A Study Of Panobinostat In Children With Refractory Hematologic Malignancies

This study is currently recruiting participants.
Verified January 2014 by Therapeutic Advances in Childhood Leukemia Consortium
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier:
NCT01321346
First received: March 21, 2011
Last updated: January 31, 2014
Last verified: January 2014
  Purpose

This study is for patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Hodgkin's Disease (HD) or Non-Hodgkin's Lymphoma (NHL). Panobinostat is a new drug that is considered investigational because it has not been approved in the United States by the Food and Drug Administration (FDA), or in any other country. Panobinostat is a histone deacetylase inhibitor (HDACi) and interferes with gene expression found in cells causing them to stop growing or die. Panobinostat has been used in several hundred adults who had leukemia, HD, NHL and other solid tumors. Panobinostat has not been given to children.

This is a phase I study. In a phase I study, drugs are tested to the highest dose that can be safely given. Drugs are given at gradually increasing dosages until there are unacceptable side effects. The goal of the Phase I study is to find out the dose of panobinostat that can be safely given to children with relapsed ALL, AML, HD and NHL.


Condition Intervention Phase
Lymphoblastic Leukemia, Acute, Childhood
Myelogenous Leukemia, Acute, Childhood
Hodgkin's Disease
Non-Hodgkin's Lymphoma
Drug: Panobinostat
Drug: Cytarabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Dose Finding Study Of Panobinostat In Children With Refractory Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by Therapeutic Advances in Childhood Leukemia Consortium:

Primary Outcome Measures:
  • To find the highest dose of oral panobinostat that can be given to patients with relapsed AML, HD or NHL without causing severe side effects. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  • To learn what kind of side effects panobinostat can cause when taken by children with relapsed ALL, AML, HD or NHL. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine whether panobinostat is a beneficial treatment for ALL, AML, HD or NHL. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • To test the amount of panobinostat in the patient's blood and spinal fluid after taking panobinostat. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • To test samples of cancer cells to see if they have chemicals that affect the way panobinostat works. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: March 2011
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Leukemia Patients
Patients with ALL and AML will be treated in one arm of the study.
Drug: Panobinostat
Dose will be assigned at study entry. Patients will take panobinostat orally 3 times a week given on a Monday, Wednesday, Friday schedule, every week. One course is 28 days (4 weeks). Patients will get 2 courses and may receive up to 8 courses total.
Other Name: LBH589
Drug: Cytarabine

All patients will receive 70 mg of intrathecal cytarabine on day "0" of course 1. The day "0" dose must be given at least 24 hours prior to initiation of panobinostat. Omit the day "0" dose of intrathecal cytarabine if the patient received intrathecal therapy within 72 hours of treatment.

All patients will receive 70 mg of intrathecal cytarabine on day "29" of course 1-8 in conjunction with their disease evaluation.

Other Names:
  • Ara-C
  • cytosine arabinoside
  • Cytosar
Experimental: Lymphoma Patients
Patients with NHL or HD will be treated in one arm of the study.
Drug: Panobinostat
Dose will be assigned at study entry. Patients will take panobinostat orally 3 times a week on a Monday, Wednesday, Friday schedule, every other week. Once course is 28 days (4 weeks). Patients will get 2 course and may receive up to 8 courses of therapy.
Other Name: LBH589

  Eligibility

Ages Eligible for Study:   8 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be ≥ 8 and ≤ 21 years of age at the time of enrollment.
  • Patients must have one of the following:

    1. Patient must have relapsed/refractory acute myelogenous leukemia (AML) with ≥ 5% blast in the bone marrow or biopsy confirmed chloroma. Patient may have CNS 1, 2 or 3 disease. Isolated CNS relapse is not eligible.
    2. Patient must have relapsed/refractory acute lymphoblastic leukemia (ALL) with ≥ 5 blasts in the bone marrow or biopsy confirmed extramedullary disease. Patient may have CNS 1, 2 or 3 disease. Isolated CNS relapse is not eligible.
    3. Patient must have relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's disease. Patients must have CNS 1 disease. Patient must have histologic verification of disease at original diagnosis. Patient must have measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry.
  • Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients less than or equal to 16 years of age. (See Appendix I for Performance Scales).
  • Patient must have a life expectancy of 8 weeks.
  • PRIOR THERAPY Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

    1. Patients with AML must have had at least 2 prior therapeutic attempts including frontline induction.
    2. Patients with ALL must have had at least 3 prior therapeutic attempts including frontline induction.
    3. Radiotherapy: At least 28 days must have elapsed since and radiation therapy.
    4. Hematopoietic Stem Cell Transplant:

      Patients who have had previous allogeneic HSCT must have grade I or less of Graft-versus-Host Disease (GVHD) and have not received immunosuppressive medication for at least 90 days.

    5. Hematopoietic grow factors: It must have been at least 7 days since the completion of therapy with GCSF or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
    6. Biologic/Immunologic (anti-neoplastic) therapy: It must be at least 28 days since the completion of therapy with a biologic/immunologic agent such as a monoclonal antibody prior to study enrollment and at least 28 days since non-study chemotherapy has been administered, excluding CNS directed therapy as described in Section 4.1.
    7. Prior HSCT for Hodgkin's Lymphoma: Patients with Hodgkin's lymphoma must have had prior attempt at autologous HSCT.
  • Renal and Hepatic Function

    1. Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times normal, the patient must have a calculated creatinine clearance or radioisotope GRF ≥ 70mL/min/1.73m2.

