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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00895934
• Collaborator: (none)
• Enrollment: 52
• Locations: 4
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 13
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: vorinostat; Drug: gemtuzumab ozogamicin; Drug: azacitidine	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

2. 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 Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: May 1, 2009
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 - Dose Finding Varying schedules and dose levels of vorinostat, azacitidine and gemtuzumab ozogamicin. Includes cohorts 1-3.	Drug: vorinostat; Given orally; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Drug: gemtuzumab ozogamicin; Given intravenously (IV); Other Names: Calicheamicin CDP-771 CMA-676 Mylotarg ; Drug: azacitidine; Given IV or subcutaneously (SC); Other Names: 5-AC 5-azacytidine azacytidine Vidaza
Experimental: Phase 2 - Treatment at Selected Dose 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; Given orally; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Drug: gemtuzumab ozogamicin; Given intravenously (IV); Other Names: Calicheamicin CDP-771 CMA-676 Mylotarg ; Drug: azacitidine; Given IV or subcutaneously (SC); Other Names: 5-AC 5-azacytidine azacytidine Vidaza

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-limiting Toxicity (Phase I) [42 days]

2. Number of Participants With Dose-limiting Toxicity After the Vorinostat Dose [Up to 3 years]

Secondary Outcome Measures

1. Number of Participants With Complete Remission [up to 3 years]

   Efficacy Defined as Best Response Achieved During Study Treatment Measured by Complete Remission (CR) Rate

2. Disease Relapse [up to 2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Hospitals and Clinics	Stanford	California	United States	94305
2	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
3	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
4	University of Washington Medical Center	Seattle	Washington	United States	98195

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Roland Walter, Fred Hutchinson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00895934
• Other Study ID Numbers: NCI-2012-01147; NCI-2012-01147; IR-6921; CDR0000642213; 2288.00; 8297; P30CA015704
• First Posted: May 8, 2009
• Last Update Posted: May 23, 2019
• Last Verified: May 1, 2019

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Azacitidine; Vorinostat; Gemtuzumab; Calicheamicins

Study Results

Participant Flow

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4
Arm/Group Description	Azacitidine 75mg/m^2/day, days 1-7, Vorinostat 200mg/day, days 1-9; and Gemtuzumab Ozogamicin 3mg/m^2, Day 8 only. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Vorinostat: Given orally Gemtuzumab ozogamicin: Given IV Azacitidine: Given IV or SC laboratory biomarker analysis: Correlative studies	Patients receive Azacitidine 75mg/m^2/day, days 1-7, Vorinostat 300mg/day, days 1-9; and Gemtuzumab Ozogamicin 3mg/m^2, Day 8 only. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Vorinostat: Given orally Gemtuzumab ozogamicin: Given IV Azacitidine: Given IV or SC laboratory biomarker analysis: Correlative studies	Patients receive Azacitidine 75mg/m^2/day, days 1-7, Vorinostat 400mg/day, days 1-9; and Gemtuzumab Ozogamicin 3mg/m^2, Day 8 only. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Vorinostat: Given orally Gemtuzumab ozogamicin: Given IV Azacitidine: Given IV or SC laboratory biomarker analysis: Correlative studies	Patients receive Azacitidine 75mg/m^2/day, days 1-7, Vorinostat 400 mg/day, days 1-9; and Gemtuzumab Ozogamicin 3mg/m^2, Days 4 and 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Vorinostat: Given orally Gemtuzumab ozogamicin: Given IV Azacitidine: Given IV or SC laboratory biomarker analysis: Correlative studies
Period Title: Dose Escalation
STARTED	3	3	3	6
COMPLETED	3	3	3	6
NOT COMPLETED	0	0	0	0
Period Title: Dose Escalation
STARTED	0	0	0	37
COMPLETED	0	0	0	37
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1 Dose-Finding Cohorts 1-3	Phase 2/Selected Dose	Total
Arm/Group Description	Patients receive vorinostat PO on days 1-9, azacitidine SC or IV over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally gemtuzumab ozogamicin: Given IV azacitidine: Given IV or SC laboratory biomarker analysis: Correlative studies	Azacitidine 75 mg/m2 SC or IV on days 1-7, vorinostat 400 mg qd po on days 1-9, gemtuzumab ozogamicin 3 mg/m2 IV on days 4 and 8. Includes cohort 4 from the Phase 1 portion of the study. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	9	43	52
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 44.4%	21 48.8%	25 48.1%
>=65 years	5 55.6%	22 51.2%	27 51.9%
Sex: Female, Male (Count of Participants)
Female	5 55.6%	18 41.9%	23 44.2%
Male	4 44.4%	25 58.1%	29 55.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 33.3%	1 2.3%	4 7.7%
Not Hispanic or Latino	6 66.7%	40 93%	46 88.5%
Unknown or Not Reported	0 0%	2 4.7%	2 3.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 11.1%	0 0%	1 1.9%
Asian	0 0%	6 14%	6 11.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 2.3%	1 1.9%
White	8 88.9%	34 79.1%	42 80.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 4.7%	2 3.8%
Region of Enrollment (Count of Participants)
United States	9 100%	43 100%	52 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-limiting Toxicity (Phase I)
Time Frame	42 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose 1	Dose 2	Dose 3	Dose 4
Arm/Group Description	Vorinostat 200, D8	Vorinostat 300, D8	Vorinostat 400, D8	Vorinostat 400, D4 and D8
Measure Participants	3	3	3	6
Number [participants]	0 0%	0 0%	0 0%	1 NaN

