Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML
Primary Purpose
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a)
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
vorinostat
gemtuzumab ozogamicin
azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Adult Acute Megakaryoblastic Leukemia (M7)
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
Sites / Locations
- Stanford University Hospitals and Clinics
- Harrison HealthPartners Hematology and Oncology-Bremerton
- Fred Hutchinson Cancer Research Center
- University of Washington Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Phase 1 - Dose Finding
Phase 2 - Treatment at Selected Dose
Arm Description
Varying schedules and dose levels of vorinostat, azacitidine and gemtuzumab ozogamicin. Includes cohorts 1-3.
Vorinostat 400 mg/day on days 1-9, azacitidine 75 mg/m2/day on days 1-7, gemtuzumab ozogamicin 3 mg/m2/day on days 4 and 8.
Outcomes
Primary Outcome Measures
Number of Participants With Dose-limiting Toxicity (Phase I)
Number of Participants With Dose-limiting Toxicity After the Vorinostat Dose
Secondary Outcome Measures
Number of Participants With Complete Remission
Efficacy Defined as Best Response Achieved During Study Treatment Measured by Complete Remission (CR) Rate
Disease Relapse
Full Information
NCT ID
NCT00895934
First Posted
May 7, 2009
Last Updated
May 2, 2019
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00895934
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)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
May 2009 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
September 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Myeloid Leukemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
52 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Phase 1 - Dose Finding
Arm Type
Experimental
Arm Description
Varying schedules and dose levels of vorinostat, azacitidine and gemtuzumab ozogamicin. Includes cohorts 1-3.
Arm Title
Phase 2 - Treatment at Selected Dose
Arm Type
Experimental
Arm Description
Vorinostat 400 mg/day on days 1-9, azacitidine 75 mg/m2/day on days 1-7, gemtuzumab ozogamicin 3 mg/m2/day on days 4 and 8.
Intervention Type
Drug
Intervention Name(s)
vorinostat
Other Intervention Name(s)
L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
gemtuzumab ozogamicin
Other Intervention Name(s)
Calicheamicin, CDP-771, CMA-676, Mylotarg
Intervention Description
Given intravenously (IV)
Intervention Type
Drug
Intervention Name(s)
azacitidine
Other Intervention Name(s)
5-AC, 5-azacytidine, azacytidine, Vidaza
Intervention Description
Given IV or subcutaneously (SC)
Primary Outcome Measure Information:
Title
Number of Participants With Dose-limiting Toxicity (Phase I)
Time Frame
42 days
Title
Number of Participants With Dose-limiting Toxicity After the Vorinostat Dose
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Number of Participants With Complete Remission
Description
Efficacy Defined as Best Response Achieved During Study Treatment Measured by Complete Remission (CR) Rate
Time Frame
up to 3 years
Title
Disease Relapse
Time Frame
up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roland Walter
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University Hospitals and Clinics
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Harrison HealthPartners Hematology and Oncology-Bremerton
City
Bremerton
State/Province
Washington
ZIP/Postal Code
98310
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
University of Washington Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24142996
Citation
Walter RB, Medeiros BC, Gardner KM, Orlowski KF, Gallegos L, Scott BL, Hendrie PC, Estey EH. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. Haematologica. 2014 Jan;99(1):54-9. doi: 10.3324/haematol.2013.096545. Epub 2013 Oct 18.
Results Reference
derived
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Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML
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