Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML

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Brief Title

Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML

Official Title

A Phase 1/2 Study of Vorinostat (Zolinza®) in Combination With Gemtuzumab Ozogamicin (Mylotarg®) and Azacitidine (Vidaza®) in Patients 50 Years of Age and Older With Relapsed/Refractory Non-APL Acute Myeloid Leukemia (AML)

Brief Summary

      The purpose of this study is to test the safety of vorinostat (Zolinza) and azacitidine
      (Vidaza) when combined with gemtuzumab ozogamicin (GO) at different dose levels. These drugs
      increase the effect of GO against leukemia cells in the test tube, but we don't know yet
      whether they also increase the anti-leukemia effect of GO in people.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the vorinostat dose with the most favorable efficacy and toxicity when combined
      with azacitidine and GO.

      SECONDARY OBJECTIVES:

      I. Describe the complete response (CR)/ CR with inadequate recovery (CRi) rate after a total
      of 6 cycles of therapy.

      II. Describe the disease-free survival of patients that achieve CR/CRi. III. Determine
      whether acute myeloid leukemia (AML) characteristics associated with preclinical GO efficacy
      predict for clinical benefit, and assess whether differentiation-inducing agents modulate
      these characteristics and lower the apoptotic threshold for calicheamicin-gamma1-induced
      cytotoxicity (in vitro correlative and mechanistic studies).

      OUTLINE: This is phase I, dose-escalation study of vorinostat followed by a phase II study.

      Patients receive vorinostat orally (PO) on days 1-9, azacitidine subcutaneously (SC) or
      intravenously (IV) over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours
      on day 4 and 8. Treatment repeats every 21 days for up to 12 courses in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 3 years.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With Dose-limiting Toxicity (Phase I)

Secondary Outcome

 Number of Participants With Complete Remission

Condition

Adult Acute Megakaryoblastic Leukemia (M7)

Intervention

vorinostat

Study Arms / Comparison Groups

 Phase 1 - Dose Finding
Description:  Varying schedules and dose levels of vorinostat, azacitidine and gemtuzumab ozogamicin. Includes cohorts 1-3.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

52

Start Date

May 2009

Completion Date

September 2013

Primary Completion Date

July 2013

Eligibility Criteria

        Inclusion Criteria:

          -  Prior morphological diagnosis of acute myeloid leukemia (AML) other then acute
             promyelocytic leukemia (APL) according to the 2001 WHO criteria; patients with
             biphenotypic AML are eligible

          -  Need for first salvage chemotherapy for persistent or relapsing disease, defined by
             standard criteria, after at least one course of conventional chemotherapy

          -  A bone marrow biopsy is not required but should be obtained if the aspirate is dilute,
             hypocellular, or not aspirable; outside marrow exams performed within the stipulated
             time period are acceptable if the slides are reviewed at the study institution

          -  Flow cytometric analysis of the marrow aspirate per institutional practice guidelines

          -  Duration of first complete remission (CR1) < 12 months (or primary resistant disease)

          -  Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT)
             if relapse occurs 6-12 months post-transplant

          -  ECOG/WHO/Zubrod performance status of 0-3 within 14 days prior to registration

          -  Off any active therapy for AML except hydroxyurea for at least 14 days prior to study
             registration, with resolution of all grade 3 and 4 non-hematological toxicities

          -  Willingness to discontinue taking any medications known to cause a risk of Torsades de
             Pointes

          -  Bilirubin =< 1.5 x Institutional Upper Limit of Normal (IULN) unless elevation is due
             to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (within 7 days prior
             to registration)

          -  SGOT (AST) and SGPT (ALT) =< 1.5 x IULN unless elevation is due to hepatic
             infiltration by AML (within 7 days prior to registration)

          -  Serum creatinine =< 1.5 x IULN (within 7 days prior to registration)

          -  No clinical or radiographical evidence of heart failure

          -  white blood cell (WBC) < 25,000/uL within 3 days prior to registration

          -  Patients with symptoms/signs of hyperleukocytosis or WBC > 100,000/uL can be treated
             with leukapheresis prior to enrollment

          -  Collection of bone marrow and peripheral blood specimens for correlative studies prior
             to study treatment is highly recommended; peripheral blood only is acceptable if the
             peripheral blast count is > 5,000/uL and > 50% of total WBC

          -  Must agree to use adequate contraception prior to and during the study

          -  Can understand and sign a written informed consent document; a legally authorized
             representative can provide consent if the patient is unable

        Exclusion Criteria:

          -  Remission or second or later relapse

          -  Diagnosis of another malignancy, unless diagnosed at least 2 years earlier and
             disease-free for at least 6 months after completion of curative intent therapy except:

               -  Treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial
                  neoplasia, if definitive treatment has been completed

               -  Organ-confined prostate cancer with no evidence of recurrent or progressive
                  disease based on prostate-specific antigen (PSA) values if hormonal therapy has
                  been initiated or a radical prostatectomy was performed

          -  Refractory/relapsing blast crisis of chronic myeloid leukemia (CML)

          -  Prior anti-AML treatment with GO, histone deacetylase (HDAC) inhibitor (including the
             use of valproic acid for control of seizure activity or other purposes), or
             demethylating agent

          -  Known hypersensitivity to GO, vorinostat, azacitidine, or mannitol

          -  Possible central nervous system (CNS) involvement with leukemia unless a lumbar
             puncture confirms no leukemic blasts in the cerebralspinal fluid (CSF)

          -  HIV-positive patients with cluster of differentiation (CD)4 count is < 200 cells/uL or
             if AIDS-related complications

          -  Pregnancy; breastfeeding should be discontinued if the mother is treated with
             vorinostat, azacitidine, and GO

          -  Uncontrolled systemic infection, despite appropriate antibiotics or other treatment)

          -  Receipt of any other investigational agents
      

Gender

All

Ages

50 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Roland Walter, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00895934

Organization ID

NCI-2012-01147

Secondary IDs

NCI-2012-01147

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Roland Walter, Principal Investigator, Fred Hutchinson Cancer Research Center


Verification Date

May 2019