > 30 and ≤ 60 msec were 
observed (16.7%). Post-baseline increase of > 60 msec was less frequent (4 patients, 4.2%). 
Absolute QTcF prolongation values of 450 msec to 480 and of > 480 to 500 msec were reported 
in 9 patients (9.6%) and in 1 patient (1.0%), respectively. Absolute QTcF prolongation above 500 
msec was not observed. Of note, the maximum change of QTcF from baseline does not coincide 
with the peak plasma concentration-time course of panobinostat suggesting a possible delayed 
effect.   


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Panobinostat was FDA approved with a Boxed Warning regarding severe and fatal cardiac events, 
arrhythmias and electrocardiogram (ECG) changes.  
 
Diarrhea 
 
Panobinostat was FDA approved with a Boxed Warning regarding severe diarrhea. 
Severe diarrhea occurred in 25% of patients treated with panobinostat. Diarrhea of any grade 
occurred in 68% of patients treated with panobinostat compared to 42% of patients in the control 
arm. Diarrhea can occur at any time. Patients must be monitored for hydration status and 
electrolyte levels, including potassium, magnesium and phosphate. 
 
Panobinostat PK in Combination with Dexamethasone 
 
In clinical studies in multiple myeloma (MM) where panobinostat was given in combination with 
bortezomib and dexamethasone, the exposure of panobinostat was decreased by 20 to 50% by the 
concomitant use of dexamethasone (Dex), which is a dose-dependent mild/moderate CYP3A4 
inducer. Furthermore, in-silico data showed that the systemic exposure of panobinostat may be 
decreased by 70% in the presence of strong inducers of CYP3A4.  Therefore, it is suggested that 
the concomitant use of strong CYP3A4 inducers be avoided. 
 
Conclusions on Human Pharmacokinetics and Metabolism 
 
Panobinostat has linear pharmacokinetics at doses of 10-30 mg. Panobinostat can be administered 
without regard to food. Panobinostat is extensively metabolized and eliminated nearly equally in 
kidney and liver. Starting dose adjustments are not necessary in patients with severe renal 
impairment. Starting dose of panobinostat should be reduced in patients with mild and moderate 
hepatic impairment, and in patients with co-administration of a strong CYP3A inhibitor. Avoid 
co-administration with medications that are strong CYP3A4 inducers and sensitive CYP2D6 
substrates or 2D6 substrates with narrow therapeutic index. Co-administration with medications 
that are strong CYP3A inducers is to be avoided when combined with panobinostat, bortezomib 
and dexamethasone60. 
 
2.4 
Rationale of Proposed Pediatric Study 
 
We propose the use of panobinostat to assess safety, tolerability, and pharmacokinetics, as well as 
initial observations of any clinical effect, in pediatric patients with recurrent/progressive diffuse 
intrinsic pontine glioma (DIPG). Our rationale is based on pre-clinical evidence including the 
sensitivity of patient-derived DIPG cell lines to histone deacetylase (HDAC) inhibitors in in vitro 
cell culture studies, and tumor inhibitory effect of panobinostat in in vivo efficacy studies 
performed using orthotopic xenograft models of DIPG.  
 
There is extensive preclinical and clinical data on this agent, which is FDA approved in adults with 
recurrent multiple myeloma at a dose of 20mg 3x/week x 2 weeks of a 3 week cycle70. 
 
In the present trial, we seek to evaluate this promising drug for use as a single agent in children 
with recurrent/progressive DIPG. The initial dose level we propose to use is approximately 80% 


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of the approved adult dose.   
 
Rationale for Amendment 4: 
We have enrolled 11 patients to date, 7 so far are evaluable (1 was inevaluable and 3 are still in 
the DLT period). Two patients enrolled onto dose level 1 and did not experience a DLT. The 
subsequent 6 patients were enrolled onto dose level 2. One patient experienced a dose limiting 
toxicity of grade 3 thrombocytopenia, and was dose reduced to level 1. One patient was 
unevaluable due to disease progression. A second patient experienced dose limiting toxicities of 
grade 4 thrombocytopenia and grade 4 neutropenia, and was dose reduced to level 1. Given 2 
occurrences of DLTs at dose level 2, the subsequent 3 patients have been enrolled onto dose level 
1. Should they tolerate dose level 1 (10mg/m2), it will be declared the maximum tolerated dose 
(MTD) for the 3 weeks on 1 week off schedule.  
 
The recommended phase 2 dose has been identified for children with recurrent/progressive DIPG 
as 10 mg/m2, and now we will evaluate panobinostat as a single agent in children with DIPG who 
have not yet progressed in a separate stratum (Stratum 2), using an alternative schedule.  Given 
the limited BBB (blood brain barrier) penetration of panobinostat, it is highly desirable to 
maximize the dose administered as part of treatment. To improve the tolerability of panobinostat, 
we propose a new schedule of Monday, Wednesday, Friday dosing every other week. In vivo DIPG 
orthotopic xenograft data show prolonged duration of tumor suppression in mice treated with 
weekly 20mg/kg systemic panobinostat compared to mice treated 10mg/kg 3 times per week 54, 
suggesting that higher doses administered less frequently may be more beneficial than lower doses 
administered more frequently.  In addition to the change in dosing schedule, we will be studying 
DIPG patients prior to progression to avoid confusion between effects of tumor progression and 
putative toxicity of the agent. Furthermore, our plans for future efficacy studies focus on DIPG 
patients prior to progression in order to maximize the likelihood of success. 
 
2.5 
Correlative Studies Background 
2.5.1 Rationale for Pharmacokinetic Studies 
 
2.5.1.1 Hypothesis  
 
The pharmacokinetics 
and 
tolerability of 
panobinostat 
in 
pediatric 
patients with 
recurrent/progressive DIPG may differ from prior studies of panobinostat in the adult population 
as well as in children with leukemia, and may be affected by prior treatment, age, body surface 
area, steroid use or concomitant medications. 
 
The pharmacokinetics and tolerability of panobinostat in pediatric patients with DIPG who have 
received standard radiation therapy but have received no other systemic therapy and have not yet 
progressed may differ from the pharmacokinetics and tolerability of panobinostat in pediatric 
patients with recurrent/progressive DIPG. More likely, the pharmacokinetics and tolerability may 
differ with an alternative dosing schedule.  
 
2.5.1.2 Preclinical and Clinical Data 
 
Because there are limited pediatric pharmacokinetic (PK) studies of this agent and none in this 


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29 
 
population, PK information from this study will be essential for evaluating toxicity and disease 
response and for refining dosing in future clinical trials of panobinostat. Mandatory 
pharmacokinetic studies are needed to characterize the full PK profile of panobinostat in this 
patient population, correlate PK with toxicities, and evaluate effects of concomitant medications 
such as dexamethasone. Insights into the biologically active dosage will be gained by relating 
panobinostat systemic exposure (e.g., AUC) to results of pharmacodynamic studies. 
 
In vitro studies indicate that panobinostat is a substrate of CYP3A4, and dexamethasone is a known 
inducer of CYP3A4. Thus, one might expect lower exposures of panobinostat when administered 
concurrently with dexamethasone. It will be important to therefore correlate pharmacodynamic 
effects of panobinostat with PK. The pharmacokinetics of panobinostat may be affected by age, 
body surface area, steroid use or concomitant medications. 
2.5.2 Rationale for Pharmacodynamic Studies 
 
2.5.2.1 Cell-free DNA in peripheral blood or urine 
 
Several tumor suppressor genes associated with the malignant phenotype are repressed by 
epigenetic mechanisms in sporadic cancers. Thus, therapy with DAC inhibitors may alter tumor 
phenotype and inhibit growth in such tumors. In collaboration with Nada Jabado, who has 
established a method to detect H3K27 in serum and urine, we will prospectively evaluate this 
method and evaluate potential changes after treatment with panobinostat. 
 
 


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3 Patient Selection 
 
All subjects must meet the following inclusion and exclusion criteria.  No exceptions will be 
given. Imaging studies to establish eligibility must be done within two weeks, prior to enrollment. 
Clinical evaluations to establish eligibility must be done within 7 days prior to enrollment.  
3.1 
INCLUSION CRITERIA FOR CHILDREN WITH RECURRENT/ PROGRESSIVE 
DIPG (Stratum 1) 
 
3.1.1 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. 
 
3.1.2 Age 
Patients must be ≥ 2 but < 22 years of age at the time of enrollment. 
 
3.1.3 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. 
 
3.1.4 Ability to Swallow 
Patient must be able to swallow capsules whole. 
 
3.1.5 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. 
 
3.1.6 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.  
 
3.1.6.1 Myelosuppressive Chemotherapy: 
Patients must have received their last dose of known myelosuppressive anticancer therapy 


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or immunotherapy at least 21 days prior to enrollment (42 days if prior nitrosourea).  
 
3.1.6.2 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.  
o 
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. 
o Note: A list of the half-lives of commonly used monoclonal antibodies is available 
on the PBTC webpage under Generic Forms and Templates.  
 
3.1.6.3 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 
 
3.1.7 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 in Table 8. Patients that do not meet the 
criteria in Table 8 but have a 24-hour Creatinine Clearance or GFR (radioisotope or 
iothalamate) ≥ 70 ml/min/1.73 m2 are eligible.  
 
Table 8 
 
Serum Creatinine for age/gender 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
2 to < 6 years 
0.8 
0.8 


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6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
• Cardiac Function:  
o Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening 
fraction of ≥ 27% by echocardiogram 
o Patient has no ventricular arrhythmias except for benign premature ventricular 
contractions. 
o Patient has a QTc interval < 450 ms. 
 
3.1.8 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. 
 
3.1.9 Fruit 
Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the 
entire study. 
 
3.1.10 Pregnancy Status 
Female patients of childbearing potential must have a negative serum or urine pregnancy test.  
 
3.1.11 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. 
 
3.1.12 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. 
3.2 
EXCLUSION CRITERIA FOR CHILDREN WITH RECURRENT/ PROGRESSIVE 
DIPG (Stratum 1) 
 
3.2.1 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. 
 


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3.2.2 Neurological Status 
Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, 
in the opinion of the treating physician. 
 
3.2.3 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. 
 
3.2.4 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. 
 
3.2.5 Other Malignancy 
Patients have a history of any other malignancy. 
 
3.2.6 Transfusions 
Patients are known to be refractory to red blood cell or platelet transfusions. 
 
3.2.7 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. 
 
3.2.8 Breastfeeding 
Female patient is breastfeeding. 
 
3.2.9 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 
3.3 
INCLUSION CRITERIA FOR CHILDREN WITH NON-PROGRESSED DIPG or 
H3K27M+ Thalamic DMG (Stratum 2) 
 
3.3.1 Diagnosis  
Patients with DIPG or H3K27M+thalamic DMG 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. 
• 
Thalamic Diffuse Midline Glioma patients will be eligible if there is tissue 


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34 
 
confirmation of the H3K27M mutation by immunohistochemistry or by gene testing 
performed in a CLIA certified laboratory of the investigator’s choice. 
 
3.3.2 Age 
Patients must be ≥ 2 but < 22 years of age at the time of enrollment. 
 
3.3.3 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. 
 
3.3.4 Ability to Swallow 
Patient must be able to swallow capsules whole. 
 
3.3.5 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. 
 
3.3.6 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.  
 
Patients must have recovered from the acute treatment-related toxicities (defined as < grade 1) of 
radiotherapy prior to entering this study.  
 
3.3.6.1 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.  
 
3.3.7 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 in Table 9. 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.  


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Table 9 
 
Serum Creatinine for age/gender 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
• Cardiac Function:  
o Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening 
fraction of ≥ 27% by echocardiogram 
o Patient has no ventricular arrhythmias except for benign premature ventricular 
contractions. 
o Patient has a QTc interval < 450 ms. 
 
3.3.8 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. 
 
3.3.9 Fruit 
Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the 
entire study. 
 
3.3.10 Pregnancy Status 
Female patients of childbearing potential must have a negative serum or urine pregnancy test.  
 
3.3.11 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. 
 
3.3.12 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. 
 
 


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3.4 
EXCLUSION CRITERIA FOR CHILDREN WITH NON-PROGRESSED DIPG or 
H3K27M+ Thalamic DMG (Stratum 2) 
 
3.4.1 Prior Therapy 
• Patients who have had > 60 Gy total radiation to the pons or thalamus (e.g. patients who 
have received re-irradiation) 
• Patients who have had valproic acid within 28 days prior to enrollment. 
 
3.4.2 Neurological Status 
Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, 
in the opinion of the treating physician. 
 
3.4.3 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. 
 
3.4.4 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. 
 
3.4.5 Other Malignancy 
Patients have a history of any other malignancy. 
 
3.4.6 Transfusions 
Patients are known to be refractory to red blood cell or platelet transfusions. 
3.4.7 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.  
 
3.4.8 Breastfeeding 
Female patient is breastfeeding. 
 
3.4.9 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 
 
3.5 
Treatment at Primary Institution 
All experimental protocol therapy should be dispensed and all on treatment imaging studies should 
be obtained at a PBTC institution. Laboratory studies, excluding pharmacokinetic and biologic 
assays, may be performed at a CLIA certified laboratory of the investigator’s choice. Imaging 
utilized to determine eligibility may be performed at an outside institution if all required imaging 


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37 
 
sequences are included and the study is deemed of adequate quality by the treating team. All 
required physical examinations, laboratory parameters need to be performed at the primary PBTC 
institution during the dose finding period of the protocol. 
3.6 
Criteria to Start Treatment 
• Subjects must start therapy within seven (7) days of enrollment. 
• Laboratory values must be no older than 7 days prior to the start of therapy. If a test that is 
repeated post enrollment and prior to the start of therapy is outside the limits for eligibility, 
it must be rechecked within 48 hours prior to the start of therapy. If rechecks are still outside 
the limits for eligibility, the patient may not receive protocol therapy and will be considered 
off study 
• Cardiac requirements: please see Section 3.3.7. 
• If, in the opinion of the treating physician, a patient’s neurologic condition significantly 
worsens within 72 hours prior to treatment, the patient should not start treatment and should 
be taken Off Study. 
 