2. Primary Outcome

Title	Number of Participants With Dose-limiting Toxicity After the Vorinostat Dose
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Dose-Finding Cohorts 1-3	Phase 2/Selected Dose
Arm/Group Description	Patients receive vorinostat PO on days 1-9, azacitidine SC or IV over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally gemtuzumab ozogamicin: Given IV azacitidine: Given IV or SC laboratory biomarker analysis: Correlative studies	Azacitidine 75 mg/m2 on days 1-7, vorinostat 400 mg qd on days 1-9, gemtuzumab ozogamicin 3 mg/m2 on days 4 and 8. Includes cohort 4 from the Phase 1 portion of the study.
Measure Participants	9	43
Number [participants]	4 44.4%	18 41.9%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2/Selected Dose
Arm/Group Description	Azacitidine 75 mg/m2 on days 1-7, vorinostat 400 mg qd on days 1-9, gemtuzumab ozogamicin 3 mg/m2 on days 4 and 8. Includes cohort 4 from the Phase 1 portion of the study.
Measure Participants	43
Count of Participants [Participants]	18 200%

4. Secondary Outcome

Title	Disease Relapse
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2/Selected Dose
Arm/Group Description	Azacitidine 75 mg/m2 on days 1-7, vorinostat 400 mg qd on days 1-9, gemtuzumab ozogamicin 3 mg/m2 on days 4 and 8. Includes cohort 4 from the Phase 1 portion of the study.
Measure Participants	18
Count of Participants [Participants]	5 55.6%

