A Study of Panobinostat in Combination With Everolimus for Children and Young Adults With Gliomas

NCT03632317 | Withdrawn Phase 2 DMC FDA Drug

• 2 other identifiers: UMCC 2018.006HUM00140679
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This phase 2 trial will evaluate the activity of Panobinostat in combination with Everolimus for children with gliomas harboring H3.1 or H3.3K27M mutation, including newly diagnosed high-grade glioma or DIPG (diffuse intrinsic pontine glioma) after radiation (stratum A) and recurrent/progressive glioma (grade II-IV, including DIPG) (stratum B).

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma

Keywords

H3.1K27M; H3.3K27M; diffuse intrinsic pontine glioma; DIPG; high-grade glioma; pediatric glioma; H3K27M; panobinostat

Outcome Measures

Primary Outcomes (5)

• Median Progression Free Survival (PFS) at 1 Year

  Median PFS at 1 year for stratum A will be measured. Progression is defined as \> 25% increase in the size of the tumor or appearance of new lesions.

  1year

• Median Progression Free Survival (PFS) at 2 Years

  Median PFS at 1 year for stratum A will be measured. Progression is defined as \> 25% increase in the size of the tumor or appearance of new lesions.

  2years

• Overall Survival at 1Year

  The proportion of patients alive at 1 year for stratum A.

  1year

• Overall Survival at 2Years

  The proportion of patients alive at 2 years for stratum A.

  2years

• Overall Response Rate (ORR) After Two Cycles of Panobinostat + Everolimus

  Overall Response Rate (ORR) After Two Cycles of Panobinostat + Everolimus for stratum B. Overall response is defined as a partial or complete response. Partial response is defined as a ≥50% decrease in size of tumor in comparison to baseline measurements. Complete response is defined as the disappearance of all abnormal signal. This includes return to normal size of the brainstem for brainstem lesions.

  84 Days

Study Arms (1)

Panobinostat and Everolimus

EXPERIMENTAL

Panobinostat daily M, W, F for 2 weeks every 28 days for the first cycle (28 days). After first cycle Panobinostat daily M, W, F for 2 weeks every 28 days combined with Everolimus daily.

Drug: Panobinostat; Drug: Everolimus

Interventions

Panobinostat DRUG

30 mg/m\^2

Panobinostat and Everolimus

Everolimus DRUG

3.0 mg/m\^2

Panobinostat and Everolimus

Eligibility Criteria

• Age: 2 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• All patients and/or a legal guardian must sign institutionally approved written informed consent and assent documents.
• Patient must be greater than 2 years and less than 30 years
• BSA (body surface area) greater than 0.3 m2
• Functional status: Karnofsky \> 50% for patients \> 16 years of age and Lansky \> 50% for patients \< 16 years of age (Karnofsky and Lansky is a scoring system used to quantify the general well being of cancer patients where 100% represents perfect health and 0% represents death). Neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 7 days. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Adequate bone marrow function
• Adequate liver function
• Adequate renal and metabolic function
• Urine protein:creatinine (UPC) ratio of \< 1; or a urinalysis that is negative for protein; or 24-hour urine protein level \< 1000 mg/dL
• Patients must have Magnesium \> 1.5 mg/dL and potassium \> 3.5 mmol/L
• Patients with known seizure disorder must have seizures adequately controlled with non- enzyme inducing antiepileptic medications
• No increase in steroid dose within the past 7 days.
• STRATUM A: histological confirmation of a newly diagnosed high-grade glioma or DIPG or STRATUM B: histological confirmation of a recurrent or progressive grade II-IV glioma (including DIPG) \[histology can come from tissue at diagnosis or relapse\]
• Primary brain or spine tumor are eligible, including tumors with metastases, multiple lesions
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy.
• Myelosuppressive chemotherapy: Must not have received within 3 weeks (6 weeks if prior nitrosourea).

You may not qualify if:

• Patients who are breastfeeding, pregnant or refuse to use an effective form of birth control are excluded. Abstinence is considered an effective form of birth control.
• Patients with uncontrolled infection are excluded.
• Inability to swallow oral pill (panobinostat does not have liquid formulation).
• Other medications: Patients receiving other anti-neoplastic agents are excluded; patients on enzyme-inducing anticonvulsive agents are excluded; patients requiring strong CYP3A4 or PGP inducers or inhibitors are excluded; patients on steroids for symptom management must be on a stable dose for 7 days prior to start of treatment.
• Allogeneic stem cell transplant: Patients within 1 year of allogeneic stem cell transplant, patients with active GVHD or requiring immunosuppression are excluded.
• Previous hypersensitivity to rapamycin or rapamycin derivatives.
• Baseline QTc of \>450 msec on EKG OR electrolyte imbalance predisposing to QTc prolongation (baseline ≥ Grade 1 hypokalemia or hyperkalemia; and baseline ≥ Grade 2 Ca++, Mg++, phosphate abnormalities). Repletion/correction is allowed to achieve eligibility. Use of QTC prolonging medications will be monitored throughout the trial.

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead

Study Sites (1)

University of Michigan Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma

Interventions

Panobinostat; Everolimus

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; Sirolimus; Macrolides; Lactones

Study Officials

• Carl Koschmann, MD

  University of Michigan Rogel Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be divided into two stratums; newly diagnosed high-grade glioma or DIPG after radiation (stratum A) and recurrent/progressive glioma (grade II-IV, including DIPG) (stratum B).

Study Record Dates

• First Submitted: August 13, 2018
• First Posted: August 15, 2018
• Study Start: October 1, 2019
• Primary Completion: October 1, 2025
• Study Completion: October 1, 2025
• Last Updated: August 19, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)