4 Registration Procedures 
4.1 
CTEP Investigator and Research Associate Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam . In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 


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Documentation Required 
IVR NPIVR AP A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at 
.  
 
4.1.1 CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). The protocol-specific 
regulatory documents are found on the PBTC website. 
 
4.1.2 IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol. The IRB approval and supporting documentation will be submitted to the CTSU 
Regulatory Office by the PBTC Protocol Coordinator.  In addition, each IRB approval will be sent 
to the protocol sponsor, NCI CCR.   Submission must be completed before the site will be approved 
to enroll patients.   For PBTC studies, the IRB approval packet will be uploaded to the PBTC.  
Once all documents are received and confirmed to be accurate and complete, the responsible 
coordinator will forward the study packet to the CTSU Regulatory Office. Study centers can check 
the status of their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU members’ website by entering credentials at 
https://www.ctsu.org.   
 


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4.1.3 Downloading Site Registration Documents:   
 
Site registration forms may be downloaded directly from the CTSU website.   
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 Click on the Regulatory tab  
 Click on the RSS Browser, then go to “printable CTSU Forms” 
 Select and download the two forms noted in Section 4.1.4.  
 
4.1.4 Requirements for PBTC-047 Site Registration: 
 
 CTSU IRB Certification  
 CTSU IRB/Regulatory Approval Transmittal Sheet  
 
4.1.5 Submitting Regulatory Documents:  
 
Submit completed forms along with a copy of your IRB Approval and approved Informed Consent 
to the PBTC via the PBTC document upload system. Once all documents are received, the 
responsible Protocol Coordinator listed on the study cover page will submit the regulatory 
documents to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU 
RSS.  
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB approval record 
to be completed: 
• Holds an active CTEP status; 
• Rostered at the site on the IRB approval and on at least one participating roster; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with PBTC; and 
• Compliance with all protocol-specific requirements (PSRs) 
 
4.1.6 Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  


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• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
4.2 
General Guidelines 
4.2.1 Prior to Consent 
 
Prior to consenting a patient, site staff must verify a slot is available by checking either the 
PBTC Protocol Status web page or using the CTSU OPEN Slot Reservation System.   
4.3 
Enrollment Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the PBTC 
registration/randomization systems for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations: Must be on an PBTC roster with the 
role of Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• The registrars must hold the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, 
the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 
1572 in RCR. The IVR or NPIVR must be assigned the appropriate OPEN-related tasks on the 
DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
 


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Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU Help 
Desk at 1-888-823-5923 or 
. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN. Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient. Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
5 Treatment Plan 
 
Treatment may be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 7. Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's tumor.  
5.1 
Agent Administration  
 
Patients with recurrent/progressive DIPG will be enrolled at the time of progression in Stratum 1. 
Therapy with panobinostat will be administered every other day, 3 times/ week, p.o. preferably on 
a Monday/Wednesday/Friday schedule for three weeks, followed by one week off of therapy.  
Three weeks of therapy plus the one week rest period (total 4 weeks) will constitute one course. 
Treatment will continue for up to 26 courses (approximately 2 years) barring progressive disease 
or unacceptable toxicity.   
 
Patients with DIPG or H3K27M+ Thalamic DMG who have not progressed will be enrolled after 
receiving standard radiation therapy in stratum 2 and cannot begin treatment until at least 14 days 
after completion of radiation. Therapy with panobinostat will be administered every other day, 3 
times/ week, every other week.  A minimum of 6 days without drug is required between 
treatment weeks. Four weeks will constitute one course. Treatment will continue for up to 26 
courses (approximately 2 years) barring progressive disease or unacceptable toxicity.   
5.1.1 Panobinostat  
Panobinostat will be provided by Secura Bio Inc. Oral panobinostat will be supplied as 5 mg, 10 
mg, 15 mg orange colored, and/or 20 mg reddish colored opaque, hard gelatin capsules. 
 
Subjects will be assigned a dose level at the time of enrollment.  See Section 5.1.6 below for details 
of dose escalation schedule. See Section 6 for dose modifications. 
 
Dosing should be adjusted based on BSA calculated at the beginning of each course of therapy. 
The dose prescribed should be rounded to the nearest deliverable dose based on the BSA 
adjustment and the available pill sizes. Dosing Tables which reflect this approach are available in 
Appendix D: Dosing Tables. Patients will be provided with a Medication Diary for panobinostat, 
instructed in its use, and asked to bring the diary as well as the remaining pill bottles with them to 
each appointment. The Patient Diary is available in  
 


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Appendix E: Patient Diary. 
Patients are encouraged to take their dose of panobinostat at the same time each day, preferably in 
the morning. Each dose of panobinostat should be taken with a 4 oz / 120 ml glass of water.  Drug 
must be taken on an empty stomach (either 1 hour before or after meals) on Course 1, Days 1 and 
3, and may be taken with or without food for the remaining doses.  Patients should be instructed 
to swallow the capsules whole and not chew them. Patients must avoid grapefruit or grapefruit 
juice and Seville (sour) oranges during the entire study. 
 
If the patient forgets to take his/her dose during the morning on a scheduled treatment day, then 
he/she should take panobinostat on that same day within 12 hours after the missed dose if possible. 
After more than 12 hours, that day’s dose should be withheld, and the patient should wait to take 
panobinostat until the next scheduled treatment day (i.e., patients should be instructed not to try to 
make-up the missed dose after 12 hours). The patient should then continue treatment with the 
original dosing schedule. If vomiting occurs within 15 minutes, the dose should be repeated. If a 
dose is missed/ unable to be given, record on the patient diary and continue counting the days of 
the course, with treatment administered on originally scheduled days.   
5.1.2 Criteria for Starting Subsequent Courses 
 
A course may be repeated every 28 days if the patient has at least stable disease, has not met any 
off treatment criteria (Section 5.3.2), has again met laboratory parameters as defined in Section 
3.1.7, and any significant toxicity has resolved to acceptable parameters as indicated in Section 6.   
 
5.1.3 Dose-Limiting Toxicity  
 
Management and dose modifications associated with adverse events are outlined in Section 6. DLT 
will be defined as any of the events listed in this section that are at least possibly related to 
panobinostat that occur during the dose-finding period regardless of expectedness. The dose-
finding period is defined as the first course of therapy in both strata.  
 
Management and dose modifications for toxicities which occur outside of the dose-finding period 
should also follow Section 6; however, these will not be considered dose limiting for the purpose 
of dose escalation.    
5.1.4 Definitions of Dose-Limiting Toxicities (DLTs):  
 
Patients who miss more than 2 doses due to toxicity will be considered to have 
experienced a DLT.  
 
5.1.4.1 Non-hematologic dose limiting toxicity is defined as:  
 
- 
Any Grade 3 or greater non-hematologic toxicities with the specific exclusion of the 
following:  
o Grade 3 nausea/vomiting that is responsive to antiemetics, and that resolves to ≤ 
Grade 2 within 5 days 
o Grade 3 electrolyte abnormality that resolves to ≤ Grade 2 within 5 days 
o Grade 3 rash that is not considered medically significant or intolerable by the 


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patient 
o Grade 3 diarrhea that resolves to ≤ Grade 1 with optimal use of anti-diarrheal 
medication 
o Grade 3 fever that resolves to ≤ Grade 2 within 5 days 
o Grade 3 infection that resolves to ≤ Grade 2 within 5 days 
 
- 
Any Grade 2 non-hematological toxicity that persists for more than 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by patients as 
to warrant treatment interruption and/or dose reduction will be considered dose 
limiting. 
- 
Any panobinostat-related non-hematological toxicity that results in a delay of 
treatment > 14 days between treatment courses  
 
5.1.4.2 Hematologic dose limiting toxicity is defined as: 
 
- Grade 4 thrombocytopenia (platelet count < 25,000/µL) 
- Grade 3 thrombocytopenia with bleeding  
- Grade 3 thrombocytopenia (platelet count ≥ 25,000 but <50,000/µL) that occurs twice 
within a treatment course will be considered a DLT. (Note: platelet transfusions are 
recommended for platelet counts <50,000/µL and transfusion should target platelet 
corrections to >100,000 /µL) 
- Myelosuppression that causes greater than a 14-day delay between treatment courses 
- Grade 4 neutropenia 
-  Grade  3 or 4 febrile neutropenia 
 
5.1.4.3 Follow-up for toxicities: 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value must be followed until resolution or stabilization of the event, or 
initiation of another antitumor treatment, or initiation of hospice/symptomatic care only, 
whichever comes first.  
All patients will be followed for adverse events and serious adverse events for at least 30 days 
following the last dose of oral panobinostat, or upon initiation of another antitumor treatment. 
5.1.5 Dose-finding Period  
 
The dose finding period begins with the initial dose of panobinostat and ends on the last day of 
course 1 (approximately 4 weeks).  Should there be a delay starting the subsequent course, dose 
finding will complete on the start date of the subsequent course.  
 
5.1.6 Dose Escalation Schema 
 
Enrollment will commence at dose level 1 i.e. 10mg/m2. The dose finding will be governed by a 
two stage continual reassessment method (CRM), as detailed in Section 13 of this protocol. No 
intra-patient dose escalations will be allowed. 
 
 


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Table 10 below provides the dose escalation schedule proposed for Stratum 1. While the starting 
dose level is lower than what has been tolerated in the pediatric Phase 1 study in hematologic 
malignancies, it reflects the dose levels agreed upon by Novartis. Also note that the dose 
increments are higher than the conventional 30% in the lower doses. This was done in order to 
avoid overlaps in the deliverable doses due to pill size limitations as applied to BSA based dosing. 
Please see Section 13.1.1 for further details. 
 
Table 10: Proposed dose escalation schedule for panobinostat in children with 
recurrent/progressive DIPG (Stratum 1) 
 
Dose 
level # 
panobinostat oral dose (mg) 
 
Minimum BSA Restriction 
0* 
5 mg/m2/day MWF, three weeks on, one week 
off (1 course = 28 days) 
Patients must have a BSA ≥ 0.80 m2  
 
1  
(starting 
dose 
level) 
10 mg/m2/day MWF, three weeks on, one week 
off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
2 
16 mg/m2/day MWF, three weeks on, one week 
off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
3 
22 mg/m2/day MWF, three weeks on, one week 
off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
4 
28 mg/m2/day MWF, three weeks on, one week 
off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2 
5 
36 mg/m2/day MWF, three weeks on, one week 
off, (1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2 
 
Panobinostat will be administered as a single 
agent 
* Dose level 0 represents a potential 
treatment dose for patients requiring a dose 
reduction from dose level 1 and may be used 
as a contingency dose level if the starting 
dose level of panobinostat is not tolerated in 
the initial cohort. 
 
 
Upon completion of Stratum 1, patients with DIPG who have received adequate radiation therapy 
but have not yet progressed will be enrolled in Stratum 2. Panobinostat will be administered every 
other day, 3 times/week, every other week p.o. preferably on a Monday/Wednesday/Friday 
schedule.  Total 4 weeks will constitute one course. Treatment will continue for up to two years 
(26 courses) unless the patient experiences progressive disease, unacceptable toxicity or any of the 
off-treatment criteria. 
 
The starting dose (dose level 1) for Stratum 2 will be 1 dose level above the highest safe dose for 
the ‘3-weeks on, 1-week off’ schedule as determined in Stratum 1. The rationale is that 1 week on 


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1 week off schedule represents a reduction in the amount of drug patients will receive per course 
and thus a dose level that is safe for ‘3-weeks on, 1-week off’ schedule should also be safe for the 
every other week schedule.. The current expectation is that 10mg/m2 will be the MTD for the ‘3-
weeks on, 1-week off’ schedule and thus we expect to start exploring the ‘every other week’ dosing 
schedule at 16 mg/m2/day. However, if 10mg/m2 dose level is determined to be unsafe in the ‘3-
weeks on, 1-week off’ schedule we will abandon that schedule and initiate dose escalation for 
Stratum 2 at 10mg/m2. The table below lists the proposed dose levels to be studied: 
 
Table 11 
Proposed dose escalation schedule for panobinostat in children with non-progressed DIPG or 
H3K27M+ Thalamic DMG (Stratum 2) 
 
If patients are unable to tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to keep the patient on study drug. If administration of panobinostat must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified according 
to Sections 6.2 and 6.3. The first course (day of first dose until initiation of Course 2) will be the 
DLT observation period.   
 
 
Dose level # 
panobinostat oral dose (mg) 
 
Minimum BSA Restriction 
-1* 
5 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.80 m2  
 
0* 
10 mg/m2/day MWF, every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
1  
 
16 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
2 
22 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.65 m2  
 
3 
28 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2  
 
4 
36 mg/m2/day MWF,  every other week  
(1 course = 28 days) 
Patients must have a BSA ≥ 0.50 m2 
 
Panobinostat will be administered as a single 
agent 
* Dose levels 0 and -1 represent potential 
treatment doses for patients requiring a 
dose reduction from dose level 1 and may be 
used as a contingency dose level if the 
starting dose level of panobinostat is not 
tolerated in the initial cohort. 
 


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5.2 
Concomitant Medications and Supportive Care Guidelines 
 
5.2.1 Potential QTc prolonging medications 
 
Concomitant medications which can prolong the QTc interval should not be used. Please see 
Appendix B: Medications Which May Cause QTc Prolongation, for a partial list of medications 
with the potential to prolong the QTc interval. Providers should consult a frequently-updated drug 
information reference for a complete list. 
 
5.2.2 CYP3A4 and CYP2D6 
 
Co-administration with medications that are strong CYP3A4 inducers should be avoided. Co-
administration with medications that are strong CYP3A4 inhibitors and sensitive CYP2D6 
substrates is feasible when medically necessary and with close monitoring. Please see Appendix 
C: Partial List of Common Moderate and Strong Inhibitors of CYP3A4, and Common 
Sensitive CYP2D6 Substrates. Providers should consult a frequently-updated drug information 
reference for a complete list. 
 
