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 currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by University of California, San Francisco
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01463046
First received: October 27, 2011
Last updated: August 18, 2014
Last verified: August 2014
  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: 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 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]

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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • Relapse-free survival [ Time Frame: The time to relapse or death from any cause from the date of confirmed morphologic CR. ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: The time to death from any cause from the day 1 of induction therapy. ] [ Designated as safety issue: No ]

Estimated Enrollment: 22
Study Start Date: January 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01463046

Contacts
Contact: Paula Fiermonte 415-885-7605 fiermontep@cc.ucsf.edu
Contact: McNancy Kang 415-476-9328 KangM@cc.ucsf.edu

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

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01463046     History of Changes
Other Study ID Numbers: 112512
Study First Received: October 27, 2011
Last Updated: August 18, 2014
Health Authority: United States: Food and Drug Administration

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

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

ClinicalTrials.gov processed this record on October 21, 2014