Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Vorinostat and Gemtuzumab in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Active	60 and over	NCI, Pharmaceutical / Industry	FHCRC-2200.00 6688, IR-6688, MERCK-FHCRC-2200.00, NCT00673153

Objectives

Primary

1. Determine the complete remission (CR)/CR with incomplete blood count recovery (CRi) rate in older patients with previously untreated acute myeloid leukemia (AML) treated with vorinostat and gemtuzumab ozogamicin. (Good risk group)
2. Determine the 30-day survival of patients treated with this regimen. (Poor risk group)

Secondary

1. Estimate the 30-day survival of patients treated with this regimen. (Good risk group)
2. Determine the CR/CRi rate in patients treated with this regimen. (Poor risk group)
3. Estimate the frequency and severity of regimen-associated toxicities in these patients.
4. Investigate the relapse-free survival of patients who achieve CR/CRi and receive maintenance therapy on this study.
5. Define cellular factors associated with clinical response to this treatment regimen and determine the mechanisms underlying the synergistic effect between gemtuzumab ozogamicin and vorinostat on primary AML cells (in vitro correlative and mechanistic studies).

Entry Criteria

Disease Characteristics:

• Morphological diagnosis of acute myeloid leukemia (AML)
  • No acute promyelocytic leukemia (FAB M3)
• Must have cytogenetic analysis performed on bone marrow specimen
  • Patients stratified into the good-risk* group are only eligible if their AML has favorable cytogenetics (core-binding factor AML) or has a normal karyotype
  • Patients stratified into the poor-risk group are eligible independent of the cytogenetic analysis

   [Note: *Protocol closed to accrual as of 6/11/2009 for good-risk patients classifed as "worse".]

• Pretreatment bone marrow and/or peripheral blood specimens available
• Previously untreated disease
• Patients with a history of antecedent myelodysplastic syndrome (MDS) are eligible, if prior treatment did not include intensive chemotherapy AND patients are off therapy for ≥ 30 days prior to study registration and recovered
  • Prior hematopoietic growth factors, thalidomide/lenalidomide, azacitidine/decitabine, arsenic trioxide, signal transduction inhibitors, or low-dose cytarabine (< 100 mg/m2/day) for treatment of MDS allowed
• No myeloid blast crisis of chronic myelogenous leukemia
• No clinical evidence suggestive of CNS involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior systemic chemotherapy for AML, except for hydroxyurea
• No prior treatment with AML induction-type chemotherapy, gemtuzumab ozogamicin, or high-dose chemotherapy with hematopoietic stem cell support
• More than 3 years since prior treatment with histone deacetylase inhibitors (HDACi), including the use of valproic acid for seizure activity or other purposes
• Must not plan to undergo treatment for prior malignancy
• No concurrent hormone therapy

Patient Characteristics:

• ECOG/WHO/Zubrod performance status 0-3
• WBC < 10,000/μL
  • Patients with WBC ≥10,000/μL must undergo cytoreduction with hydroxyurea prior to study enrollment
  • Patients with symptoms/signs of hyperleukocytosis or WBC > 100,000/μL may be treated with leukapheresis prior to study enrollment
• Bilirubin ≤ 2.5 times upper limit of normal (ULN) (unless elevation is thought to be due to hepatic infiltration by AML, Gilbert’s syndrome, or hemolysis)
• ALT and AST ≤ 1.5 times ULN (unless elevation is thought to be due to hepatic infiltration by AML)
• Serum creatinine ≤ 1.5 times ULN
• Not pregnant or nursing
• For women: postmenopausal status or negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study therapy
• LVEF ≥ 40% by MUGA scan or echocardiogram
• No clinical evidence of congestive heart failure
• No other malignancy unless the patient was diagnosed ≥ 2 years ago AND has been disease-free for ≥ 6 months following completion of curative intent therapy
  • Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia are eligible provided definitive treatment for the condition has been completed
  • Patients with organ-confined prostate cancer are eligible provided there is no evidence of recurrent or progressive disease, based on prostate-specific antigen (PSA) values, AND hormonal therapy has been initiated or a radical prostatectomy has been performed
• No known hypersensitivity to hydroxyurea, gemtuzumab ozogamicin, or vorinostat
• No HIV positivity
• No uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection AND infection has not improved despite appropriate antibiotics or other treatment)

Expected Enrollment

Outcomes

Complete remission (CR) or CR with incomplete blood count recovery (CRi) rate (Good risk group)
30-day survival (Poor risk group)

30-day survival (Good risk group)
CR/CRi rate (Poor risk group)
Frequency and severity of regimen-associated toxicities
Relapse-free survival

Outline

This is a multicenter study. Patients are stratified according to risk status (good risk [60-69 years of age OR ECOG/WHO/ZUBROD performance status (PS) 0-1] vs poor risk [≥ 70 years of age AND ECOG/WHO/ZUBROD PS 2-3]).

• Remission induction therapy: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Patients achieving a complete remission (CR) or CR with incomplete blood count recovery (CRi) proceed to consolidation therapy. Patients with residual leukemia (≥ 5% blasts) and no hypocellularity receive a second course of induction therapy beginning between days 15-22. Patients achieving a CR or CRi after the third course proceed to consolidation therapy. Patients with continued persistent disease (≥ 5% blasts) are removed from the study.
• Consolidation therapy: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8 in the absence of disease progression or unacceptable toxicity. Patients who remain in CR or CRi proceed to maintenance therapy.
• Maintenance therapy: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Roland Walter, MD, PhD, Principal investigator		Ph: 206-667-3599

U.S.A.
California
	Stanford
	Stanford Cancer Center
		Clinical Trials Office - Stanford Cancer Center	Ph:  650-498-7061
			Email: cctoffice@stanford.edu
Illinois
	Chicago
	Robert H. Lurie Comprehensive Cancer Center at Northwestern University
		Clinical Trials Office - Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Ph:  312-695-1301
			Email: cancer@northwestern.edu
Michigan
	Detroit
	Barbara Ann Karmanos Cancer Institute
		Clinical Trials Office - Barbara Ann Karmanos Cancer Institute	Ph:  313-576-9363
North Carolina
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Clinical Trials Office - Wake Forest University Comprehensive Cancer Center	Ph:  336-713-6771
Texas
	Houston
	M. D. Anderson Cancer Center at University of Texas
		Clinical Trials Office - M. D. Anderson Cancer Center at the University of Texas	Ph:  713-792-3245
Washington
	Seattle
	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
		Roland Walter, MD, PhD	Ph:  800-804-8824
	Seattle Cancer Care Alliance
		Clinical Trials Office - Seattle Cancer Care Alliance	Ph:  800-804-8824
	Veterans Affairs Medical Center - Seattle
		William Schubach, MD	Ph:  206-764-2265 800-329-8387

Registry Information
Official Title		Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid or SAHA; Zolinza™) in Combination with Gemtuzumab Ozogamicin (Mylotarg™) as Induction and Post-Remission Therapy in Older Patients with Previously Untreated Non-M3 Acute Myeloid Leukemia
Trial Start Date		2008-03-26
Trial Completion Date		2013-12-31 (estimated)
Registered in ClinicalTrials.gov		NCT00673153
Date Submitted to PDQ		2008-04-25
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA15704

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