5.2.3 Steroids 
 
Corticosteroids should be used at the lowest dose to control symptoms of edema and mass effect, 
and discontinued, if possible. Use of corticosteroids should be recorded in the PBTC Rave 
database. 
 
5.2.4 Anticonvulsants 
 
Anticonvulsants drugs should be used, if indicated. Use of anticonvulsants should be recorded in 
the PBTC Rave database. Note: Use of valproic acid or enzyme inducing anti-convulsants is 
prohibited on this trial. Note that levetiractam (Keppra) may cause prolongation of the QTc and 
patients who must remain on Keppra should be closely monitored. 
 
5.2.5 Growth Factors 
 
Routine use of growth factors (i.e. G-CSF, GM-CSF and erythropoietin) is not permitted.  
However, therapeutic use of G-CSF or GM-CSF in patients with serious neutropenic conditions, 
such as sepsis, may be considered at the investigator’s discretion. Use of growth factors should be 
recorded in the PBTC Rave database. 
 
5.2.6 Anti-emetics  
 
The use of anti-emetics will be at the investigator’s discretion.  Use of anti-emetics should be 
recorded in the PBTC Rave database.  Steroids should not be used as anti-emetics when possible. 
 
5.2.7 Febrile neutropenia 
 
Febrile neutropenia should be managed according to the local institutional guidelines.  Measures 


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include laboratory testing, blood and urine cultures, and institution of broad spectrum antibiotics. 
 
5.2.8 Pneumocystis jiroveci pneumonia (PJP) prophylaxis 
 
The use of medication (e.g., Bactrim) for PJP prophylaxis in patients on chronic steroids is 
recommended but is at the investigator’s discretion. 
 
5.2.9 Neurosurgical or other surgical procedures 
 
If a neurosurgical procedure or other surgical procedure is required for a reason other than tumor 
progression (i.e. the onset of hydrocephalus), these procedures should be documented, but will not 
constitute criteria for declaring the patient “off therapy”.  Panobinostat should be held until the 
patient is clinically stable and has recovered from the acute effects of surgery. 
 
5.2.10 Diarrhea 
 
Patients should be advised to drink plenty of water or rehydration fluids to avoid dehydration if 
diarrhea occurs. Should diarrhea occur, investigators should ensure that patients have loperamide 
on hand and follow the loperamide dosing guidelines in Table 12 below, at first onset of the 
symptom. Dehydration prevention and correction of electrolyte disturbances should be practiced 
as per institution’s SOP.  Stool count and consistency should be noted in the patient diary if 
treatment for diarrhea is instituted. 
 
Refer to Table 13 for details of panobinostat dose reduction, and Table 12 below for details of 
suggested loperamide dosing based on patients body weight. 
 
Table 12 
 
Weight Specific Guidelines for Therapeutic Use of Loperamide 
Weight (kg) 
Initial (Loading) 
Loperamide dose (mg) 
Subsequent daytime 
loperamide dose 
Subsequent nighttime 
loperamide dose 
8-10 
1 
0.5mg q 3h 
0.75mg q 4h 
10-20 
1 
1mg q 3h 
1mg q 4h 
20-30 
2 
1mg q 3h 
2mg q 4h 
30-42 
2 
1mg q 2h 
2mg q4h 
42 
4 
2mg q 2h 
4mg q 4h 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s) or disease progression, treatment may 
continue for 26 courses (approximately 2 years) or until one of the Off Treatment Criteria applies 
as noted in Section 5.3.2. 
 
5.3.1 On Study Data Submission Schedule 
 
Pre-treatment, on-study and off-treatment data, as well as patient response data are to be recorded 
in the electronic data collection screens using the PBTC Rave database.  See the Required Data 


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and Timetable for Submission form located on the PBTC-047 Protocol webpage for the schedule.  
For assistance, contact the PBTC Protocol Coordinator listed on the cover page. An optional 
roadmap is located on the PBTC-047 Protocol Webpage. 
 
5.3.2 Off Treatment Criteria 
 
At the discontinuation of treatment, the “Off Treatment Date” is to be recorded in the eCRF and 
is to be consistent with the reason given for going off treatment. The “Last Treatment Date” is 
defined as the last date that the patient received protocol based therapy.  Date of “off treatment” 
must be the greatest of the date of last treatment, date of procedure, date of patient assessment, 
notification of patient/family decision, or decision made by the physician that resulted in the 
patient being taken off protocol treatment.  The reason for discontinuation of treatment must be 
documented by the attending investigator in the medical record and recorded in the eCRF.  
Patients will be considered Off Treatment for the following reasons: 
 Development of unacceptable toxicity as outlined in Section 5.1.3. See Section 7 for 
specific adverse event reporting requirements. 
 Progressive disease (PD) as described in Section 11.2.4.  
 Development of a medical or psychiatric illness or social issue that in the investigator's 
judgment renders the patient incapable of further therapy on this protocol or the treating 
physician determines continuation on this study is not in the patient’s best interest.  
 The patient, parent or legal guardian refuses further treatment on this protocol. In this case 
the investigator should clarify if the family also wishes to withdraw consent for continued 
participation for data collection purposes.  
 Completion of all protocol defined treatment 
 Pregnancy 
 Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
 
Patients who are off protocol therapy must be followed until an “Off Study Criterion” is met. 
5.3.3 Data Submission Schedule for Patients Off-Treatment  
 
Patients will be followed initially for the resolution of all toxicities considered at least possibly 
related to panobinostat occurring while on treatment and for 30 days after the last administration 
of study drug. Patients will continue to be followed for 3 years from the initiation of protocol 
treatment for the monitoring of unexpected later developing toxicities or other morbidity and to 
document disease progression and survival. Once patients are off-treatment and treatment-related 
toxicities have resolved or another treatment started, follow up during this 3-year period may be 
done electronically or by phone.  Data should be updated quarterly in the PBTC Rave database. 
 
5.3.4 Criteria for Removal from Study 
 
The date and reason for the patient coming off study must be documented in the eCRF and the 
OBDMC must be notified according to standard reporting guidelines (see Sections 7 for adverse 
events, Section 5.3.5 for Data submission for Off Study, Section 12 for Data Reporting, and the 
Required Data and Timetable Submission from located on the PBTC-047 protocol webpage).  
 


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• Patient determined to be ineligible. 
• Parent, patient, or guardian withdraws consent for continued participation. 
• Patient death while on study. The IRB, Study Chair and OBDMC must be notified as per 
Section 7.3. 
• Patients removed from treatment for reasons other than withdrawal of consent or Death 
will be followed until three years have elapsed from the date of initiation of protocol 
therapy on this study.   
 
5.3.5 Data Submission for Patients Off-Study 
 
No data will be collected documenting treatment or reporting events or disease status that occur 
subsequent to the official “off study” date, with the exception of adverse events with an attribution 
of possible, probable, or definite that occur after the “off study” date for agents being studied under 
an IND (see Section 7).   
 
6 Dosing Delays/ Dose Modification 
 
6.1 
Notification of Study Chair 
 
The study chair or co-chair must be notified of any dosage modifications, prior to the 
implementation of the dose modification 
 
6.2 
Hematologic and Non-Hematologic Adverse Events and Management 
 
The criteria for dose modifications for study drug-related toxicity are detailed in Table 13. 
 
Dose Modification for Hematological Toxicity 
 
If a patient experiences dose-limiting hematological toxicity as outlined in Section 5.1.4.2  (i.e. 
grade 4 thrombocytopenia [< 25 x 109/L] or grade 3 thrombocytopenia [< 50 and ≥ 25 x 109/L] 
with bleeding,  or grade 3 twice within 1 treatment cycle or grade 4, or grade 3 or 4 febrile 
neutropenia)  treatment will be withheld. Platelets should be transfused to a count of > 100 x 109/L 
(i.e. a post-transfusion platelet count should be obtained). Counts should then be checked every 3-
4 days (and when medically indicated) during this time.  
 
If the toxicity resolves to meet on study parameters within 14 days of drug discontinuation, 
provided there is no current active bleeding in the case of dose-limiting thrombocytopenia, the 
patient may resume therapy at one dose level lower. Patients who are dose-reduced for toxicity 
will not have their dose re-escalated. 
 
If toxicity does not resolve to meet on study parameters within 14 days of drug discontinuation, 
the patient must be removed from protocol therapy. 
 
Only one dose-reduction per patient is allowed.  If any dose-limiting toxicity occurs in a patient 
already dose-reduced for toxicity, the patient must be removed from protocol therapy. 
 


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Table 13 
 
 
Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study drug-
related non-hematological toxicity (excluding QT prolongation) 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a course of therapy 
(including intended day of dosing)  Note: 
If dose limiting toxicity does not resolve 
after holding drug for 14 days, patient will 
be removed from treatment 
NON-HEMATOLOGICAL TOXICITIES 
CARDIAC 
Cardiac - Prolonged QT interval** 
Please refer to Section 6.3. 
GASTROINTESTINAL 
Diarrhea 
Grade 2 (4-6 stools/day over 
baseline, etc.) despite the use of 
optimal antidiarrheal medications 
None.  
If unacceptable to patient or medically 
concerning, then hold until recovery to ≤ 
grade 1, or baseline, up to 14 days, then 
restart original schedule at unchanged dose 
level 
Grade 3 (≥ 7 stools/day over 
baseline, etc.) despite the use of 
optimal antidiarrheal medications 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then restart original schedule  
reduced by one dose level 
Grade 4 (life-threatening 
consequences, hemodynamic 
collapse, etc.) despite the use of 
optimal antidiarrheal medications 
Discontinue panobinostat dosing 
Vomiting/Nausea*** 
Grade 1, 2 not requiring treatment 
or controlled using standard anti-
emetics 
Maintain dose level 
Grade 3  that resolves  to ≤ grade 
2 with standard emetics within 5 
days   
Maintain dose level 
Grade 3 or 4 vomiting or Grade 3 
nausea that cannot be controlled 
or does not resolve to ≤ grade 2 
within 5 days  despite the use of 
standard anti-emetics 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then restart panobinostat reduced 
by one dose level 
FATIGUE 
Fatigue 
Grade 3 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then: 
• If resolved within 7 days after 
suspending panobinostat, then restart 
panobinostat at an unchanged dose level 
• If resolved in more than 7 days after 
suspending panobinostat, then restart 
panobinostat reduced by one dose level 


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Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a course of therapy 
(including intended day of dosing)  Note: 
If dose limiting toxicity does not resolve 
after holding drug for 14 days, patient will 
be removed from treatment 
NON-HEMATOLOGICAL TOXICITIES 
Grade 4 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then: 
• restart panobinostat reduced by one dose 
level 
HEPATIC 
Total Bilirubin 
Grade 3 or 4 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then restart panobinostat reduced 
by one dose level 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the indirect component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then reduction of one dose level and continuation of treatment is at the discretion of 
the Investigator. 
AST/SGOT, ALT/SGPT 
> 5-10 x ULN 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1 or 
baseline, then: 
• If resolved within 7 days, then: 
• restart panobinostat at unchanged dose 
level 
• 
If resolved in more than 7 days, then 
reduce panobinostat by one dose level 
> 10 x ULN 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then: 
• restart panobinostat reduced by one 
dose level 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.0 or 5.0; see Section 7.2) 
 ** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing 
*** See also concomitant medication Section 5.2. 
 
6.3 
Dose Modifications for Prolonged QTc 
 
All cardiac events should be treated according to the local standard of care and referred to a 
cardiologist if clinically indicated. The localized readings of ECGs will use the Fridericia 
correction for QTC interval assessment: QTcF. Any final decisions concerning dose modifications 
or permanently discontinuing the patient from study drug due to QTcF prolongation will be based 
on the Investigator’s clinical assessment. Any plan to deviate from these guidelines must be 
previously discussed and agreed upon with the PI. 
 
 


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Patients must have QTcF < 450 msec to be eligible for the trial. If QTcF is ≥ 450 msec or above 
60 msec from pre-treatment ECG, correct any electrolyte abnormalities (hypokalemia, 
hypomagnesemia, hypocalcemia), and conduct triplicate ECGs (5 minutes apart) and calculate 
average QTcF. If the average QTcF from the triplicate ECGs remains > 450ms, patient must not 
be dosed. Pre-dose ECG monitoring is mandatory on days 1 and 5 of course 1, and day 1 of courses 
2 through 4. Post dose ECG (3 hours post dosing) is mandatory only on days 1and 5 of course 1. 
On day 5 of course 1, ECG may be performed at a local institution but results must be faxed to 
treating institution within the same day.  
 
If a pre-treatment or post-dose ECG shows a QTcF > 500ms, patient is not eligible for further 
treatment. If any of these mandatory ECGs show QTcF ≥ 450 msec or 60 msec above baseline, 
dosing should be held and the above specified measures including follow-up triplicate ECGs and 
correction of electrolyte abnormalities should be performed.  If QTcF abnormality resolves, 
patients should resume treatment and have QTcF checked pre-dose on day 1 of each course for at 
least the next 3 subsequent courses. Additional QTcF monitoring should be performed if clinically 
indicated. If a patient cannot be dosed due to prolonged QTcF for more than 7 days since last dose, 
patient must be discontinued from study treatment. 
 
Table 14 
 
Dose Reductions for QTc Prolongation 
Time Point 
Average QTcF* 
Action 
Screening 
≥ 450 msec 
Patient is not eligible to enroll 
pre-dose course 1 
day 1 
≥ 470 msec 
Delay treatment 
Correct any electrolyte abnormal values 
** and repeat ECG, if the average QTcF ≥ 
470 msec, do not dose 
Above 500 msec 
Patient is not eligible to receive any 
treatment 
Pre-dose course 1 
day 5 
Pre-dose day 1 of 
subsequent courses 
≥ 450 msec or above 60 msec 
from baseline for any pre-dose 
ECG after the patient has 
commenced treatment*** 
Omit dose 
If unresolved within 7 days, discontinue 
treatment 
If resolved within 7 days, resume 
treatment at prior dose for initial 
occurrence or at reduced dose if recurrent 
Above 500 msec 
Permanently discontinue treatment 
*QTcF: Heart rate corrected QT interval using the Fredericia formula: QTc=QT/RR0.33 
**: serum potassium, magnesium, calcium,  
***If a single pre-dose QTcF is ≥ 450 msec or 60 msec from baseline, subsequent ECGs should be 
performed in triplicate 
 
 
 
 
 
 


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7 Adverse Events: List and Reporting Requirements 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of AEs (Section 7.2) and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting (via CTEP-AERS) in addition to routine reporting. 
The coding of attribution in the PBTC Rave database pertains to adverse events related to 
panobinostat.  
 
