Clinical Trials /

Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

NCT02717455

Description:

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 that has not yet gotten worse. Currently, only Stratum 2 is enrolling patients.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma
  • Official Title: Phase 1 Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

Clinical Trial IDs

  • ORG STUDY ID: PBTC-047
  • NCT ID: NCT02717455
  • NCT ALIAS: NCT02899715

Conditions

  • Glioma

Interventions

DrugSynonymsArms
LBH589PanobinostatTreatment (STRATUM 1)

Purpose

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 that has not yet gotten worse. Currently, only Stratum 2 is enrolling patients.

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (STRATUM 1)ExperimentalPatients with recurrent/progressive DIPG will be enrolled at the time of progression. All patients will take the study drug panobinostat (LBH589).
  • LBH589
Treatment (STRATUM 2)ExperimentalPatients with non-progressed DIPG will be enrolled. All patients will take the study drug panobinostat (LBH589).
  • LBH589

Eligibility Criteria

        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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To describe the toxicity profile and the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG
Time Frame:26 courses (approximately 2 years)
Safety Issue:
Description:Adverse Events

Secondary Outcome Measures

Measure:To describe the progression-free survival (PFS) and overall survival (OS) of children with recurrent or progressive DIPG who are treated with panobinostat
Time Frame:26 courses (approximately 2 years)
Safety Issue:
Description:Evaluated Response per imaging or clinical progression
Measure:To describe the progression-free survival (PFS) and overall survival (OS) of children with non-progressed DIPG who are treated with panobinostat
Time Frame:26 courses (approximately 2 years)
Safety Issue:
Description:Evaluated Response per imaging or clinical progression
Measure:To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment.
Time Frame:Day 1 of courses 1, 2, 4, 6, and 12
Safety Issue:
Description:Pharmacodynamics: Cell-free DNA - Blood and Urine (Optional)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pediatric Brain Tumor Consortium

Trial Keywords

  • Diffuse Intrinsic Pontine Glioma

Last Updated

September 23, 2019