Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

NCT02717455 | Completed Phase 1 Results DMC

• 2 other identifiers: PBTC-0475UM1CA081457
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 10

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.

Conditions

Glioma

Keywords

Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; H3K27M; DIPG; DMG

Outcome Measures

Primary Outcomes (8)

• Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)

  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.

  4 weeks

• Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 1

  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).

  4 weeks

• Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 2

  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).

  4 weeks

• Volume of Distribution (Vd)

  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.

  Up to day 3

• Elimination Rate (Kel)

  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.

  Up to day 3

• Half-life (t1/2)

  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.

  Up to day 3

• Clearance (CL/F)

  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.

  Up to day 3

• Area Under the Curve (AUC)

  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.

  Up to day 3

Secondary Outcomes (8)

• 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

• Overall Survival (OS) in Stratum 1

  From date on treatment until date of death due to any cause or date of last follow-up

• 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

• Overall Survival (OS) in Stratum 2

  From date on treatment until date of death due to any cause or date of last follow-up

• 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.

Study Arms (2)

Treatment (STRATUM 1)

EXPERIMENTAL

Patients with recurrent/progressive DIPG will be enrolled at the time of progression. All patients will take the study drug panobinostat (LBH589).

Drug: LBH589

Treatment (STRATUM 2)

EXPERIMENTAL

Patients with non-progressed DIPG or H3K27M+ Thalamic DMG will be enrolled. All patients will take the study drug panobinostat (LBH589).

Drug: LBH589

Interventions

LBH589 DRUG

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.

Also known as: Panobinostat

Treatment (STRATUM 1); Treatment (STRATUM 2)

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• DIAGNOSIS - Patients with progressive DIPG or H3K27M+ Thalamic DMG , 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.
• Thalamic Diffuse Midline Glioma patients will be eligible if there is tissue confirmation of the H3K27M mutation by immunohistochemistry or by gene testing performed in a CLIA certified laboratory of the investigator's choice.
• 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.)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pediatric Brain Tumor Consortium: lead
• National Cancer Institute (NCI): collaborator

Study Sites (10)

Children's Hospital Los Angeles

Los Angeles, California, 90026, United States

Location

Stanford University and Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

National Cancer Institute

Bethesda, Maryland, 20892, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma

Interventions

Panobinostat

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Arzu Onar-Thomas
• Organization: St. Jude Children's Research Hospital

arzu.onar@stjude.org

901-595-5499

Study Officials

• Michelle Monje, MD, Phd

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2016
• First Posted: March 23, 2016
• Study Start: June 28, 2016
• Primary Completion: February 14, 2022
• Study Completion: March 31, 2024
• Last Updated: April 25, 2024
• Results First Posted: April 25, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (10)