Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

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 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 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 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 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.

STRATUM 1 - INCLUSION CRITERIA

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

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

- Patients with pontine lesions that do not meet these radiographic criteria will
be eligible if there is histologic confirmation of malignant glioma WHO II-IV.

- AGE - Patients must be ≥ 2 but < 22 years of age at the time of enrollment.

- BSA

- Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2.

- Patients must have a BSA ≥ 0.65 m2 for doses of 10mg/m2 - 22 mg/m2.

- Patients must have a BSA ≥ 0.50 m2 for doses of 28 mg/m2 - 36 mg/m2.

- ABILITY TO SWALLOW - Patient must be able to swallow capsules whole.

- PERFORMANCE STATUS - Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky
Performance Score (LPS for ≤ 16 years of age) assessed within 7 days of enrollment
must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who
are up in a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score.

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

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

- INVESTIGATIONAL/ BIOLOGIC AGENT:

- Biologic or investigational agent (anti-neoplastic): Patient must have recovered
from any acute toxicity potentially related to the agent and received their last
dose of the investigational or biologic agent ≥ 7 days prior to study enrollment.
(For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur, and discussed with the principal investigator.)

- Monoclonal antibody treatment and agents with known prolonged half-lives: At
least three half-lives must have elapsed prior to enrollment. (Note: A list of
the half-lives of commonly used monoclonal antibodies is available on the PBTC
webpage under Generic Forms and Templates.)

- RADIATION THERAPY - Patients must have had their last fraction of:

- Craniospinal irradiation or radiation to ≥ 50% of pelvis > 3 months prior to
enrollment.

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

- Local palliative irradiation other than previously irradiated primary site (small
port) ≥ 14 days

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

- Absolute neutrophil count ≥ 1,000/mm3

- Platelets ≥ 100,000/ mm3 (unsupported, defined as no platelet transfusion within
7 days, and recovery from post-transfusion nadir)

- Hemoglobin ≥ 8 g/dl (may receive transfusions)

- Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)

- ALT(SGPT) < 3 x institutional upper limit of normal

- Albumin ≥ 3 g/dl

- Potassium ≥ LLN

- Serum total calcium (correct for serum albumin) or ionized calcium ≥ LLN

- Serum creatinine based on age/gender as noted below. Patients that do not meet
the criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotope
or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for
age/gender:

- Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)

- Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)

- Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)

- Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

- Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

- Cardiac Function:

- Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR
shortening fraction of ≥ 27% by echocardiogram

- Patient has no ventricular arrhythmias except for benign premature
ventricular contractions.

- Patient has a QTc interval < 450 ms.

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

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

- PREGNANCY STATUS - Female patients of childbearing potential must have a negative
serum or urine pregnancy test.

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

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

STRATUM 1 - EXCLUSION CRITERIA

- PRIOR THERAPY

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

- Patients have had prior HDAC, DAC, HSP90 inhibitors for the treatment of their
DIPG.

- Patients have had valproic acid within 28 days prior to enrollment.

- Patients have had prior bone marrow transplant.

- NEUROLOGICAL STATUS - Patients have significant acute deterioration in neurologic
status in 72 hours prior to enrollment, in the opinion of the treating physician.

- GASTROINTESTINAL

- Patients have impairment of GI function or GI disease that may significantly
alter the absorption of panobinostat; for example severe inflammatory bowel
disease.

- Patients have diarrhea > CTCAE grade 2.

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

- OTHER MALIGNANCY - Patients have a history of any other malignancy.

- TRANSFUSIONS - Patients are known to be refractory to red blood cell or platelet
transfusions.

- CONCURRENT THERAPY

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

- Patients who are required to receive any medication which can prolong the QTc
interval. Please see Protocol Appendix B: Medications Which May Cause QTc
Prolongation.

- BREASTFEEDING - Female patient IS breastfeeding.

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

STRATUM 2 - INCLUSION CRITERIA

- DIAGNOSIS - Patients with DIPG who have not yet progressed by clinical or radiographic
criteria.

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

- Patients with pontine lesions that do not meet these radiographic criteria will
be eligible if there is histologic confirmation of malignant glioma WHO II-IV.

- AGE - Patients must be ≥ 2 but < 22 years of age at the time of enrollment.

- BSA Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2. Patients must have a BSA ≥
0.65 m2 for doses of 10mg/m2 - 22 mg/m2. Patients must have a BSA ≥ 0.50 m2 for doses
of 28 mg/m2 - 36 mg/m2.

- ABILITY TO SWALLOW - Patient must be able to swallow capsules whole.

- PERFORMANCE STATUS - Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky
Performance Score (LPS for ≤ 16 years of age) assessed within 7 days of enrollment
must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who
are up in a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score.

- PRIOR THERAPY - Patients must have received a minimum of 54 Gy focal irradiation
administered over approximately 42 days prior to enrollment. Patients must not have
received any other prior therapy for treatment of their CNS malignancy besides
standard radiation therapy.

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

- RADIATION THERAPY - Patients must have had their last fraction of focal irradiation to
the primary site > 14 days prior to enrollment. Patients must not have received local
palliative irradiation or craniospinal irradiation.

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

- Absolute neutrophil count ≥ 1,000/mm3

- Platelets ≥ 100,000/ mm3 (unsupported, defined as no platelet transfusion within
7 days, and recovery from post-transfusion nadir)

- Hemoglobin ≥ 8 g/dl (may receive transfusions)

- Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)

- ALT(SGPT) < 3 x institutional upper limit of normal

- Albumin ≥ 3 g/dl

- Potassium ≥ LLN

- Serum total calcium (correct for serum albumin) or ionized calcium ≥ LLN

- Serum creatinine based on age/gender as noted below. Patients that do not meet
the criteria in Table 9 but have a 24-hour Creatinine Clearance or GFR
(radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible.

- Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)

- Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)

- Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)

- Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

- Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

- CARDIAC FUNCTION:

- Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening
fraction of ≥ 27% by echocardiogram

- Patient has no ventricular arrhythmias except for benign premature ventricular
contractions.

- Patient has a QTc interval < 450 ms.

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

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

- PREGNANCY STATUS - Female patients of childbearing potential must have a negative
serum or urine pregnancy test.

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

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

STRATUM 2 - EXCLUSION CRITERIA

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

- NEUROLOGICAL STATUS - Patients have significant acute deterioration in neurologic
status in 72 hours prior to enrollment, in the opinion of the treating physician.

- GASTROINTESTINAL

- Patients have impairment of GI function or GI disease that may significantly
alter the absorption of panobinostat; for example severe inflammatory bowel
disease.

- Patients have diarrhea > CTCAE grade 2.

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

- OTHER MALIGNANCY - Patients have a history of any other malignancy.

- TRANSFUSIONS - Patients are known to be refractory to red blood cell or platelet
transfusions.

- CONCURRENT THERAPY

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

- Patients who are required to receive any medication which can prolong the QTc
interval. Please see Appendix B: Medications Which May Cause QTc Prolongation.

- BREASTFEEDING - Female patient is breastfeeding.

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