      • Pediatric Population (age <18): Calculated creatinine clearance ≥ 90 ml/min/1.73m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR)
      • Adult Population (age >18): Serum creatinine <1.0 mg/dL; if serum creatinine >1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2
    2. Patient's ALT must be < 5 x institutional upper limit of norm ULN.
    3. Patient's total bilirubin must be ≤ 1.5 x ULN.
  • Cardiac Function

    a. Patient must have a shortening fraction ≥ 29% or an ejection fraction ≥ 40% by ECHO/MUGA.

  • Reproductive Function

    1. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
    2. Female patients with infants must agree not to breastfeed their infants while on this study.
    3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.

Exclusion Criteria:

  • Patients will be excluded if they are unable to swallow capsules whole.
  • Patients will be excluded if they have received previous therapy with HDAC, DAC, HSP90 inhibitors or valproic acid anticancer therapy. Valproic acid therapy is not allowed for any reason while on this study.
  • AML patients who are candidates for allogeneic stem cell transplant are excluded.
  • Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.
  • Gastrointestinal Function

    1. Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
    2. Patients with diarrhea > CTCAE grade 2.
  • Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period, excluding CNS directed therapy upfront for AML patients and continuing for CNS positive patients as described in Section 4.1. Cyto-reduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start or protocol therapy.
  • Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  • Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required.
  • Cardiac Exclusion Criteria:

Patients will be excluded if these meet any of the following:

  1. History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with the study chair prior to enrollment).
  2. Any history of ventricular fibrillation or torsade de pointes.
  3. Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.
  4. Screening ECG with a QTc > 450 msec.
  5. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug.
  6. Right bundle branch block + left anterior hemiblock (bifascicular block).
  7. Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug.
  8. Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
  9. Patients with leukemia must not be known to be refractory to red blood cell or platelet transfusions.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01321346

Contacts
Contact: Jeannette M van der Giessen 323-361-8725 jvandergiessen@chla.usc.edu
Contact: Elena Eckroth 323-361-5429 eeckroth@chla.usc.edu

Locations
United States, Arizona
Phoenix Children's Hospital Not yet recruiting
Phoenix, Arizona, United States
United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Principal Investigator: Paul S. Gaynon, MD         
Sub-Investigator: Theresa Harned, MD         
UCSF School of Medicine Not yet recruiting
San Francisco, California, United States, 94143-0106
Principal Investigator: Steven DuBois, MD         
United States, Florida
University of Miami Cancer Center Not yet recruiting
Miami, Florida, United States, 33136
Principal Investigator: John Goldberg, MD         
United States, Georgia
Children's Healthcare of Atlanta, Emory University Not yet recruiting
Atlanta, Georgia, United States
United States, Illinois
Children's Memorial Not yet recruiting
Chicago, Illinois, United States
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States
United States, Massachusetts
Dana Farber Not yet recruiting
Boston, Massachusetts, United States
United States, Michigan
C.S. Mott Children's Hospital Not yet recruiting
Ann Arbor, Michigan, United States, 48109-0914
Principal Investigator: Raymond Hutchinson, MD         
United States, Minnesota
Childrens Hospital & Clinics of Minnesota Not yet recruiting
Minneapolis, Minnesota, United States, 55404-4597
Principal Investigator: Bruce Bostrom, MD         
Principal Investigator: Yoav Messinger, MD         
University of Minnesota Children's Hospital Not yet recruiting
Minneapolis, Minnesota, United States
Principal Investigator: Mike Burke, MD         
United States, New York
Children's Hospital New York-Presbyterian Not yet recruiting
New York, New York, United States, 10032
Principal Investigator: Julia Glade-Bender, MD         
New York University Medical Center Not yet recruiting
New York, New York, United States, 10016
Principal Investigator: Elizabeth Raetz, MD         
United States, North Carolina
Levine Children's Hospital at Carolinas Medical Center Not yet recruiting
Charlotte, North Carolina, United States, 28203
Contact: Javier Oesterheld, MD         
Principal Investigator: Javier Oesterheld, MD         
United States, Ohio
Nationwide Childrens Hospital Not yet recruiting
Columbus, Ohio, United States
Principal Investigator: Sandeep Soni, MD         
United States, Oregon
Oregon Health and Science University Not yet recruiting
Portland, Oregon, United States
Principal Investigator: Eneida Nemecek, MD         
United States, Tennessee
St. Jude Not yet recruiting
Memphis, Tennessee, United States, 38105-3678
Contact: Deepa Bhojwani, MD         
Vanderbilt Children's Hospital Not yet recruiting
Nashville, Tennessee, United States
Principal Investigator: Haydar Frangoul, MD         
United States, Washington
Seattle Children's Hospital Not yet recruiting
Seattle, Washington, United States, 98105
Principal Investigator: Blythe Thompson, MD         
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Novartis
  More Information

Additional Information:
No publications provided

Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01321346     History of Changes
Other Study ID Numbers: T2009-012
Study First Received: March 21, 2011
Last Updated: January 31, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Relapse
Lymphoblastic
Leukemia
Panobinostat
LBH589
Refractory
Hodgkin's
Non-Hodgkin's Lymphoma
Lymphoma
Myelogenous
Acute
Childhood
Pediatric
ALL
AML
NHL
HD

Additional relevant MeSH terms:
Hodgkin Disease
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Lymphoma
Lymphoma, Non-Hodgkin
Acute Disease
Hematologic Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Neoplasms by Site
Hematologic Diseases
Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents

ClinicalTrials.gov processed this record on April 23, 2014