• Baseline Abnormalities 
Any baseline (pretreatment) abnormalities observed during the initial physical examination should 
be recorded in the PBTC Rave database. 
 
• Treatment or within 30 days of treatment 
Only record adverse events grades 1 and 2 if the attribution is at least possibly related to 
panobinostat.  Record all adverse events grades 3 through 4 and deaths), regardless of attribution 
on the electronic case report forms. 
7.1 
Adverse Events and Potential Risks for Panobinostat 
7.1.1 Very Common adverse events occurring in ≥ 10% of subjects treated with panobinostat 
include, but may not be limited to: 
 
AE Category 
Event Descriptions Included: 
Infections and infestations 
Upper respiratory tract infection, Pneumonia 
Metabolism and nutrition 
disorders 
Decreased appetite 
Psychiatric disorders 
Insomnia 
Nervous system disorders 
Dizziness, Headache 
Cardiac disorders 
Electrocardiographic abnormalities such as ST-
segment depression and T-wave abnormalities 
Vascular disorders 
Hypotension 
Respiratory, thoracic and 
mediastinal disorders 
Cough, Dyspnea 
Gastrointestinal disorders 
Diarrhea, Nausea, Vomiting, Abdominal pain, 
Dyspepsia 
General disorders and 
administration site conditions 
Fatigue, Edema peripheral, Pyrexia, Asthenia 
Investigations 
Weight decreased 
Hematologic 
Thrombocytopenia, Anemia, Leukopenia, 
Neutropenia, Lymphopenia 
Biochemistry 
Blood creatinine increased, Hypokalemia, 
Hypophosphatemia, Hyponatremia, 
Hyperbilirubinemia, SGPT Alanine amino 


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transaminase (ALT) increased, SGOT Aspartate 
amino transaminase (AST) increased 
Cardiac disorders 
Arrhythmias 
 
7.1.2 Common adverse events occurring in 1% to 9% of subjects treated with panobinostat: 
 
AE Category 
Event Descriptions Included: 
Infections and 
infestations 
Septic shock, urinary tract infection, viral infection, oral 
herpes, clostridium difficile colitis, otitis media, cellulitis, 
sepsis, gastroenteritis, lower respiratory tract infection, 
candidiasis 
Endocrine disorders 
Hypothyroidism 
Metabolism and 
nutrition disorders 
Hyperglycemia, dehydration, hypoalbuminemia, fluid 
retention, hyperuricemia, hypocalcemia, hypomagnesemia 
Nervous system 
disorders 
Intracranial hemorrhage, syncope, tremor, dysgeusia 
Eye disorders 
Conjunctival hemorrhage 
Cardiac disorders 
Bradycardia, atrial fibrillation, sinus tachycardia, 
tachycardia, palpitations; cardiac ischemic events 
Vascular disorders 
Hypertension, hematoma, orthostatic hypotension 
Respiratory, thoracic 
and mediastinal 
disorders 
Respiratory failure, rales, wheezing, epistaxis 
Gastrointestinal 
disorders 
Gastrointestinal hemorrhage, hematochezia, gastritis, 
cheilitis, abdominal distension, dry mouth, flatulence 
Hepatobiliary disorders 
Hepatic function abnormal 
Skin and subcutaneous 
disorders 
Skin lesions, rash, erythema 
Musculoskeletal and 
connective tissue 
disorders 
Joint swelling 
Renal and urinary 
disorders 
Renal failure, hematuria, urinary incontinence 
General disorders and 
administration site 
conditions 
Chills, malaise 
Investigations 
Blood urea increased, glomerular filtration rate decreased, 
blood alkaline phosphatase increased, electrocardiogram 
QT prolonged 
 
 
 
 


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7.1.3 Uncommon adverse events occurring in < 1% of subjects treated with panobinostat: 
 
AE Category 
Event Descriptions Included: 
Infections and 
infestations 
Pneumonia fungal, hepatitis B, aspergillosis; infection-
related deaths, primarily pneumonia and/or sepsis that 
could be associated with respiratory or multi organ failure 
Cardiac disorders 
Myocardial infarction 
Vascular disorders 
Hemorrhagic shock; gastrointestinal and pulmonary 
hemorrhage-related death 
Respiratory, thoracic 
and mediastinal 
disorders 
Pulmonary hemorrhage, hemoptysis 
Gastrointestinal 
disorders 
Colitis, hematemesis, gastrointestinal pain 
Skin and subcutaneous 
disorders 
Petechie 
              (Panobinostat Investigator Brochure 202060, Farydak® (panobinostat) Package Insert70) 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for recording AEs in the RAVE database.  The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for  (CTCAE) 
version 5.0 will be utilized for expedited AE reporting beginning April 1, 2018. All 
appropriate treatment areas should have access to a copy of the CTCAE versions 4.0 and 
5.0.  A copy of the CTCAE versions 4.0 and 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expedited Adverse Event Reporting  
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  The reporting 
procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be 
downloaded from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly 
outlined in Table 15 and  
Table 16. 


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In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made by 
telephone at 901-595-5762 to the PBTC Operations Office. Once Internet connectivity is restored, 
the 24-hour notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
7.3.1 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  For this 
protocol the following groups must be copied on expedited reports (24-hour notification and the 
complete report) submitted via CTEP-AERS: 
 
IND Holder: 
Center for Cancer Research 
National Cancer Institute  
 
 
 
 
 
 
 
Study Chair:  
Michelle Monje, MD PhD 
 
 
 
 
 
 
 
PBTC OBDMC: 
 
Suresh (Rama) Ramanathan 
Protocol Coordinator- Pediatric Brain Tumor 
Consortium 
 
 
 
Study Co-Chair: 
Kathy Warren, M.D. 
 
 
 
 
 
 
John Glod, M.D. 
 
 
 
 
 
The PBTC Operations Office will send the SAE/ CTEP-AERS report, within 24 hours of their 
awareness of the event to Secura Bio Inc. by email 
. 
 
The IND Holder, NCI Center for Cancer Research, shall notify the FDA of any event that is both 
a serious suspected adverse reaction and unexpected in accordance with FDA rules and regulations 
(21 CFR 312.32). Follow-up information to a safety report will be submitted, as requested. 


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The IND Sponsor or designee will submit a report of the unexpected, suspected adverse event to 
the FDA using the FDA’s reporting form (FDA 3500A MedWatch Form) and guidelines. The 
report should describe the event as fully as possible. Supporting documentation (lab reports, 
summary notes, and autopsy report) should accompany the report. A fatal or immediately life-
threatening suspected adverse event will be reported to the FDA within 7 calendar days of the 
receipt of the initial report by the IND sponsor. A non-fatal, non-life threatening unexpected, 
suspected, serious adverse event will be reported to the FDA within 15 calendar days of receipt of 
the initial report by the IND Sponsor.  
 
The PBTC OBDMC will post all IND Safety Letters on the PBTC-047 webpage. Sites will be 
notified via email of the receipt of the IND Safety Letter(s) and instructed to submit these to their 
local IRB in accordance with the institution‘s requirements. 
 
A copy of the Annual Progress Reports is submitted by the IND holder as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators by the sponsor-investigator. Additionally, a copy of these reports will be submitted to 
CTEP at the time of submission to the appropriate regulatory agency. 
7.3.2 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial enrollment 
on all reports. 
 
Note:  A death on treatment requires both routine and expedited reporting regardless of causality, 
unless as noted below.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
 
Table 15 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 


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may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
7.3.3 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-
AERS.  However, they still must be reported through the routine reporting mechanism (Section 
7): 
 
Table 16 
 
CTCAE SOC Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Investigations 
Lymphopenia 
≤ 4 
Not required 
Any 
 
 
7.3.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine (CTMS or CDUS) study data submissions.  AEs 
reported through CTEP-AERS must also be reported in routine study data submissions. 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 


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done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times during 
the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
7.3.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy such as acute myelocytic leukemia 
(AML) 
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.3.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
 
7.3.7 NCI Guidance for Reporting Protocol Deviations 
 
The site must enter all protocol deviations into the PBTC RAVE database. Participating centers 
must also submit the report to their IRB in accordance with their institutional policies.  Protocol 
deviation data entered in the PBTC RAVE database will be imported periodically to the NCI 
Protocol Support Office. 
 
 
 


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8 Agent Information 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
8.1 
Panobinostat 
 
Chemical Name: 2-Hydroxypropanoic acid, compd. with 2(E)-N-hydroxy-3-[4-[[[2-(2-methyl-
1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (1:1) 
 
Other Names: (LBH589-lactate); Farydak® 
 
Classification: Histone Deacetylase (HDAC) Inhibitor 
 
CAS Registry Number: 404950-80-7 
 
Molecular Formula:  C21H23N3O2·H2O monohydrate 
 
 
 
M.W.: 439.50416 g/mol 
 
Mechanism of Action: May include effects on epigenetic mechanisms of gene expression as well 
as modulation of acetylation and function of histones 
 
Formulation: Oral formulation: hard gelatin capsules contain panobinostat lactate salt at dosage 
strengths of 5 mg, 10 mg, 15 mg and 20 mg as anhydrous free base. The 5mg and 15mg capsules 
are packaged in high-density polyethylene (HDPE) bottles with an induction seal and plastic CR 
closure. The 10mg and 20mg formulations are packaged in blister packs with 6-ct capsules/pack. 
The 5 mg formulation will no longer be available after July 2021. 
 
Storage:  Store in a very tight packaging with water permeation <0.5 mg/day/liter, protect from 
light. Store below 25°C. 
 
Stability: The shelf life for the capsule formulations is assigned based on ongoing stability studies. 
 
Availability: Panobinostat capsules are provided by Secura Bio Inc. 
 
Route of Administration:   Capsules are to be taken orally by mouth and swallowed whole. 
8.2 
Agent Ordering  
 
Panobinostat may be requested by the Principal Investigator or designees at each participating 
institution. All regulatory documents, as required by the PBTC, must be current and up to date 
prior to requesting the study drugs. Drug request form can be found on the PBTC-047 protocol 
and resources webpage under https://www.pbtc.org/members/Protocols/protocols.htm. The form 
can 
be 
emailed 
to 
 
and 
 
at 
 at Secura Bio Inc. (Phone number 
).   
 


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The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents, using the NCI Drug Accountability Record 
Form (DARF).  See the CTEP home page at http://ctep.cancer.gov or the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage. 
8.3 
Agent Inventory Records 
 
Study personnel must ensure that all study medication and supplies are kept in a secure locked area 
with access limited to authorized personnel.  This study product must not be used outside the 
context of this protocol.  Under no circumstances should the investigator or site personnel supply 
study product to other investigators or clinics or allow the supplies to be used other than as directed 
by this protocol. 
 
The investigator and/or the responsible site personnel must maintain accurate records of the receipt 
of all study medication shipped by National Cancer Institute or its designee, including, but not 
limited to, the date received, lot number, amount received, and the disposition of all study 
medication.  Sites may use the NCI Drug Accountability Record Form (DARF) for this purpose.  
Current dispensing records must also be maintained that include the date and amount of medication 
dispensed, relevant batch or bottle code numbers, and study number assigned to the subject. The 
NCI DARF can be found at (http://ctep.cancer.gov/protocolDevelopment/requisition_agents/docs/ 
accountability.pdf), the NCI DARF can also be found on the PBTC website under Generic Forms 
and Templates. 
 
 
 


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9 Pathology, Biomarker, Correlative, and Neuro-Imaging 
 
This section contains the collection, shipping and handling information for all planned biomarker 
and exploratory correlative studies, neuropathology review and research imaging.  The table below 
identifies the tests, sample type and amount, analyzing laboratory and whether it is required or 
optional.  For additional details, please review the associated section below.  
 
Table 17 
 
Test Name 
 
Sample Type  
Analyzing Laboratory 
Required or 
Optional 
Section 
ID 
PBTC Repository  
FFPE tumor material and 
blood 
Children’s Hospital Los 
Angeles 
Optional 
9.1 
Pharmacokinetics 
Plasma 
 Figg Lab, NCI 
Required 
9.2 
Pharmacodynamics: 
Cell-free DNA 
Blood 
McGill University 
Optional 
9.3 
 
9.1 
Pathology Central Review and Biorepository  
 
The Pathology Central Review and Biorepository (CRB)’s function is to collect, distribute and 
store specimens for central pathology review and planned correlative studies which support the 
laboratory objectives of this protocol.   
 
The CRB will also serve as a central repository for specimens collected for future research and left 
over specimens (tumor tissue, blood, urine or CSF) returned to the repository following the 
planned analysis from patients who consent to long term storage of unused specimen.  These 
samples will be stored in the repository for undefined future studies which support the mission of 
the PBTC.  If the patient does not consent to participation in the repository, correlative study 
samples should be submitted following the guidelines in the appropriate correlative study 
section below. If the patient does not consent to long term storage, remaining correlative 
study samples will be destroyed once the PBTC-047 analysis is complete. 
 
9.1.1 PBTC CRB Submission Guidelines  
 
If the patient consents to provide slides for submission to the repository at the time of 
participation in a PBTC trial the following should be submitted:  
 
• Tumor material  
Slides from the original and/or recurrent surgery should be prepared for storage. The site 
should provide up to twenty (20) unstained sections cut at 4µm in thickness on (+) slides 
from the most representative section. Fewer unstained sections may be submitted based on 
size and availability of tissue.  Preference is for tissue that has not previously been 
frozen.   The corresponding pathology report(s) including immunohistochemical, special 
stains, and molecular/genetic results is to be uploaded to the PBTC using the secure File 
Upload system.  These reports will be made available to the pathologist via a link in the 
ProtoLab. 


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Suitability of sections would be established by preparing one (1) H&E to ensure that the 
sections meet the following criteria:  
o Histologically representative of the reported lesion 
o Contain at least 60% viable tumor 
o No more than 40% necrosis 
 
• Pre-Treatment Peripheral Blood Mononuclear Cells and Plasma 
PBMC may be collected by processing a 2-5ml whole blood specimen with Ficoll or 
collecting the specimen in a BD Vacutainer™ CPT™ Cell Preparation Tube with Sodium 
Citrate as noted below. Once separated, all pellets must be snap frozen and stored at least 
at -20oC prior to dry ice shipment 
 
Specimen Collection and Processing by Ficoll tube 
o Collect 2 - 5ml of fresh blood into an EDTA tube. 
o Transfer blood into a sterile 50-mL tube and add double the amount of PBS. MIX 
GENTLY. 
o Set up another tube containing half of its total volume of Ficoll. For example, if 
there is 15 mL of blood + PBS, then use 7.5 mL of Ficoll (2:1 ratio). 
o At very slow pace (approx. 2 mL/minute), layer the blood + PBS mixture onto the 
Ficoll so that the solutions DO NOT MIX. Spin the blood/Ficoll at 750 g in slow 
mode for 30 minutes @ 25ºC. After spin you will see four distinct layers: plasma 
(top layer), white fluffy ring (2nd layer), Ficoll (3rd layer), and blood (bottom 
layer). 
o Remove plasma layer down to about 1 mL above the white fluffy ring and 
dispense into cryovials.  Freeze the cryovials within 1 hour of collection and store 
immediately at -20°C or colder. 
o Collect the entire white fluffy ring. If ring is hard to see, also take extra liquid 
above. Then discard everything else. 
o Place this fraction of white blood cells into a fresh 50 mL sterile tube with 20 mL 
of PBS.  Spin down for 10 minutes @ 25ºC, 750 g in fast mode. Remove the 
supernatant. Add back to pellet 1 mL of PBS and spin for 5 min. at 4°C at 
10000rpm. Remove supernatant.  
o Freeze the pellet of WBCs in a 2ml cryovial and store at -80ºC until shipment. 
o Ensure that all tubes are clearly labeled with the PBTC patient accession number. 
Please ensure that the labeling system used is designed to withstand temperatures 
down to -80oC. Samples should be stored at -80ºC until shipment. For short term 
storage (2-3 weeks) -20ºC is acceptable. NOTE 4ºC IS NOT ACCEPTABLE 
STORAGE.  
* If it is not possible to collect the PBMC by Ficoll gradient then separation of PBMC 
can be conducted using CPT tube separation as an alternative. However, the 
PBMC pellet MUST BE frozen immediately and stored at -80oC. 
 
Collection and Processing by CPT tube 
o Peripheral blood should be collected in a BD Vacutainer CPT™ Cell Preparation 
Tube with Sodium Citrate. 8ml and 4ml CPT tubes can be obtained from Fisher 


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Scientific (Cat# 02-685-125, 02-688-81) or Becton-Dickinson (BD No.362761, 
362760).  The 8ml tubes have a 6ml minimum draw and the 4ml tubes have a 3ml 
minimum draw.  
o Centrifuge the CPT™ tube at 1500 x g for 30 minutes at room temperature (20o C 
to 25o C). DO NOT APPLY THE BREAK ON THE CENTRIFUGE.  Use 
acceleration 5, brake 0 (“slow mode”).   
o It may be necessary to spin the tube longer to ensure that all of the red blood cell 
components have been separated from the plasma layer through the polyester gel 
barrier. 
o The tube should be removed immediately from the centrifuge. The mononuclear 
layer and plasma lie above the polyester gel plug. 
o Using a sterile pipette, remove as much of the plasma component (upper half of the 
CPT tube) without disturbing the mononuclear layer if possible and aliquot it into 
cryovials.  Freeze the cryovials within 1 hour of collection and store immediately 
at -20°C or colder. 
o Transfer mononuclear cell layer (and some residual plasma layer) to a labeled 15-
mL conical centrifuge tube and add 5ml sterile room temperature magnesium or 
calcium-free phosphate buffered saline (PBS) to fill the conical tube and recap. 
o Centrifuge at 450 x g for 10 minutes at room temperature (20o C to 25o C).  Use 
acceleration 9, brake (“fast mode”).  
o Remove supernatant, being careful not to aspirate the cellular pellet at the bottom 
of the tube.  
o Add 1mL of sterile PBS to the pellet and gently re-suspend by pipetting up and 
down. Transfer the entire suspended pellet to the labeled 2ml cryovial.   
o Centrifuge the cryovial at 450 x g for 5 minutes (or spin down the microcentrifuge 
tube at 1300 x g for 5 minutes) at room temperature. Discard the supernatant. 
o Store the cell pellet cryovial frozen at -80ºC. For short term storage (2-3 weeks) -
20o C is acceptable. 
 
• If the patient consents to other secondary correlative studies as outlined in Section 9.3, the 
following specimens may also be submitted to the CRB for distribution and storage: 
o Peripheral blood cells: quantity and schedule of collection as outlined in Section 
9.3.1 and 9.3.2 
 
9.1.1.1 Handling of Specimens 
 
• Slides are to be labeled with the study ID and the patient PBTC Accession # and these 
slides should be designated as PBTCR # (where the # assigned from 1 to 20, or the highest 
number of unstained sections prepared, sequentially) or PBTCR H&E for the H&E stained 
section.  
• Scrolls or Formalin Fixed, Paraffin Embedded (FFPE) tumor materials are to be labeled 
with the PBTC Accession # and the PBTC study for which the sample is provided.  Scrolls 
or FFPE tumor material should be shipped in a separate box (NOT with dry ice) at room 
temperature.  


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• Blood samples are to be labeled with the PBTC Accession # and the PBTC study for which 
the sample is provided.  Samples should be shipped in a separate box with 2-day supply of 
dry ice per Section 9.3.2. 
• Urine samples are to be labeled with the PBTC Accession # and the PBTC study for which 
the sample is provided. Samples should be shipped overnight on dry ice. Urine sample no 
longer collected as of version 8.0. 
  
9.1.1.2 Shipment of Specimens 
 
Samples collected for the repository should be sent to the PBTC CRB via FedEx by completing 
the Internet form at http://www.fedex.com/us/ and requesting FedEx to use the cc function to e-
mail 
. FedEx user ID and password for pathology 
shipping can be found at PBTC-047 protocol webpage. All specimens should be shipped to the 
below address, with a completed transmittal form which can be found on PBTC-047 webpage. 
 
PBTC CRB 
 
 
 
 
 
 
 
 
9.1.2 Pathology Central Review (Optional) 
 
Central pathology review is optional for this study. In consenting patients, samples for central 
pathology review will be completed from the slides submitted to the PBTC CRB. In patients who 
have not consented to the PBTC CRB, slides may be submitted only for purposes of pathology 
central review for this protocol.  
 
Pathologist review for this study will include the following elements:  
• Examination of H&E stained slides and, if the tumor being reviewed is residual, recurrent 
or metastatic, examination of H&E slides from the original primary tumor. For each subject 
one H&E stained slide per one representative block from the brain tumor, removed either 
at initial diagnosis or relapse, should be submitted for review. 
• Review of the corresponding pathology report(s) of the immunohistochemical, special 
stains, and molecular/genetic results from current and/or original primary tumor 
• If necessary, review of immunohistochemical or special stained slides. Slides submitted to 
the PBTC CRB will be digitized to 40X. H&E stained sections will be retained and filed 
at the CRB.  Original immunohistochemical or special stain slides will be returned to the 
submitting institution. 
 


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9.2 
Pharmacokinetics – Plasma (Required) 
 
Plasma pharmacokinetic studies are mandatory and will be obtained from all patients enrolled on 
this study.  
 
9.2.1  Collection of Specimens 
 
Sampling Strategy for Pharmacokinetic Study (Note: Patients should take Panobinostat in a 
fasting state on Days 1 and 3 of Course 1 only) 
 
• On Day 1 of Course 1, serial blood samples of 2 ml each for panobinostat pharmacokinetic 
studies will be collected at the following times: pre-dose and at 0.5, 1, 2, 4, 8 (±1), and 24 
(±4) hours after the oral dose.  
• On Day 3 of Course 1 (pre-dose 2), a single sample of 2 ml will be collected prior to the 
drug dose. 
 
9.2.2  Handling of Specimens 
 
At each time point, 2 ml of blood will be collected into appropriately labeled tubes containing 
Sodium Heparin. 2 ml of blood is needed to provide approximately 2 aliquots plasma for 
pharmacokinetic analysis. The Pharmacokinetic data collection form should be completed with the 
exact time that the sample is drawn as well as the exact time that the drug is administered.  The 
PK data collection form is located on the PBTC-047 webpage.   
During the sample collection and processing steps, the blood and plasma should be kept out of 
direct sunlight and unfiltered lab light. Upon collection of the blood PK samples in Na Heparin 
blood collection tubes, keep the blood samples on wet ice at all times prior to processing to plasma. 
Within 30 minutes of collection, samples will be centrifuged at approximately 2000 x g for about 
10 minutes at 4°C (Note: If a refrigerated centrifuge is not available, please refer to the Shipping 
Manual located on the PBTC-047 webpage for further instructions).  The plasma will be stored in 
an appropriately labeled amber screw-capped polypropylene tube and stored immediately at 
approximately -20°C.  
9.2.3 Shipping of Specimens 
 
Samples should be shipped for delivery Monday through Thursday with a generous amount of dry 
ice enclosed to safeguard against shipping delays. Weekend and holiday deliveries should be 
avoided. At the start of the study, each participating institution should refer to the PBTC-047 
website for instructions to request a Pharmacokinetics Kit for each patient enrolled on the study. 
 
Samples should be batched and shipped within 30 days of the last sample being taken. The site 
should use the PBTC-047 FedEx account details, located on the PBTC member website. Ship all 
pharmacokinetic samples frozen and on dry ice, along with a completed Pharmacokinetics Sample 
Transmittal Form located on the PBTC-047 webpage to: 
 
 


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Figg Lab 
 
 
 
Samples must be shipped from the site to the respective receiving laboratory within 30 days of last 
sample collection in order to receive cost reimbursement. The sample collection and shipping dates 
must be documented in the eCRF. Samples will be stored at this receiving laboratory, until 
additional details regarding the analyzing laboratory are available, which will be included in a 
forthcoming amendment. 
 
9.2.4  Assay description including Site Performing Correlative Study 
 
The purpose of this study is to evaluate and characterize the plasma pharmacokinetics of 
panobinostat in children with recurrent/progressive and non-progressed  DIPG or H3K27M+ 
Thalamic DMG.  100 μL of clinical sample in human plasma in Na heparin (or K3EDTA) stored 
at -70ºC±10 is used in protein precipitation treatment (PPT). After sample treatment, the sealed 
plate is transferred onto auto-sampler of HPLC and then analyzed by an LC-MS/MS system. The 
dilution factors include 1/5, 1/20 and 1/50.  
9.3 
Pharmacodynamics: Cell-free DNA – Blood and Urine (Optional) 
 
As an ancillary/exploratory study in consenting patients, blood and/ or urine will be collected to 
detect histone mutation status in cell-free DNA, via Microfluidic analysis of cell-free DNA.  
 
9.3.1 Collection of Specimens 
 
• Blood Sample 
2-3 ml of serum peripheral blood for plasma will be collected on days 1 of courses 1, 2, 4, 
6, and 12, pre-dose into K2-EDTA lavender top tubes.   
 
• Urine Sample (No longer need to be collected as of version 8.0) 
 
3-5 ml of urine will be collected on days 1 of courses 1, 2, 4, 6, and 12 pre-dose, 
 
preferably in the morning time.  
 
9.3.2 Handling and Shipping of Specimens 
 
• Blood Sample 
At each time point, 2-3 ml of blood will be collected into appropriately labeled tubes 
containing K2-EDTA. Blood samples must be labeled with the PBTC accession number, 
protocol ID and date of collection. Samples should be batched for shipment once each 
patient’s complete set has been collected and processed and shipped within 30 days of the 
last sample being taken. Blood samples should be shipped Monday through Wednesday 
via Federal Express Priority Overnight using the FedEx account information and 
transmittal form, located on the PBTC-047 webpage. Weekend deliveries are not 
permitted. Receipt and processing of biological materials will be recorded in ProtoLab, as 


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appropriate, by staff at the analyzing laboratory. The sites sending the materials must 
document sample collection and shipping dates in the eCRF.   
 
During the sample collection and processing steps, the blood and plasma should be kept 
out of direct sunlight and unfiltered lab light. Upon collection of the blood cell-free DNA 
in K2-EDTA blood collection tubes, samples should be processed as soon as possible to 
minimize hemolysis and contamination due to DNA released from nucleated blood cells. 
Samples should be centrifuged at 800 x g for about 10 minutes at 4° C. The supernatants 
should then be transferred to new 1.5ml tubes, keeping the pellet for blood DNA extraction 
if needed. Then, the supernatants should be centrifuged at 16000 x g for about 10 minutes 
at 4° C. Aliquot the supernatants by 1ml and store at -80° C until use. Blood samples will 
be shipped overnight via Federal Express Monday through Wednesday with a 2-day supply 
of dry ice.  Specimens will only be received Tuesday through Thursday.  
 
Specimens should be sent to the following address:  
Damien Faury  
 
 
 
  
 
Please notify Damien Faury of a pending shipment along with the FedEx tracking number 
by telephone. 
 
• Urine Sample (No longer collected as of version 8.0) 
Collect 3-5 ml per time point, preferably in the morning to increase cfDNA concentration. 
Immediately freshly collected urine samples should be mixed with 0.5M EDTA pH 8.0 to 
a final concentration of 10mM EDTA (dilution 1/50), to inhibit possible nuclease found in 
urine. The samples should then be kept at -80°C until shipment. Urine samples must be 
labeled with the PBTC accession number, protocol ID and date of collection.  Samples 
should be batched for shipment once each patient’s complete set has been collected and 
processed and shipped within 30 days of the last sample being taken. Urine samples should 
be shipped Priority Overnight on dry ice via Federal Express Monday through Wednesday. 
Specimens will only be received Tuesday through Thursday.  
 
