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

Study Overview
=================
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.

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)

Conditions
-----------------
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

Intervention / Treatment
-----------------
* Drug: vorinostat
* Drug: gemtuzumab ozogamicin
* Drug: azacitidine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Dose Finding<br>Varying schedules and dose levels of vorinostat, azacitidine and gemtuzumab ozogamicin. Includes cohorts 1-3. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Drug: gemtuzumab ozogamicin<br>* Given intravenously (IV)<br>* Other names: Mylotarg;Drug: azacitidine<br>* Given IV or subcutaneously (SC)<br>* Other names: Vidaza;|
| Experimental: Phase 2 - Treatment at Selected Dose<br>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. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Drug: gemtuzumab ozogamicin<br>* Given intravenously (IV)<br>* Other names: Mylotarg;Drug: azacitidine<br>* Given IV or subcutaneously (SC)<br>* Other names: Vidaza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicity (Phase I) |  | 42 days | 
| Number of Participants With Dose-limiting Toxicity After the Vorinostat Dose |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Remission | Efficacy Defined as Best Response Achieved During Study Treatment Measured by Complete Remission (CR) Rate | up to 3 years | 
| Disease Relapse |  | up to 2 years |