Phase I Dose Finding and Proof-of-concept Study of Panobinostat With Standard Dose Cytarabine and Daunorubicin for Untreated Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome

NCT01463046 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 112512
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to see if Panobinostat is safe to give to patients and to determine the best dose to give in combination with standard cytarabine and daunorubicin chemotherapy.

Conditions

Acute Myeloid Leukemia; Advanced Myelodysplastic Syndrome

Keywords

leukemia; AML; AMS; panobinostat; cytarabine; daunorubicin; HDAC

Outcome Measures

Primary Outcomes (2)

• The maximum tolerated dose (MTD) for the combination of panobinostat with standard-dose cytarabine and daunorubicin (7+3) for untreated AML and advanced MDS in the elderly.

  Start of induction therapy until 21 days after the last dose of induction or second induction therapy or until count recovery in patients without residual disease, whichever is longer

• The recommended Phase II dose for the combination of panobinostat with standard-dose cytarabine and daunorubicin (7+3) for untreated AML and advanced MDS in the elderly.

  Start of induction therapy until 21 days after the last dose of induction or second induction therapy or until count recovery in patients without residual disease, whichever is longer

Secondary Outcomes (4)

• Response rate (OR, CR, CRi) for AML using Revised Recommendations of the International Working Group

  18 days after the start of induction therapy or 37 days after the second induction therapy or when white blood cell count recovers, whichever is first.

• Response rate (OR, CR, CRi) for AMS using International Working Group response criteria in myelodysplasia

  18 days after the start of induction therapy or 37 days after the second induction therapy or when white blood cell count recovers, whichever is first.

• Relapse-free survival

  The time to relapse or death from any cause from the date of confirmed morphologic CR.

• Overall Survival

  The time to death from any cause from the day 1 of induction therapy.

Study Arms (1)

Panobinostat

EXPERIMENTAL

Drug: Panobinostat; Drug: Cytarabine; Drug: Daunorubicin

Interventions

Panobinostat DRUG

Induction - 20-60 mg (1-3 20 mg capsules) PO on days 1,3,5 and 8 Second induction - 20-60 mg (1-3 20 mg capsules) PO days 1,3 and 5 Consolidation - 20-60 mg (1-3 20 mg capsules) PO on days 1,3,5 and 8

Also known as: LBH589

Panobinostat

Cytarabine DRUG

Induction - 100 mg/m2 continuous IV daily for 7 doses on day 3-9. Second induction - 100 mg/m2 continuous IV daily for 7 doses on day 3-7. Dosing for consolidation - 100 mg/m2 continuous IV daily for 7 doses on day 3-9.

Also known as: ara-C

Panobinostat

Daunorubicin DRUG

Induction - 60 mg/m2 IV over 15-30 minutes daily for 3 doses on day 3-5. Second induction - 60 mg/m2 IV over 15-30 minutes daily for 2 doses on day 3 and 4. Dosing for consolidation - 60 mg/m2 IV over 15-30 minutes daily for 3 doses on day 3-5.

Also known as: Cerubidine

Panobinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Untreated histologically confirmed acute myeloid leukemia OR advanced myelodysplastic syndrome (INT-2 or High risk) not previously treated with anthracycline-based chemotherapy OR a therapy-related myeloid neoplasm
• Male or female aged ≥ 60 years
• ECOG performance status 0-2
• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• Absence of major metabolic, renal and hepatic impairment as defined by the following laboratory parameters: AST and ALT ≤ 2.5 x ULN Serum bilirubin ≤ 1.5 x ULN Albumin \> 3.0 g/dl Serum potassium ≥ LLN Total serum calcium \[corrected for serum albumin\] or ionized calcium ≥LLN Serum magnesium ≥ LLN
• Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
• Prior treatment of myelodysplastic syndrome or myeloproliferative neoplasm acceptable

You may not qualify if:

• Acute promyelocytic leukemia (FAB M3 AML)
• Known central nervous system involvement by leukemia
• Isolated myeloid sarcoma not meeting bone marrow criteria for AML or MDS
• Cumulative anthracycline exposure greater than 200 mg/m2 doxorubicin isotoxic equivalents (See Appendix A6 for conversions)
• Prior HDAC inhibitor, DAC inhibitor, Hsp90 inhibitor or valproic acid for the treatment of cancer
• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
• Prior allogeneic hematopoietic stem cell transplant
• Prior solid organ transplant
• Active bleeding diathesis or current treatment with therapeutic doses of sodium warfarin (Coumadin®) or other vitamin K active agents (Note: mini-dose of Coumadin® (e.g., 1 mg/day) or anti-coagulants given to maintain intravenous line patency, as well as unfractionated or low molecular weight heparin therapy are permitted)
• Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
• History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with Novartis prior to enrollment) Any history of ventricular fibrillation or torsade de pointes Bradycardia defined as HR\< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm Screening ECG with a QTcF \> 450 msec Right bundle branch block + left anterior hemiblock (bifascicular block) Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction \<50% by MUGA scan or by transthoracic echocardiogram Other clinically significant heart disease (e.g. uncontrolled hypertension, or history of labile hypertension)
• Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
• Patients with active diarrhea \> CTCAE grade 2
• Known HIV infection
• Known active Hepatitis B or Hepatitis C virus infection

Sponsors & Collaborators

• University of California, San Francisco: lead
• Novartis: collaborator

Study Sites (1)

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

Panobinostat; Cytarabine; Daunorubicin

Condition Hierarchy (Ancestors)

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

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; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Charalambos Andreadis, M.D.

  University of California, San Francisco

  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: October 27, 2011
• First Posted: November 1, 2011
• Study Start: January 1, 2012
• Primary Completion: November 14, 2015
• Study Completion: December 1, 2018
• Last Updated: April 22, 2019

Record last verified: 2019-04

Locations

US (1)