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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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01463046
First Posted: November 1, 2011
Last Update Posted: June 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Novartis
Information provided by (Responsible Party):
University of California, San Francisco
  Purpose
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.

Condition Intervention Phase
Acute Myeloid Leukemia Advanced Myelodysplastic Syndrome Drug: Panobinostat Drug: Cytarabine Drug: Daunorubicin Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose Finding and Proof-of-concept Study of the Histone Deacetylase Inhibitor Panobinostat (LBH589) in Combination With Standard Dose Cytarabine and Daunorubicin for Older Patients With Untreated Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • 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. [ Time Frame: 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. [ Time Frame: 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 Outcome Measures:
  • Response rate (OR, CR, CRi) for AML using Revised Recommendations of the International Working Group [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: The time to relapse or death from any cause from the date of confirmed morphologic CR. ]
  • Overall Survival [ Time Frame: The time to death from any cause from the day 1 of induction therapy. ]

Enrollment: 28
Study Start Date: January 2012
Estimated Study Completion Date: December 2017
Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat Drug: Panobinostat

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

Other Name: LBH589
Drug: Cytarabine

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.

Other Name: ara-C
Drug: Daunorubicin

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.

Other Name: Cerubidine

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values that could in the opinion of the investigator cause unacceptable safety risks or compromise compliance with the protocol.
  • Active second malignancy except localized prostate cancer, basal cell carcinoma of the skin and carcinoma in situ of the skin or cervix
  • Patients who are unwilling to stop the use of herbal remedies while on the Treatment Phase of the study
  • Concomitant use of drugs with a risk of prolonging the QT interval and/or causing torsades de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug. Concomitant use of strong CYP3A4 inhibitors.
  • Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (which ever is longer) and who have not recovered from side effects of those therapies.
  • Patients who have received either immunotherapy within < 8 weeks; chemotherapy within < 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within < 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.
  • Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  • Treatment with investigational agent within 30 days prior to enrollment
  • Male patients whose sexual partners are women of childbearing potential not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom.
  • Unwilling to accept blood product transfusions
  • Unable to swallow pills
  • Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01463046


Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
Novartis
Investigators
Principal Investigator: Charalambos Andreadis, M.D. University of California, San Francisco
  More Information

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01463046     History of Changes
Other Study ID Numbers: 112512
First Submitted: October 27, 2011
First Posted: November 1, 2011
Last Update Posted: June 12, 2017
Last Verified: June 2017

Keywords provided by University of California, San Francisco:
leukemia
AML
AMS
panobinostat
cytarabine
daunorubicin
HDAC

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Panobinostat
Daunorubicin
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors