A Study Of Panobinostat In Children With Refractory Hematologic Malignancies

Non-Hodgkin's Lymphoma Clinical Trial

Official title:

A Phase I Dose Finding Study Of Panobinostat In Children With Refractory Hematologic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01321346
• Other study ID #: T2009-012
• Status: Completed
• Phase: Phase 1
• First received: March 21, 2011
• Last updated: November 20, 2015
• Start date: March 2011

Study information

• Verified date: November 2015
• Source: Therapeutic Advances in Childhood Leukemia Consortium
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 8 Years to 21 Years

Eligibility

Inclusion Criteria:

• Patients must be = 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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Disease
• Hodgkin Disease
• Hodgkin's Disease
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoblastic Leukemia, Acute, Childhood
• Lymphoma, Non-Hodgkin
• Myelogenous Leukemia, Acute, Childhood
• Non-Hodgkin's Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	C.S. Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta, Emory University	Atlanta	Georgia
United States	Dana Farber	Boston	Massachusetts
United States	Levine Children's Hospital at Carolinas Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital	Chicago	Illinois
United States	Rainbow Babies	Cleveland	Ohio
United States	Nationwide Childrens Hospital	Columbus	Ohio
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	St. Jude	Memphis	Tennessee
United States	University of Miami Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt Children's Hospital	Nashville	Tennessee
United States	Children's Hospital New York-Presbyterian	New York	New York
United States	New York University Medical Center	New York	New York
United States	Oregon Health and Science University	Portland	Oregon
United States	Primary Children's	Salt Lake City	Utah
United States	UCSF School of Medicine	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Therapeutic Advances in Childhood Leukemia Consortium	Novartis

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		8 weeks	Yes
Primary	To learn what kind of side effects panobinostat can cause when taken by children with relapsed ALL, AML, HD or NHL.		8 weeks	Yes
Secondary	To determine whether panobinostat is a beneficial treatment for ALL, AML, HD or NHL.		8 weeks	No
Secondary	To test the amount of panobinostat in the patient's blood and spinal fluid after taking panobinostat.		3 years	No
Secondary	To test samples of cancer cells to see if they have chemicals that affect the way panobinostat works.		3 years	No

External Links

•   TACL Consortium Web Site