Panobinostat With Fludarabine and Cytarabine for Treatment of Children With Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT02676323 | Terminated Phase 1 FDA Drug

• 2 other identifiers: PANAMLNCI-2016-00098
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 7

Brief Summary

Cancer is the uncontrolled growth of human cells. The growth of normal human cells is controlled by multiple mechanisms. Panobinostat belongs to a class of chemotherapy drugs called "histone deacetylase (HDAC) inhibitors." HDAC inhibitors like panobinostat block enzymes known as histone deacetylases, which stops cancer cells from dividing and causes them to die. Fludarabine and cytarabine are chemotherapy drugs that are commonly used to treat pediatric patients with refractory or relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The purpose of this study is to test the safety of panobinostat and to find the highest dose of panobinostat that can be given safely when it is combined with fludarabine and cytarabine. This pilot study will be done in two parts: The goal of Part 1 of the study is to find the highest tolerable dose of panobinostat that can be given to patients with AML or MDS, when it is combined with fludarabine and cytarabine. Once that dose is determined, participants will be enrolled on Part 2: Dose Expansion, to look at the effect of the panobinostat/fludarabine/cytarabine combination in patients with leukemia/MDS. PRIMARY OBJECTIVE:

• Determine a tolerable dose of panobinostat when given in combination with fludarabine and cytarabine in pediatric patients with relapsed or refractory AML or MDS. SECONDARY OBJECTIVES:
• Characterize the pharmacokinetics of panobinostat after the first dose and at steady-state.
• Estimate the overall response rate to the combination of panobinostat, fludarabine, and cytarabine.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome

Keywords

Maximum tolerated dose; Childhood leukemia; Hematological malignancies

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD)

  Any participant who experiences non-hematologic dose-limiting toxicity (DLT) during the first 28 days after taking the initial dose of panobinostat and before receiving non-protocol therapy is considered evaluable for toxicity. Non-hematologic DLT includes any Grade 5 event and any Grade 3 or 4 event that is at least possibly related to panobinostat, unless the event is clearly due to extraneous causes or disease progression. Hematologic DLT includes failure to recover counts by Day 56 in the absence of persistent leukemia. Participants without DLTs who receive at least 5 of the 6 prescribed cycle I doses of panobinostat and can be followed for 28 days (56 days for evaluation of hematologic toxicity) after their initial dose of panobinostat are considered evaluable for toxicity. Participants who are not evaluable for toxicity will be replaced. The MTD is defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT.

  Up to 56 days following first dose of panobinostat

Secondary Outcomes (10)

• Clearance (CL)

  From baseline pre-dose day 1 through 48 hours after panobinostat administration

• Clearance (CL)

  On day 8 from pre-dose through 48 hours after panobinostat administration

• Drug Absorption (ka)

  From baseline pre-dose day 1 through 48 hours after panobinostat administration

• Drug Absorption (ka)

  On day 8 from pre-dose through 48 hours after panobinostat administration

• Area under curve (AUC)

  From baseline pre-dose day 1 through 48 hours after panobinostat administration

Study Arms (1)

Treatment

EXPERIMENTAL

Participants will be given panobinostat in combination with fludarabine and cytarabine. Treatment consists of one course of therapy given over 12 days. Participants will also receive intrathecal triples and leucovorin

Drug: Panobinostat; Drug: Fludarabine; Drug: Cytarabine; Drug: Intrathecal Triples; Drug: Leucovorin

Interventions

Panobinostat DRUG

Panobinostat will be given orally (PO) on days 1, 3, 5, 8, 10, and 12.

Also known as: LBH589

Treatment

Fludarabine DRUG

Fludarabine will be given intravenously (IV), 30 mg/m\^2/dose over 30 minutes, daily for 5 days (days 8-12).

Also known as: Fludara®, Fludarabine phosphate, 2-fluoro-ara-AMP

Treatment

Cytarabine DRUG

Cytarabine will be given IV, 2 gram/m\^2/dose over 4 hours, daily for 5 days (days 8-12).

Also known as: Cytosine arabinoside, Ara-C, Cytosar®

Treatment

Intrathecal Triples DRUG

Given intrathecally (IT).

Also known as: ITMHA, methotrexate/hydrocortisone/cytarabine

Treatment

Leucovorin DRUG

Leucovorin (5 mg/m\^2/dose, max 5 mg) may be given PO or IV at 24 and 30 hours after each ITMHA.

Also known as: Leucovorin calcium, Leucovorin rescue

Treatment

Eligibility Criteria

• Age: Up to 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants must have a diagnosis of AML or MDS and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT).
• Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy.
• Patients with AML must have ≥ 5% leukemic blasts in the bone marrow or increasing levels of minimal residual disease (MRD) in the bone marrow as assessed by flow cytometry. If an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood.
• Adequate organ function defined as the following:
• Direct bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
• AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
• Creatinine ≤ 1.5 x ULN for age
• Serum albumin \> 3.0 g/dl
• Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%.
• Age ≤ 24 years
• Patients must be able to swallow capsules
• Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are \> 16 years old.
• Patients must have fully recovered from the acute effects of all prior therapy and must meet the following criteria:
• At least 14 days must have elapsed since the completion of myelosuppressive therapy
• At least 24 hours must have elapsed since the completion of low-dose chemotherapy, such as hydroxyurea or low-dose cytarabine (up to 200 mg/m\^2/day).

You may not qualify if:

• Must not be pregnant or breastfeeding. Female patients who are sexually active and of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients who are sexually active must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. For both male and female patients who are sexually active, effective methods of contraception must be used throughout the study and for three months following the last dose. Abstinence is an acceptable form of contraception.
• Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow failure syndromes are not eligible.
• Use of investigational agents within 30 days.
• Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, study participation, follow up, or interpretation of study research.
• Uncontrolled infection within one week of the first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable.
• Known human immunodeficiency virus infection (pre-study testing not required).
• Patient with diarrhea \> CTCAE grade 2. (CTCAE version 4.0)
• Impaired cardiac function or clinically significant cardiac diseases, history of arrhythmia (including ventricular fibrillation or torsade de pointes), bradycardia \<50 bpm, screening ECG with prolonged QTc (\> 450 msec), uncontrolled hypertension or any history or presence of sustained ventricular tachyarrhythmia.
• Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
• 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 treatment. Granisetron may be administered, but antiemetics associated with QT prolongation (e.g., ondansetron) are not allowed.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (7)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital and Health Center

San Diego, California, 92123, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Hematologic Neoplasms

Interventions

Panobinostat; fludarabine; fludarabine phosphate; Cytarabine; Methotrexate; Leucovorin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes

Study Officials

• Jeffrey E. Rubnitz, MD,PhD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2016
• First Posted: February 8, 2016
• Study Start: May 3, 2016
• Primary Completion: April 9, 2018
• Study Completion: April 9, 2018
• Last Updated: November 14, 2018

Record last verified: 2018-11

Locations

US (7)