Specimens should be sent to the following address:  
 
Damien Faury  
 
 
 


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Please notify Damien Faury of a pending shipment along with the FedEx tracking number 
by telephone. 
 
9.3.3  Assay description including Site Performing Correlative Study 
 
The purpose of this study is to confirm on-target effects. Samples will be thawed on ice then up to 
3 ml of plasma or 5 ml of urine will be processed. Cell-free nucleic acids will be extracted using 
the QIAmp circulating Nucleic Acid kit (Qiagen). Samples will be eluted in 20-30 ul of elution 
buffer and then quantified with Picogreen assay. A ddPCR (droplet digital PCR) duplex assay will 
be run on 5 ul of each extraction using the QX-100 system from BioRad. The conditions of the 
different assays have already been optimized to detect both wild-type (HEX probe) or mutant 
(FAM probe). Results will be analyzed using QuantaSoft software. 
 
9.4 
Neuroimaging Studies 
 
Patients will have MRI Brain with and without contrast with diffusion performed prior to therapy, 
every 2 courses for the first 6 courses, and after every 3 courses thereafter, until time of progression 
or completion of treatment.  MRI Spine should be performed prior to therapy and at the same time 
points as standard MRI Brain, if clinically indicated. The MR parameters will be listed on the 
PBTC NIC web page under MR protocols.  Only scans showing a response, the confirmation scan 
obtained approximately 8 weeks later if available, and the corresponding baseline scan will be 
uploaded for central review. 
9.4.1 Imaging Guidelines 
 
9.4.1.1 Brain MR with and without gadolinium will be obtained preferably on the 3T magnet 
consisting of: 
 
• Sagittal T1 MPRAGE (slice thickness 1.0, 25 cm FOV) 
• Axial T2 images (slice thickness 2mm skip 0, 20 cm FOV) 
• Axial T2 FLAIR images (slice thickness 4mm skip 0, 20 cm FOV) 
• Axial DTI images (slice thickness 2.0 mm skip 0, 22 cm FOV); 35 directions, b-values: 0 
and 1000 s/mm2 
• Post gadolinium sagittal T1 SPACE (slice thickness 0.9 mm skip 0, 22 cm FOV) 
• Axial T1 post gadolinium images through the whole brain (slice thickness 4mm skip 0, 
20 cm FOV) 
 
9.4.1.2 Brain MR with and without gadolinium on 1.5 T: 
 
• Sagittal T1 (slice thickness 5 mm skip 1 mm, 22 cm FOV) 
• Axial T2 images (slice thickness 4 mm skip 0 mm, 20 cm FOV) 


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• Axial T2 FLAIR images (slice thickness 5 mm skip 0 mm, 20 cm FOV) 
• Axial DWI, 6 directions (slice thickness 5 mm skip 0 mm, 26 cm FOV) 
• Post gadolinium sagittal 3DFSPGR images (slice thickness 1.5 mm no skip, 24 cm FOV) 
• Axial T1 post gadolinium (slice thickness 3 mm no skip, 16 cm 
9.4.1.3 Protocol for Spine 
 
• Sagittal T1 images should be after gadolinium (slice thickness 3 mm skip 0).   
• Axial T1 images are after gadolinium (slice thickness 3mm skip 0).  Axial T2 images are 
optional 
9.4.2  Image Transfer 
 
Standard MRI with gadolinium and diffusion images obtained at each time point, including 
progression during the extended follow-up period if applicable, will be electronically transferred 
to the PBTC Neuroimaging Center (NIC).  All patient specific data are stripped from the images 
and replaced with PBTC Accession numbers prior to transmitting the images to the NIC. All image 
data transfer is accomplished using PGP (pretty-good-privacy) 128-bit encryption which meets 
industry standard for secure communication 
 
9.4.3  Neuroimaging Review 
 
Local review of MR imaging studies at each site and central review of the MR imaging studies 
will be conducted through the PBTC Neuroimaging Center (NIC).  The NIC will review the 
imaging studies at study completion.  
 
NIC review will include assessment of response to therapy (as feasible). All patients with a 
documented PR/CR at any time point will have central review of the scan showing response, the 
confirmation scan obtained approximately 8 weeks later, as well as the corresponding baseline 
scan conducted for confirmation. 
 
9.5 
Autopsy Studies 
 
Sites are encouraged to obtain an autopsy when possible and appropriate on enrolled patients. 
Performing pathologists will be requested to look for evidence and extent of immune cell 
infiltration in the specimen.   
 
Specifically, it is recommended that the following assessments be made and documented in the 
autopsy report:  
 
9.5.1 Determine areas of necrosis and attempt analysis for cause/etiology, if possible.  
 
9.5.2 Determine the extent of lymphocyte infiltration particularly in adjacent areas of edema / 
inflammation. 
 


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In addition, 15-20 slides will be requested to perform staining for characterization of infiltrating 
lymphocyte population and other studies. Please ensure this is covered in your site's autopsy consent 
form. 
 
 


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10 Study Calendar  
Data is to be submitted according to the Data submission timelines located on the PBTC-047 
webpage. 
 
Table 18 
 
 
Pre-
therapy 
Course 1 
Courses 2- 
Course 26 
Completion/ 
Discontinuation 
Of Treatment 
Off Tx 
Follow-up 
Physical Assessments 
 
 
 
 
 
Panobinostat Administration, 
patients with 
recurrent/progressive DIPG 
(Stratum 1) 
 
1 x/day, 3x/week 
every other day 
for 3 weeks. 
1 week rest 
1 x/day, 3x/week 
every other day 
for 3 weeks. 
1 week rest 
 
 
Panobinostat Administration, 
patients with non-progressed 
DIPG or H3K27M+ 
Thalamic DMG (Stratum 2) 
 
1 x/day, 3x/week 
every other week 
1 x/day, 3x/week 
every other week 
 
 
Medical history 
X 
Weekly 
X 
X 
 
Physical exam /height/weight 
X 
Weekly 
X 
X 
 
Vital signs 
X 
Weekly 
X 
X 
 
Performance status 
X 
 
X 
X 
 
Neurologic exam 
X 
 
X 
X 
 
Laboratory Evaluations 
 
 
 
 
 
CBC  
WBC, HgB, Platelets, ANC, 
ALC A 
X 
Weekly 
X 
X 
 
Serum Chemistry  
Sodium, Potassium, 
Bicarbonate, Chloride, 
Calcium, BUN, Creatinine, 
Glucose, Phosphorous, 
Magnesium, Albumin, Total 
Protein, SGPT(ALT), 
SGOT(AST), Total Bilirubin 
X 
X 
X 
X 
 
Serum or Urine pregnancy 
test (for females of 
childbearing potential)  
X 
X 
X 
 
 
TSH, free T4 
X 
 
 
X 
 
Other Assessments 
 
 
 
 
 
EKG A 
X 
Day 1, and Day 5 
(3rd dose): Pre-
dose and 3 hrs 
post dose 
Pre-dose Day 1 of 
Course 2,3,4 
 
 
Echocardiogram or MUGA 
X 
 
 
X 
 
Imaging Assessments 
 
 
 
 
 


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Pre-
therapy 
Course 1 
Courses 2- 
Course 26 
Completion/ 
Discontinuation 
Of Treatment 
Off Tx 
Follow-up 
Brain MRI (standard) B 
X 
 
After every 2 
courses for the 
first 6 courses, 
then after every 3 
courses until 
progression 
End of Tx or 
progression 
Every 3 
months until 
progression 
Brain MRI with diffusion B 
X 
 
After every 2 
courses for the 
first 6 courses, 
then after every 3 
courses until 
progression  
End of Tx or 
progression 
Every 3 
months until 
progression 
Spinal MRI (if clinically  
indicated) B,C 
X 
 
After every 2 
courses for the 
first 6 courses, 
then after every 3 
courses until 
progression  
End of Tx or 
progression 
Every 3 
months until 
progression 
A This should also be done whenever clinically indicated. 
B All required imaging dates are to be entered in the database. However, only scans showing a partial response or complete 
response, and that same subject’s baseline scan, will be uploaded. 
C MRI Spine should be done at the indicated time and when clinically indicated.  If no disease is present within the spine 
at baseline, spine MRIs will be obtained as clinically indicated and at the discretion of the primary treating physician. 
 
Table 19 
 
Correlative Laboratory 
Studies 
Pre-therapy 
Course 1 
Course 2, 4, 6, 12 
Tumor Tissue and Blood for 
Biorepository (optional) 
X 
 
 
Pharmacokinetics Plasma 
(required) 
 
• Day 1: pre-dose and at 0.5, 1, 2, 
4, 8 (±1), and 24 (±4) hours after 
the oral dose.  
• Day 3 (2nd dose): single sample 
will be collected prior to the dose 
 
Pharmacodynamics: Cell-
free DNA – Blood 
(optional) 
 
Day 1, Courses 1, 2, 4, 6, 12, prior to drug dose 
(Optional Biorepository: Leftover Sample Storage for Future 
Research) 
Pharmacodynamics: Cell-
free DNA – Urine 
(optional)  
 
Day 1, Courses 1, 2, 4, 6, 12, prior to drug dose, preferably in 
morning (No longer collected as of version 8.0)  
 
 
 
 
 
 


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11 Measurement of Effect 
 
Although the clinical benefit of panobinostat has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated by MRI after every 2 courses for the first 6 courses, then every 3 
courses and when clinically indicated until disease progression or off-study criteria are met.  
  
11.1 Definitions 
 
11.1.1 Evaluable for Toxicity 
 
Patients who receive at least 1 dose of the study regimen and are removed from treatment for 
toxicity during the first course (dose-finding period) are evaluable for estimating the MTD. 
 
Patients who receive approximately 83-85% of prescribed therapy (i.e. ≥8/9 doses in stratum 1 and 
≥5/6 doses in stratum 2) during the dose-finding period but who progress prior to completing the 
course may be considered evaluable for estimating the MTD, as long as no additional anti-cancer 
therapy or supportive care that would confound the interpretation of any observed toxicity or side 
effect is given. Patients must have completed all of the clinical and laboratory monitoring 
requirements specified by the protocol up to the time of disease progression for them to be 
considered evaluable for MTD estimation. 
 
Patients who receive less than 83-85% of the protocol specified therapy (i.e. miss >1 dose) and 
who go off treatment for reasons other than toxicity (e.g., progressive disease, withdrawal of 
consent etc.) during the dose finding period will be considered inevaluable for estimating the MTD 
and may be replaced. 
 
Patients who complete all therapy during the dose-finding period but who fail to comply with all 
the specified clinical and laboratory monitoring requirements for the first course may be 
considered inevaluable for estimating the MTD and may be replaced. 
 
11.1.2 Evaluable for Radiographic Response 
 
Only those patients who have measurable disease present at baseline, have received at least one 
course of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the first scheduled MRI 
will also be considered evaluable.) 
 
 


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11.2 Tumor Response Criteria  
 
11.2.1 Complete Response (CR) 
 
Complete disappearance on MR of all evaluable tumor and mass effect, on a stable or decreasing 
dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or 
improving neurologic examination.  If CSF was positive, it must be negative.  
 
11.2.2 Partial Response (PR) 
 
Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared 
with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied 
by a stable or improving neurologic examination.  Axial FLAIR images will be used for tumor 
measurements. 
 
11.2.3 Stable Disease (SD) 
 
Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and MR/CT 
imaging meets neither the criteria for PR nor the criteria for Progressive Disease 
 
11.2.4 Progressive Disease (PD) 
 
Progressive Disease (PD): 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 a greater than 25% 
increase in the bi-dimensional measurement, taking as a reference the smallest disease 
measurement recorded since the start of protocol therapy, OR the appearance of a new tumor 
lesion.   
 
Increasing doses of corticosteroids required to maintain stable neurological status should be 
strongly considered as a sign of clinical progression unless in the context of recent wean or 
transient neurologic change due e.g. to radiation effects.  
  
11.2.5 Progression-Free Survival (PFS) 
 
Interval of time between date of initiation of protocol treatment and minimum date of 
documentation of PD, death due to any cause, or date of last follow-up. 
 
12 Data Reporting/ Regulatory Requirements 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this trial. 
Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments.  


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Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the PBTC roster at the enrolling site of: Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required.  
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and click 
on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able to 
access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be accessed 
by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata 
instead of the Rave EDC link; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will display under the study 
name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE. or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
12.2 Method 
 
This study will be monitored using CDUS-Abbreviated reporting, and as such no adverse event 
reporting (routine or expedited) is required to be reported via CDUS. 
12.3 Responsibility for Data Submission  
 
The OBDMC for the PBTC is responsible for compiling and submitting CDUS data to CTEP for 
all participants and for providing the data to the Principal Investigator and sponsor for review.   
12.4 CTEP Multicenter Guidelines 
 


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The specific responsibilities of the Principal Investigator and the Coordinating Center:  
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from the pharmaceutical company to all 
participating institutions for submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order agents 
directly from the Secura Bio Inc.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the sponsor. 
12.5 Collaborative Agreements Language  
 
A Clinical Trial Agreement will be in place to document study operations between Secura Bio Inc. 
and the PBTC. A Materials Transfer Agreement will be in place to document correlative study 
operations between the applicable labs and analyzing centers, and the PBTC. 
12.6 Genomic Data Sharing Plan 
 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
 
13 Statistical Considerations 
13.1 Study Design/Endpoints 
 
Six dose levels are proposed and all may or may not be investigated, primarily dependent upon 
whether or not toxicity at dose level 1 results in de-escalation to dose level 0. Enrollment will 
commence at dose level 10mg/m2 for Stratum 1 and at 1 dose level above the Stratum 1 
MTD/RP2D in Stratum 2. If the ‘3 weeks on, 1 week off’ schedule is abandoned in Stratum 1 
without determining the MTD, then we will initiate dose escalation in Stratum 2 at 10mg/m2. Dose 
finding will be governed by a two stage continual reassessment method (CRM) which will be 
applied separately in the two strata. No intra-patient dose escalations will be allowed. 
 