Adverse Events

Time Frame	Adverse events are collected from the start of treatment until 30 days after the last dose.
Arm/Group Title	Phase 1 Dose-Finding		Phase 2
Arm/Group Description	Patients receive vorinostat PO on days 1-9, azacitidine SC or IV over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory biomarker analysis: correlative studies		Azacitidine 75 mg/m2 on days 1-7, vorinostat 400 mg qd on days 1-9, gemtuzumab ozogamicin 3 mg/m2 on days 4 and 8. Includes cohort 4 from the Phase 1 portion of the study. Laboratory biomarker analysis: correlative studies
All Cause Mortality
	Phase 1 Dose-Finding		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase 1 Dose-Finding		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/15 (40%)		13/43 (30.2%)
Blood and lymphatic system disorders
febrile neutropenia	2/15 (13.3%)	3	1/43 (2.3%)	1
Cardiac disorders
hypotension	1/15 (6.7%)	1	2/43 (4.7%)	2
General disorders
multi-organ failure	0/15 (0%)	0	1/43 (2.3%)	1
death, NOS	1/15 (6.7%)	1	1/43 (2.3%)	1
Infections and infestations
infection with neutropenia	1/15 (6.7%)	2	1/43 (2.3%)	2
sepsis	0/15 (0%)	0	4/43 (9.3%)	4
Metabolism and nutrition disorders
hypokalemia	0/15 (0%)	0	2/43 (4.7%)	3
Respiratory, thoracic and mediastinal disorders
hypoxia	1/15 (6.7%)	1	1/43 (2.3%)	1
Other (Not Including Serious) Adverse Events
	Phase 1 Dose-Finding		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/15 (60%)		43/43 (100%)
Blood and lymphatic system disorders
bleeding	4/15 (26.7%)	4	19/43 (44.2%)	19
anemia	8/15 (53.3%)	11	25/43 (58.1%)	33
pancytopenia	0/15 (0%)	0	13/43 (30.2%)	17
febrile neutropenia	1/15 (6.7%)	1	31/43 (72.1%)	44
lymphopenia	4/15 (26.7%)	6	0/43 (0%)	0
neutropenia	3/15 (20%)	4	17/43 (39.5%)	26
thrombocytopenia	5/15 (33.3%)	6	25/43 (58.1%)	38
leukopenia	6/15 (40%)	7	23/43 (53.5%)	32
Cardiac disorders
cardiac chest pain	0/15 (0%)	0	2/43 (4.7%)	2
prolonged QTc	0/15 (0%)	0	4/43 (9.3%)	4
hypertension	1/15 (6.7%)	1	9/43 (20.9%)	11
hypotension	2/15 (13.3%)	2	9/43 (20.9%)	9
sinus tachycardia	1/15 (6.7%)	1	14/43 (32.6%)	17
Gastrointestinal disorders
colitis	0/15 (0%)	0	4/43 (9.3%)	4
constipation	5/15 (33.3%)	6	15/43 (34.9%)	18
diarrhea	5/15 (33.3%)	5	22/43 (51.2%)	26
mucositis	0/15 (0%)	0	6/43 (14%)	7
nausea	8/15 (53.3%)	10	33/43 (76.7%)	47
vomiting	6/15 (40%)	8	17/43 (39.5%)	25
General disorders
abdominal pain	1/15 (6.7%)	1	5/43 (11.6%)	6
chills	2/15 (13.3%)	2	19/43 (44.2%)	19
edema	2/15 (13.3%)	2	11/43 (25.6%)	12
fatigue	4/15 (26.7%)	5	29/43 (67.4%)	39
fever	0/15 (0%)	0	16/43 (37.2%)	20
pain	3/15 (20%)	4	14/43 (32.6%)	15
malaise	0/15 (0%)	0	3/43 (7%)	3
Hepatobiliary disorders
elevated liver function tests	6/15 (40%)	14	15/43 (34.9%)	32
Immune system disorders
allergic reaction	0/15 (0%)	0	2/43 (4.7%)	3
infusion reaction	0/15 (0%)	0	4/43 (9.3%)	5
Infections and infestations
infection	5/15 (33.3%)	9	37/43 (86%)	43
sepsis	0/15 (0%)	0	9/43 (20.9%)	9
Injury, poisoning and procedural complications
fall	0/15 (0%)	0	3/43 (7%)	4
Metabolism and nutrition disorders
acidosis	1/15 (6.7%)	1	2/43 (4.7%)	2
blood chemistry changes	9/15 (60%)	67	43/43 (100%)	86
anorexia	1/15 (6.7%)	1	23/43 (53.5%)	34
Musculoskeletal and connective tissue disorders
back pain	0/15 (0%)	0	3/43 (7%)	3
bone pain	0/15 (0%)	0	2/43 (4.7%)	2
muscle weakness	0/15 (0%)	0	5/43 (11.6%)	6
non-cardiac chest pain	2/15 (13.3%)	3	3/43 (7%)	3
Nervous system disorders
dizziness	2/15 (13.3%)	3	11/43 (25.6%)	11
headache	2/15 (13.3%)	2	8/43 (18.6%)	9
Psychiatric disorders
anxiety	0/15 (0%)	0	7/43 (16.3%)	7
confusion	0/15 (0%)	0	8/43 (18.6%)	8
depression	2/15 (13.3%)	3	4/43 (9.3%)	4
Renal and urinary disorders
acute kidney injury	1/15 (6.7%)	1	5/43 (11.6%)	5
Respiratory, thoracic and mediastinal disorders
aspiration	0/15 (0%)	0	4/43 (9.3%)	4
cough	0/15 (0%)	0	16/43 (37.2%)	17
dyspnea	1/15 (6.7%)	1	14/43 (32.6%)	14
hypoxia	0/15 (0%)	0	8/43 (18.6%)	9
pleural effusion	0/15 (0%)	0	5/43 (11.6%)	5
pulmonary edema	0/15 (0%)	0	4/43 (9.3%)	4
respiratory failure	0/15 (0%)	0	3/43 (7%)	3
wheezing	0/15 (0%)	0	3/43 (7%)	3
Skin and subcutaneous tissue disorders
erythema multiforme	0/15 (0%)	0	3/43 (7%)	3
skin disorders	3/15 (20%)	3	15/43 (34.9%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.