Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma
- Registration Number
- NCT02717455
- Lead Sponsor
- Pediatric Brain Tumor Consortium
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 53
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Treatment (STRATUM 1) LBH589 Patients with recurrent/progressive DIPG will be enrolled at the time of progression. All patients will take the study drug panobinostat (LBH589). Treatment (STRATUM 2) LBH589 Patients with non-progressed DIPG or H3K27M+ Thalamic DMG will be enrolled. All patients will take the study drug panobinostat (LBH589).
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 2 4 weeks The MTD of panobinostat was defined as the dose at which the continual reassessment method (CRM) estimated that 25% of patients were expected to experience DLTs. For Stratum 2, non-progressed DIPG or H3K27M+ thalamic diffuse malignant glioma (DMG) patients who completed conventional radiation treatment were eligible. All patients enrolled on this stratum had DIPG tumors and were treated with the "3 times/week, every other week" schedule (1 course = 28 days).
Volume of Distribution (Vd) Up to day 3 Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Volume of distribution (Vd) was estimated using a noncompartmental method.
Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 1 4 weeks The MTD of panobinostat was defined as the dose at which the continual reassessment method (CRM) estimated that 25% of patients were expected to experience DLTs. Stratum 1 consisted of recurrent or progressive diffuse intrinsic pontine glioma (DIPG) patients who were treated with the "3 times/week, three weeks on, one week off" schedule (1 course = 28 days).
Half-life (t1/2) Up to day 3 Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Half-life (t1/2) was estimated using a noncompartmental method.
Clearance (CL/F) Up to day 3 Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Clearance (CL/F) was estimated using a noncompartmental method.
Area Under the Curve (AUC) Up to day 3 Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. The area under the curve (AUC) was estimated using a noncompartmental method and calculated from time of dosing to the last measurable concentration.
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs) 4 weeks DLTs were defined as adverse events that were at least possibly related to panobinostat that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding, grade 3 thrombocytopenia that occurs twice within a treatment course, myelosuppression that causes greater than a 14-day delay between treatment courses, grade 4 neutropenia, grade 3 or 4 febrile neutropenia. Non-hematologic DLTs included any grade 3 or greater non-hematologic toxicities with a few exclusions (such as grade 3 nausea/vomiting that is responsive to antiemetics and that resolves to grade 2 or lower within 5 days, etc.), any grade 2 non-hematological toxicity that persists for more than 7 days and is considered sufficiently medically significant or sufficiently intolerable by patients, and any panobinostat-related non-hematological toxicity that results in a delay of treatment \> 14 days between treatment courses.
Elimination Rate (Kel) Up to day 3 Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Elimination rate (Kel) was estimated using a noncompartmental method.
- Secondary Outcome Measures
Name Time Method Percentage of Patients With H3F3A K27M Mutation Detected in Blood Samples Blood samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1. Cell-free DNA based assay was used to determine whether H3F3A K27M mutation could be detected in patients' blood samples. Percentage of patients in whom this mutation was detected was summarized within each stratum and at each time point.
Percentage of Patients With H3F3A K27M Mutation Detected in Urine Samples Urine samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1. Per protocol, cell-free DNA based assay was to be used to determine whether H3F3A K27M mutation could be detected in patients' urine samples, and percentage of patients in whom this mutation was detected would be summarized within each stratum and at each time point. With current technologies available to the lab, no patients had cell-free DNA assay results from urine samples.
Progression-free Survival (PFS) in Stratum 2 From date on treatment until date of PD or death due to any cause or date of last follow-up PFS was measured from the time of treatment initiation until the time of progressive disease (PD) or death due to any cause for patients with an event, or until the time of last follow-up for patients who were progression free.
Overall Survival (OS) in Stratum 2 From date on treatment until date of death due to any cause or date of last follow-up OS was measured from the time of treatment initiation until the time of death due to any cause for patients who died, or until the time of last follow-up for patients who survived.
Percentage of Patients With Hist1H3B K27M Mutation Detected in Blood Samples Blood samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1. Cell-free DNA based assay was used to determine whether Hist1H3B K27M mutation could be detected in patients' blood samples. Percentage of patients in whom this mutation was detected was summarized within each stratum and at each time point.
Progression-free Survival (PFS) in Stratum 1 From date on treatment until date of PD or death due to any cause or date of last follow-up PFS was measured from the time of treatment initiation until the time of progressive disease (PD) or death due to any cause for patients with an event, or until the time of last follow-up for patients who were progression free.
Overall Survival (OS) in Stratum 1 From date on treatment until date of death due to any cause or date of last follow-up OS was measured from the time of treatment initiation until the time of death due to any cause for patients who died, or until the time of last follow-up for patients who survived.
Percentage of Patients With Hist1H3B K27M Mutation Detected in Urine Samples Urine samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1. Per protocol, cell-free DNA based assay was to be used to determine whether Hist1H3B K27M mutation could be detected in patients' urine samples, and percentage of patients in whom this mutation was detected would be summarized within each stratum and at each time point. With current technologies available to the lab, no patients had cell-free DNA assay results from urine samples.
Trial Locations
- Locations (10)
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Stanford University and Lucile Packard Children's Hospital
🇺🇸Palo Alto, California, United States
National Cancer Institute
🇺🇸Bethesda, Maryland, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States