13.1.1 Proposed Dose Levels and BSA Based Dosing  
 
Since panobinostat is an oral agent and supplied in fixed capsule sizes, the deliverable doses based 
on BSA considerations are limited to the rounding constraints as set by the minimum capsule size. 
Taking this into consideration along with the starting dose of 10mg/m2 in Stratum 1 we developed 
an algorithm that enabled us to choose dose levels that would avoid overlaps in BSA adjusted 
doses in our patient cohorts. The following plot illustrates the BSA adjusted doses that the patients 
would receive at the proposed dose levels based on a minimum capsule size of 5mg. For the lower 
dose levels we have also utilized minimum BSA restrictions for enrollment to avoid these overlaps. 
Dosing nomograms are provided in Appendix D: Dosing Tables to facilitate correct dosing of 
patients based on this approach. 
 
Figure 2: BSA Adjusted Doses vs. Body Surface Are for the Proposed Dose Levels 


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13.1.2 Dose Finding Algorithm 
 
Likelihood Based 2-Stage CRM: 
In this trial we will use the likelihood-based 2-stage CRM71,72,73 as the dose finding algorithm for 
estimating the MTD. We will use the dfcrm package71 available in R to operationally execute this 
approach. The toxicity probability of 0.25 is determined as the target probability to be associated 
with the MTD for both strata. That is, the MTD is defined as the dose at which the model estimates 
that 25% of patients would be expected to experience dose-limiting toxicities (DLT).  
 
With pre-determined dose levels to be investigated, the practical implementation is to call the 
“MTD” the proposed dose level nearest to the value identified by the model (dose-finding MTD). 
The trial will continue until the MTD recommendation can be made based on at least 6 patients 
treated at that dose level; the model recommends a level lower than the lowest proposed level; or 
6 patients have been studied at the highest pre-determined dose level and the model suggests 
escalation. In the event that the model recommends a level lower than the lowest proposed level 
or 6 patients have been studied at the highest pre-determined dose level and the model suggests 
escalation, an estimate of the MTD will not be available, though a Phase II dose may still be 
recommended utilizing also the available PK and clinical data. If the trial results in an MTD, the 
reports of this study will include the model estimated MTD as well as the “dose-finding MTD” 
based on the fixed proposed levels. 
 
We will initiate the dose finding algorithm, so called the first-stage, using an empirical approach 
until the first DLT is observed. Once the first DLT is observed, we will switch to a CRM design 
(second stage) and will use a likelihood-based algorithm to guide dose finding. Since we are using 


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a likelihood based approach, the use of the first stage is needed as the model cannot estimate the 
MTD unless some heterogeneity is observed in the toxicity outcomes i.e. at least 1 DLT and 1 non-
DLT. 
 
Details of the Dose Finding Algorithm for Stratum 1: 
 
First Stage: 
We will initiate enrollment at dose level 1 and in the absence of any DLTs we will enroll the 
following numbers of patients at each dose level. This enrollment sequence has been shown to be 
coherent71 for the target probability of 25%. Note that enrolling 3 patients at dose level 1 would 
make this enrollment sequence non-coherent: 
 
Planned Enrollment per Dose Level in the absence of any DLTs 
Dose level 
0 
1 
2 
3 4 
5 
Number of Patients to be Enrolled 
0 
2 
3 
3 3 
6 
 
Until the first DLT is observed, using an approach similar to empirical methods e.g. 3+3 or 
Rolling-6, we will make the above-described number of slots available at each dose level and will 
wait until all patients have completed the DLT assessment before escalating to the next dose level. 
In the absence of a DLT in the prior dose levels, once we reach the highest dose, we will make 6 
slots available. 
 
Second Stage: 
Once the first DLT is observed, we will switch to a CRM design (second stage) and will use a 
likelihood-based algorithm via the empiric function (also called the power function, F(x,β)=xβ for 
0<x<1) to guide dose finding. This function has been shown to perform well under a wide variety 
of scenarios using the two-stage CRM. Following the detailed guidance in Cheung et al, 201171 
and using 25% as target probability for the MTD, we have calibrated this design via the following 
statistical parameters: 
- 
An indifference interval was defined with a half width of 7% i.e. if the model identifies a 
dose as the MTD in the interval 18% to 32% (25%±7%), the investigators will be 
indifferent to this choice. 
- 
Dose level 3 is chosen as the initial guess for the MTD in line with the recommendations 
in Cheung et al, 201171. 
- 
Based on the above assumptions, the skeleton (initial guesses for the toxicity probabilities) 
is estimated as the following: 
The initial toxicity probability assumptions (the skeleton) 
Dose level 
0 
1 
2 
3 
4 
5 
Toxicity probability 
0.02 0.05 0.13 0.25 0.40 0.54 
 
- 
MTD will be declared as the dose level at which at least 6 patients have been treated and 
the algorithm does not recommend escalation or de-escalation.  
o Once the MTD is declared or the Phase II recommended dose is identified, we will 
enroll 6 additional patients at this dose level to better characterize the toxicity and 
pharmacokinetic profile of this dose level. We will monitor the DLTs in this 


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expanded cohort in a similar fashion and if the toxicities in this expanded cohort 
suggest that the initially declared MTD may be too toxic, we will reduce the dose 
level and study additional patients at the lower dose until 12 patients have been 
treated at this dose level and the model does not suggest de-escalation.  
While the purest form of the CRM calls for fully sequential dose assignments, we will implement 
some restrictions in an effort to be conservative in dose escalations: 
- 
We will escalate 1 dose level at a time without skipping doses. 
- 
Once the second-stage is initiated, at each new dose level three slots will be made available 
and we will require that all patients complete the DLT assessment before additional patients 
can enroll. Furthermore, we will restrict enrollment so that no more than 3 patients will 
have DLT evaluation pending at any given point in time. 
- 
Once a dose level has been visited once and 2 evaluable patients have been treated there, 
subsequent patients will be assigned to the dose level closest to the current estimate of the 
MTD without skipping a level, if the decision is to escalate. In the event that the model 
recommends de-escalation, skipping dose levels is permitted. If the first dose level (dose 
level 1) is found to have unacceptable toxicity, additional patients will be treated at dose 
level 0. 
- 
It is typical to encounter study eligible patients who are initially enrolled to the dose-
finding phase and are later deemed inevaluable for dose-finding for some reason, such as 
incomplete course of treatment. Our version of the CRM requires that at least two patients 
are not only enrolled at a given previously unstudied dose level but are also evaluable for 
dose-finding. If two patients are enrolled to a level and one is deemed inevaluable for dose-
finding, then the inevaluable patient must be replaced to ensure that at least two evaluable 
patients have been treated at that level, regardless of the outcome of the evaluable patient, 
unless the algorithm recommends de-escalation following a DLT outcome from the first 
patient.  
- 
Per CTEP’s recommendation we will also employ the following 2 restrictions in an attempt 
to minimize exposure of patients to dose levels that may be too toxic: 
o New patients will not be assigned to a dose level above a dose level where ≥ 33% 
of patients have experienced a DLT. 
o New patients will not be assigned to a dose level at which 4 or more patients have 
been treated and ≥ 33% of the patients have experienced a DLT. 
 
Details of the Dose Finding Algorithm for Stratum 2: 
 
First Stage: 
We will initiate enrollment 1 dose level above the highest safe dose studied in Stratum 1 (denoted 
generically as dose level 1 below) and in the absence of any DLTs we will enroll the following 
numbers of patients at each dose level.  
 
Planned Enrollment per Dose Level in the absence of any DLTs 
Dose level 
1 
2 
3 4 
Number of Patients to be Enrolled 
3 
3 
3 6 
 


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Until the first DLT is observed, using an approach similar to empirical methods e.g. 3+3 or 
Rolling-6, we will make the above-described number of slots available at each dose level and will 
wait until all patients have completed the DLT assessment before escalating to the next dose level. 
In the absence of a DLT in the prior dose levels, once we reach the highest dose, we will make 6 
slots available. 
 
Second Stage: 
Once the first DLT is observed, we will switch to a CRM design (second stage) and will use a 
likelihood-based algorithm via the empiric function (also called the power function, F(x,β)=xβ for 
0<x<1) to guide dose finding. This function has been shown to perform well under a wide variety 
of scenarios using the two-stage CRM. Following the detailed guidance in Cheung et al, 201171 
and using 25% as target probability for the MTD, we have calibrated this design via the following 
statistical parameters: 
- 
An indifference interval was defined with a half width of 7% i.e. if the model identifies a 
dose as the MTD in the interval 18% to 32% (25%±7%), the investigators will be 
indifferent to this choice. 
- 
Dose level 2 is chosen as the initial guess for the MTD in line with the observed toxicity 
information from Stratum 1  
- 
Based on the above assumptions, the skeleton (initial guesses for the toxicity probabilities) 
is estimated as the following: 
The initial toxicity probability assumptions (the skeleton) 
Dose level 
0 
1 
2 
3 
4 
Toxicity probability 
0.05 0.13 0.25 0.40 0.54 
 
- 
MTD will be declared as the dose level at which at least 6 patients have been treated and 
the algorithm does not recommend escalation or de-escalation.  
o Once the MTD is declared or the Phase II recommended dose is identified, we will 
enroll 6 additional patients at this dose level to better characterize the toxicity and 
pharmacokinetic profile of this dose. We will monitor the DLTs in this expanded 
cohort in a similar fashion and if the toxicities in this expanded cohort suggest that 
the initially declared MTD may be too toxic, we will reduce the dose level and 
study additional patients at the lower dose until 12 patients have been treated at this 
dose level and the model does not suggest de-escalation. If the accrual is slow and 
the expansion cohort does not reach 12 subjects in a reasonable time and if the DLT 
outcome of the additional patients will not affect the MTD estimate, enrollment 
may be declared as complete. This decision will be made by the study team, IND 
Sponsor and the PBTC leadership in collaboration with the PBTC DSMB. 
While the purest form of the CRM calls for fully sequential dose assignments, we will implement 
some restrictions in an effort to be conservative in dose escalations: 
- 
We will escalate 1 dose level at a time without skipping doses. 
- 
Once the second-stage is initiated, at each new dose level three slots will be made available 
and we will require that all patients complete the DLT assessment before additional patients 
can enroll unless the DLT information from the pending patients do not change the 
escalation/de-escalation decision.  


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- 
Once a dose level has been visited once and at least 2 evaluable patients have been treated 
there, subsequent patients will be assigned to the dose level closest to the current estimate 
of the MTD without skipping a level. If the first dose level (dose level 1) is found to have 
unacceptable toxicity, additional patients will be treated at dose level 0. 
- 
It is typical to encounter study eligible patients who are initially enrolled to the dose-
finding phase and are later deemed inevaluable for dose-finding for some reason, such as 
incomplete course of treatment. Our version of the CRM requires that at least two patients 
are not only enrolled at a given previously unstudied dose level, but are also evaluable for 
dose-finding. If two patients are enrolled to a level and one is deemed inevaluable for dose-
finding, then the inevaluable patient must be replaced to ensure that at least two evaluable 
patients have been treated at that level, regardless of the outcome of the evaluable patient, 
unless the algorithm recommends de-escalation following a DLT outcome from the first 
patient.  
- 
Per CTEP’s recommendation we will also employ the following 2 restrictions in an attempt 
to minimize exposure of patients to dose levels that may be too toxic: 
o New patients will not be assigned to a dose level above a dose level where ≥ 33% 
of patients have experienced a DLT. 
o New patients will not be assigned to a dose level at which 4 or more patients have 
been treated and ≥ 33% of the patients have experienced a DLT. 
13.1.3 Contingencies 
 
If all proposed levels are investigated with acceptable toxicity, consideration will be given to 
amending the protocol to include higher dose levels. This deliberate decision will be made by the 
study committee and the sponsor and will be implemented via an amendment. In the event that 
higher doses are not studied and 12 patients have been treated at the highest dose level without the 
CRM suggesting de-escalation, then the highest dose level may be recommended for further study 
in subsequent trials.  
 
In the event of a single fatal drug-related adverse event, the OBDMC will suspend registration 
pending discussion with the Study Chair, the PBTC DSMB, and others as necessary.  
 
13.2 Sample Size/Accrual Rate 
 
The projected accrual rate is 1-2 patients per month, based on prior PBTC trials for similar patient 
populations. With 2 dose levels studied in Stratum 1 and possible 4 dose levels (we believe it is 
unlikely we will study both dose level 0 and dose level 4) in Stratum 2, the total sample size is 
expected to be approximately 40-50 patients accrued in approximately 1.5-2 years. These estimates 
do not take into account any unusual circumstances such as initial MTD turning out to be too toxic 
following additional toxicities in the expansion cohort etc. The gender and minority distribution 
of the study population is expected to be as follows in Table 20: 
 
Update for Version 8: 
At the time of drafting of version 8 of the protocol, dose level 3 in Stratum 2 was declared as too 
toxic after the expansion cohort. When de-escalation to dose level 2 was initiated, 47 patients had 
been enrolled on the trial: 6 of those were treated at dose level 2 of Stratum 2 and 3 were treated 


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at dose level 1 of Stratum 2, Thus, in order to adequately assess the tolerability of dose level 2 or 
dose level 1 if further de-escalation is needed, with this amendment the maximum sample size in 
this trial will be increased to 70. This maximum sample size also accounts for potential inevaluable 
subjects. 
 
