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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03632317
Recruitment Status : Withdrawn (low accrual)
First Posted : August 15, 2018
Last Update Posted : August 19, 2019
Sponsor:
Information provided by (Responsible Party):
University of Michigan Rogel Cancer Center

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).

Condition or disease Intervention/treatment Phase
Glioma Diffuse Intrinsic Pontine Glioma Drug: Panobinostat Drug: Everolimus Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Intervention Model Description: 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).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Panobinostat in Combination With Everolimus for Children and Young Adults With Gliomas Harboring H3.3 or H3.1 K27M Mutation
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : October 2025
Estimated Study Completion Date : October 2025


Arm Intervention/treatment
Experimental: Panobinostat and Everolimus
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
30 mg/m^2

Drug: Everolimus
3.0 mg/m^2




Primary Outcome Measures :
  1. Median Progression Free Survival (PFS) at 1 Year [ Time Frame: 1year ]
    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.

  2. Median Progression Free Survival (PFS) at 2 Years [ Time Frame: 2years ]
    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.

  3. Overall Survival at 1Year [ Time Frame: 1year ]
    The proportion of patients alive at 1 year for stratum A.

  4. Overall Survival at 2Years [ Time Frame: 2years ]
    The proportion of patients alive at 2 years for stratum A.

  5. Overall Response Rate (ORR) After Two Cycles of Panobinostat + Everolimus [ Time Frame: 84 Days ]
    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.



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Ages Eligible for Study:   2 Years to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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).
  • Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor, 14 days for long-acting (e.g. PEG-filgrastim)
  • Biologic (anti-neoplastic agent): At least 7 days or 3 half-lives (whichever is longer) since the completion of therapy with a biologic agent.
  • Radiation therapy: Strata A: ≥ 2 weeks and ≤ to 12 weeks must have elapsed from radiation. Strata B: ≥ 2 weeks must have elapsed from focal radiation.
  • Surgery: > 3 weeks from major surgery. If recent craniotomy, adequate wound healing must be determined by neurosurgical team.
  • Autologous Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and ≥ 4 weeks must have elapsed.
  • H3K27M mutation: Participants must have a mutation in H3.3 K27M or H3.1 K27M as identified by tumor (FFPE or fresh, diagnosis or relapse tissue, but relapse tissue preferred) sequencing, or by CLIA-certified immunohistochemistry staining positive for H3K27M, as defined by review by U of M neuro-pathology.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03632317


Locations
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United States, Michigan
University of Michigan Cancer Center
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan Rogel Cancer Center
Investigators
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Principal Investigator: Carl Koschmann, MD University of Michigan Rogel Cancer Center

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Responsible Party: University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier: NCT03632317     History of Changes
Other Study ID Numbers: UMCC 2018.006
HUM00140679 ( Other Identifier: University of Michigan )
First Posted: August 15, 2018    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by University of Michigan Rogel Cancer Center:
H3.1K27M
H3.3K27M
diffuse intrinsic pontine glioma
DIPG
high-grade glioma
pediatric glioma
H3K27M
panobinostat
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Sirolimus
Everolimus
Panobinostat
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action