Table 20: Gender and Minority Accrual Estimates 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
3 
3 
0 
0 
6 
Native Hawaiian or Other 
Pacific Islander 
1 
0 
0 
0 
1 
Black or African 
American 
7 
7 
1 
1 
16 
White 
14 
18 
3 
3 
38 
More Than One Race 
3 
3 
1 
1 
8 
Total 
28 
32 
5 
5 
70 
 
13.3 Analysis of Secondary Endpoints 
13.3.1 Statistical Analysis of Pharmacokinetics/Pharmacogenetics 
 
Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and 
graphical form separately for each stratum. Pharmacokinetic parameters of interest, such as 
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) will 
be estimated using compartmental methods. Non-linear mixed effects models and non-
compartmental methods will also be considered. Dose proportionality in pharmacokinetic 
parameters will also be investigated. As feasible, we will also investigate the associations between 
PK parameters and clinical and demographic variables such as toxicity, response, and PFS. We 
will also explore associations between PK parameters and number of prior treatments, age, body 
surface area, steroid use or concomitant medications 
 In addition to estimating individual pharmacokinetic parameters, we will also estimate the 
population parameters by taking into account both the inter- and intra-subject variability.  
 
 


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13.3.2 Pharmacodynamic Studies: 
 
For cell-free DNA based assays where the intent is to determine whether K27 mutations can be 
detected in patients’ blood or urine, we will summarize the percentage of patients in whom this 
mutation is detected within each stratum and at each time point. We will also numerically 
summarize changes across time within a patient. 
 
For this study we will consider exploratory studies correlating these findings with various PK 
parameters as well as with PFS and OS, as feasible within each stratum. 
 
13.3.3 Descriptive Efficacy Assessments 
 
Another secondary aim of this study is to estimate the PFS and OS associated with panobinostat 
treatment. PFS will be measured from the 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. OS is measured similarly with the 
endpoint of death. We will also report any objective responses that have been observed along with 
duration of response as well as dose levels at which such responses were observed. Efficacy 
analyses will be conducted separately for each stratum. 
 
 


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apoptosis of imatinib mesylate-sensitive or-refractory chronic myelogenous leukemia-
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combination of panobinostat (LBH589) and dexamethasone with either bortezomib or 
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Appendix A: Performance Scales 
 
 
 
MODIFIED LANSKY SCORE (Score as 0 - 100) 
A.  Normal Range 
  100 = Fully active 
90 = Minor restrictions in physically strenuous play 
80 = Restricted in strenuous play, tires more easily, otherwise active 
 
B.  Mild to moderate restriction 
70 = Both greater restrictions of and less time spent in active play 
60 = Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 = Considerable assistance required for any active play; full able to engage in quiet play 
 
C.  Moderate to severe restriction 
40 = Able to initiate quiet activities 
30 = Needs considerable assistance for quiet activity 
20 = Limited to very passive activity initiated by others e.g. TV) 
10 = Completely disabled, not even passive play 
  0 = Unresponsive, coma 
 
KARNOFSKY SCALE 
100 = Normal; no complaints 
90 = Able to carry on normal activities; minor signs or symptoms of disease 
80 = Normal activity with effort 
70 = Cares for self.  Unable to carry on normal activity or to do active work 
60 = Requires occasional assistance but able to care for most of his/her needs 
50 = Requires considerable assistance and frequent medical care 
40 = Disabled; requires special care and assistance 
30 = Severely disabled; hospitalization indicated though death not imminent 
20 = Very sick.  Hospitalization necessary.  Active support treatment necessary. 
10 = Moribund 
  0 = Dead 
 


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Appendix B: Medications Which May Cause QTc Prolongation 
 
The following table presents a list of drugs that may prolong the QTc.  These drugs are prohibited 
during the study. Providers should consult a frequently-updated drug information reference for a 
complete list. 
 
Table 21 
 
Alfuzocin 
Foscarnet 
Ondansetron 
Amantadine 
Fosphenytoin 
Pentamidine 
Amiodarone (cordarone) 
Gatifloxacin 
Pimozide 
Amitriptyline 
Gemifloxacin 
Procainamide 
Arsenic trioxide 
Grepafloxacin 
Protiptyline 
Azithromycin 
Halofantrine 
Quetiapine 
Bepridil 
Haloperidol 
Quinidine 
Chloral hydrate 
Ibutilide 
Quinine 
Chloroquine 
Imipramine 
Risperidone 
Chlorpromazine 
Indapamide 
Salmeterol 
Cisapride 
Isradipine 
Sotalol 
Clarithromycin 
Levofloxacin 
Sparfloxacin 
Cloroquine 
Levomethadyl 
Sumatriptan 
Desipramine 
Lithium 
Tacrolimus 
Disopyramide 
Mesoridazine 
Tamoxifen 
Dofetilide 
Methadone 
Telithromycin 
Dolesetron 
Moexipril/HCTZ 
Thioridazine 
Domperidone 
Moxifloxacin 
Tizanidine 
Doxepin 
Naratriptan 
Vardenifil 
Droperidol 
Nicardipine 
Venlaflaxine 
Erythromycin 
Nortriptyline 
Voriconizole 
Felbamate 
Octreotide 
Ziprasidone 
Flecainide 
Ofloxacin 
Zolmitriptan 
 
 


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Appendix C: Partial List of Common Moderate and Strong Inhibitors of 
CYP3A4, and Common Sensitive CYP2D6 Substrates 
 
This appendix is a partial list of common moderate to strong inhibitors of CYP3A4, and common 
sensitive CYP2D6 substrates.  Providers should consult a frequently-updated drug information 
reference for a complete list. 
 
Table 22 
 
Common Moderate and Strong Inhibitors of CYP3A4 
HIV Antivirals: 
   indinavir 
   nelfinavir 
   ritonavir 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
grapefruit juice 
verapamil 
diltiazem 
cimetidine 
amiodarone 
NOT azithromycin 
chloramphenicol 
ciprofloxacin 
delaviridine 
diethyldithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
voriconazole 
 
 
Table 23 
 
Common Sensitive CYP2D6 Substrates 
Beta Blockers: 
   carvedilol 
   S-metoprolol 
   propafenone 
   timolol 
Antidepressants: 
   amitriptyline 
   clomipramine 
   desipramine 
   imipramine 
   paroxetine 
Antipsychotics: 
   haloperidol 
dexfenfluramine 
dextromethorphan 
duloxetine 
encainide 
flecainide 
fluoxetine 
fluvoxamine 
lidocaine 
metoclopramide 
methoxyamphetamine 
mexilletine 
minaprine 
nebivolol 


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   perphenazine 
   risperidone→9OH 
   thioridazine 
   zuclopenthixol 
alprenolol 
amphetamine 
aripiprazole 
atomoxetine 
bufuralol 
chlorpheniramine 
chlorpromazine 
codeine (→O-desMe) 
debrisoquine 
nortriptyline 
ondansetron 
oxycodone 
perhexiline 
phenacetin 
phenformin 
promethazine 
propranolol 
sparteine 
tamoxifen 
tramadol 
venlafaxine 
 
 


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Appendix D: Dosing Tables 
 
5 mg/m2  
(Patients with BSAs <0.8m2 are not eligible to be treated at this dose) 
Min BSA 
(m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
Min BSA (m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
0.80 
1.49 
5 
1.50 
2.5 
10 
10 mg/m2 
(Patients with BSAs <0.65m2 are not eligible to be treated at this dose) 
Min BSA 
(m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
Min BSA (m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
0.65 
0.78 
5 
1.75 
2.25 
20 
0.79 
1.25 
10 
2.26 
2.50 
25 
1.26 
1.74 
15 
 
 
 
16 mg/m2 
(Patients with BSAs <0.65m2 are not eligible to be treated at this dose) 
Min BSA 
(m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
Min BSA (m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
0.65 
0.78 
10 
1.72 
2.03 
30 
0.79 
1.09 
15 
2.04 
2.34 
35 
1.10 
1.40 
20 
2.35 
2.5 
40 
1.41 
1.71 
25 
 
 
 
22 mg/m2 
(Patients with BSAs <0.65m2 are not eligible to be treated at this dose) 
Min BSA 
(m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
Min BSA (m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
0.65 
0.78 
15 
1.71 
1.93 
40 
0.79 
1.02 
20 
1.94 
2.15 
45 
1.03 
1.24 
25 
2.16 
2.38 
50 
1.25 
1.47 
30 
2.39 
2.50 
55 
1.48 
1.70 
35 
 
 
 
28 mg/m2 
(Patients with BSAs <0.50m2 are not eligible to be treated at this dose) 
Min BSA 
(m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Min BSA (m2) 
Max BSA 
(m2) 
Daily 
panobinostat 


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Dose (mg) 
Dose (mg) 
0.50 
0.62 
15 
1.52 
1.69 
45 
0.63 
0.78 
20 
1.70 
1.87 
50 
0.79 
0.98 
25 
1.88 
2.05 
55 
0.99 
1.16 
30 
2.06 
2.23 
60 
1.17 
1.33 
35 
2.24 
2.41 
65 
1.34 
1.51 
40 
2.42 
2.50 
70 
36 mg/m2 
(Patients with BSAs <0.50m2 are not eligible to be treated at this dose) 
Min BSA 
(m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
Min BSA (m2) 
Max BSA 
(m2) 
Daily 
panobinostat 
Dose (mg) 
0.5 
0.62 
20 
1.60 
1.73 
60 
0.63 
0.76 
25 
1.74 
1.87 
65 
0.77 
0.90 
30 
1.88 
2.01 
70 
0.91 
1.04 
35 
2.02 
2.15 
75 
1.05 
1.18 
40 
2.16 
2.29 
80 
1.19 
1.31 
45 
2.30 
2.43 
85 
1.32 
1.45 
50 
2.44 
2.50 
90 
1.46 
1.59 
55 
 
 
 
 
 


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Appendix E: Patient Diary 
 
Protocol: PBTC-047, Stratum 1 
 
 
Drug: Panobinostat 
 
Patient Name: ____________________________________ 
 
 
 
 
 
 
Course#: _____               
BSA: _____ 
 
 
Dose: _____ mg/m2/day 
 
Start Date: ____/____/______  
End Date: ____/____/______ 
 
Patients are encouraged to take their dose of panobinostat at the same time each day, preferably in the 
morning. Each dose of panobinostat should be taken with a 4 oz / 120 ml glass of water.  Drug must be 
taken on an empty stomach (either 1 hour before or after meals) on Course 1, Day 1 (1st dose) and Day 3 
(2nd dose) and may be taken with or without food for the remaining doses.  Patients should be instructed to 
swallow the capsules whole and not chew them. Patients must avoid grapefruit or grapefruit juice and 
Seville (sour) oranges during the entire study. 
 
If the patient forgets to take his/her dose during the morning on a scheduled treatment day, then he/she 
should take panobinostat on that same day within 12 hours after the missed dose if possible. After more 
than 12 hours, that day’s dose should be withheld, and the patient should wait to take panobinostat until the 
next scheduled treatment day (i.e., patients should be instructed not to try to make-up the missed dose after 
12 hours). The patient should then continue treatment with the original dosing schedule. If vomiting occurs 
within 15 minutes, the dose should be repeated. If a dose is missed/ unable to be given, record on the patient 
diary and continue counting the days of the course, with treatment administered on originally scheduled 
days.   
EXAMPLE 
Date 
Time 
Total dose 
taken 
Comments 
Example: He felt nauseated an hour after taking the drug, but 
did not vomit. 
Day 1 
1 / 15 / 15 
  8 : 30 
AM    PM 
15 mg 
 
Date 
Time 
Total dose 
taken 
 
Comments 
1st Week of Course 
 
: 
AM    PM 
 
 
Dose 1 
 
: 
AM    PM 
 
Dose 2 
 
: 
AM    PM 
 
Dose 3 
 
: 
AM    PM 
 
2nd Week of Course 
 
: 
AM    PM 
 
 
Dose 4 
 
: 
AM    PM 
 
Dose 5 
 
: 
AM    PM 
 
Dose 6 
 
: 
AM    PM 
 
3rd Week of Course 
 
: 
AM    PM 
 
 
Dose 7 
 
: 
AM    PM 
 
Dose 8 
 
: 
AM    PM 
 
Dose 9 
 
: 
AM    PM 
 
4th Week of Course 
Rest, No Drug 
 
 
 
 
 


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Protocol: PBTC-047, Stratum 2 
 
 
Drug: Panobinostat 
 
Patient Name: ____________________________________ 
 
 
 
 
 
 
Course#: _____               
BSA: _____ 
 
 
Dose: _____ mg/m2/day 
 
Start Date: ____/____/______  
End Date: ____/____/______ 
 
Patients are encouraged to take their dose of panobinostat at the same time each day, preferably in the 
morning. Each dose of panobinostat should be taken with a 4 oz / 120 ml glass of water.  Drug must be 
taken on an empty stomach (either 1 hour before or after meals) on Course 1, Day 1 (1st dose) and Day 3 
(2nd dose) and may be taken with or without food for the remaining doses.  Patients should be instructed 
to swallow the capsules whole and not chew them. Patients must avoid grapefruit or grapefruit juice and 
Seville (sour) oranges during the entire study. 
 
If the patient forgets to take his/her dose during the morning on a scheduled treatment day, then he/she 
should take panobinostat on that same day within 12 hours after the missed dose if possible. After more 
than 12 hours, that day’s dose should be withheld, and the patient should wait to take panobinostat until the 
next scheduled treatment day (i.e., patients should be instructed not to try to make-up the missed dose after 
12 hours). The patient should then continue treatment with the original dosing schedule. If vomiting occurs 
within 15 minutes, the dose should be repeated. If a dose is missed/ unable to be given, record on the patient 
diary and continue counting the days of the course, with treatment administered on originally scheduled 
days.   
EXAMPLE 
Date 
Time 
Total dose 
taken 
Comments 
Example: He felt nauseated an hour after taking the drug, but 
did not vomit. 
Day 1 
1 / 15 / 15 
  8 : 30 
AM    PM 
15 mg 
 
Date 
Time 
Total dose 
taken 
 
Comments 
1st Week of Course 
 
Dose 1 
 
: 
AM    PM 
 
Dose 2 
 
: 
AM    PM 
 
Dose 3 
 
: 
AM    PM 
 
2nd Week of Course 
Rest, No Drug 
 
3rd Week of Course 
 
Dose 4 
 
: 
AM    PM 
 
Dose 5 
 
: 
AM    PM 
 
Dose 6 
 
: 
AM    PM 
 
4th Week of Course 
Rest, No Drug