PXD101 in Treating Patients With Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00357032
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 50
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial is studying how well PXD101 works in treating patients with relapsed or refractory acute myeloid leukemia or older patients with newly diagnosed acute myeloid leukemia. PXD101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia	Drug: belinostat; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Evaluate the response rate (complete response and partial response) in patients with acute myeloid leukemia treated with PXD101.

SECONDARY OBJECTIVES:

1. Evaluate the overall survival of these patients. II. Evaluate the duration of response in these patients. III. Evaluate the toxicity of this drug in these patients.

TERTIARY OBJECTIVES:

1. Evaluate molecular response to PXD101.

OUTLINE:

Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples are obtained before and after study treatment for laboratory studies.

After completion of study treatment, patients are followed periodically for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of PXD101 in Patients With Relapsed or Refractory Acute Myelogenous Leukemia or Patients Over 60 With Newly-Diagnosed Acute Myelogenous Leukemia
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (belinostat) Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity.	Drug: belinostat; Given IV; Other Names: PXD101 ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate [Up to 1 year]

   Clinical responses were measured according to International Working Group criteria. Bone marrow studies were repeated at a minimum of every three cycles. Per International Working Group criteria: Complete Response (CR): Repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia

Secondary Outcome Measures

1. Overall Survival [Up to 1 year]

   Survival endpoints will be summarized by the method of Kaplan-Meier

2. Duration of Response [Up to 1 year]

   From time of documented treatment response (CR or PR) until progression of death. Complete Response (CR): Repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia. Partial Resonse (PR): requires the same hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to a post-treatment value of 5% to 25% in the bone marrow aspirate. (If the pre-treatment blast percentage was 50-100%, this must decrease to a value between 5-25%. If the pre-treatment blast percentage was 20-49%, this must decrease by at least half to a value greater than 5%.) A value ≤ 5% is also considered a PR if Auer rods are present.

3. Toxicity Summary [Up to 1 year]

   Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 and above toxicities possibly, probably or definitely related to treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed acute myelogenous leukemia

• The diagnosis must be made by bone marrow aspirate and biopsy; patients must have routine cytochemical evaluation along with immunophenotyping done by flow cytometry; cytogenetic analysis must also be performed

• For patients age 18-59 years, at least one prior regimen of induction chemotherapy is required; patients who have been treated with bone marrow or stem cell transplantation are eligible; there is no prior therapy requirement for patients age > 60

• Patients for whom potentially curative treatment is available must be offered this treatment and decline

• Life expectancy of greater than 3 months

• ECOG performance status =< 2 (Karnofsky >= 60%)

• Serum total bilirubin =< 2.0 mg/dl

• AST and ALT =< 2.5 times upper limit of normal (ULN)

• Creatinine clearance >= 60 mL/min OR creatinine < 1.5 times ULN

• Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of PXD101 will be determined following review of their case by the principal investigator

• Efforts should be made to switch patients with gliomas or brain metastases who are taking enzyme inducing anticonvulsant agents to other medications

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

• Patients taking hydroxyurea for the purpose of cytoreduction should discontinue this medication at least 24 hours prior to the initiation of therapy with PXD101

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients may not be receiving any other investigational agents

• Patients with known central nervous system (CNS) disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101

• Patients may not have had prior treatment with another HDAC inhibitor within 1 week of initiation of therapy with PXD101; patients receiving valproic acid should stop this medication at least 1 week prior to therapy with PXD101

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness that could compromise compliance with study requirements

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with PXD101

• HIV-positive patients are ineligible

• Patients with a marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval 500 msec), Long QT Syndrome, or the required use of concomitant medication on PXD101 infusion days that may cause Torsade de Pointes (including disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, bepridil, amiodarone, arsenic trioxide, cisapride, lidoflazine, clarithromycin, erythromycin, halofantrine, pentamidine, sparfloxacin, domperidone, droperidol, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, and methadone)

• Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, congestive heart failure related to primary cardiac disease, a condition requiring anti-arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to trial entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kenneth Foon, City of Hope Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00357032
• Other Study ID Numbers: NCI-2012-02838; PHII-68; N01CM62209
• First Posted: Jul 27, 2006
• Last Update Posted: Apr 17, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Belinostat

Study Results

Participant Flow

Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	78
Sex: Female, Male (Count of Participants)
Female	7 58.3%
Male	5 41.7%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate
Description	Clinical responses were measured according to International Working Group criteria. Bone marrow studies were repeated at a minimum of every three cycles. Per International Working Group criteria: Complete Response (CR): Repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	12
Number [percentage of subjects]	0

2. Secondary Outcome

Title	Overall Survival
Description	Survival endpoints will be summarized by the method of Kaplan-Meier
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	12
Median (95% Confidence Interval) [Months]	9.1

3. Secondary Outcome

Title	Duration of Response
Description	From time of documented treatment response (CR or PR) until progression of death. Complete Response (CR): Repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia. Partial Resonse (PR): requires the same hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to a post-treatment value of 5% to 25% in the bone marrow aspirate. (If the pre-treatment blast percentage was 50-100%, this must decrease to a value between 5-25%. If the pre-treatment blast percentage was 20-49%, this must decrease by at least half to a value greater than 5%.) A value ≤ 5% is also considered a PR if Auer rods are present.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

There were no formal CRs or PRs seen among the first cohort of 12 patients, resulting in the study's closure. As a result data were not collected.The study was completed as planned and stopped due to futility as written per protocol. It was not terminated prematurely as accrual proceeded per protocol.

Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Toxicity Summary
Description	Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 and above toxicities possibly, probably or definitely related to treatment.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	12
Grade 3 : Dehydration	1 8.3%
Grade 3 : Febrile neutropenia	1 8.3%
Grade 3 : Hematoma	0 0%
Grade 3 : Mucositis/stomatitis	1 8.3%
Grade 3 : Nausea	1 8.3%
Grade 3 : Prolonged QTc interval	1 8.3%
Grade 3 : Sodium, serum-low	1 8.3%
Grade 4 : Dehydration	0 0%
Grade 4 : Febrile neutropenia	0 0%
Grade 4 : Hematoma	1 8.3%
Grade 4 : Mucositis/stomatitis	0 0%
Grade 4 : Nausea	0 0%
Grade 4 : Prolonged QTc interval	0 0%
Grade 4 : Sodium, serum-low	0 0%

Adverse Events

Time Frame	Adverse events were collected over a period of 12 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Belinostat)
Arm/Group Description	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity. belinostat: Given IV laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Belinostat)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Belinostat)
	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)
Blood and lymphatic system disorders
Febrile neutropenia	2/12 (16.7%)	3
Hemoglobin decreased	2/12 (16.7%)	2
Gastrointestinal disorders
Constipation	1/12 (8.3%)	1
Ear, nose and throat examination abnormal	1/12 (8.3%)	1
General disorders
Chills	1/12 (8.3%)	1
Fever	1/12 (8.3%)	1
Pain	1/12 (8.3%)	1
Infections and infestations
Bladder infection	1/12 (8.3%)	1
Pneumonia	1/12 (8.3%)	1
Sepsis	2/12 (16.7%)	2
Skin infection	1/12 (8.3%)	3
Investigations
Electrocardiogram QTc interval prolonged	2/12 (16.7%)	2
Platelet count decreased	1/12 (8.3%)	1
Metabolism and nutrition disorders
Hypokalemia	1/12 (8.3%)	1
Hyponatremia	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	1/12 (8.3%)	1
Muscle weakness lower limb	1/12 (8.3%)	1
Nervous system disorders
Intracranial hemorrhage	1/12 (8.3%)	1
Seizure	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/12 (8.3%)	1
Hypoxia	1/12 (8.3%)	1
Vascular disorders
Hematoma	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Belinostat)
	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)
Blood and lymphatic system disorders
Febrile neutropenia	1/12 (8.3%)	1
Hemoglobin decreased	7/12 (58.3%)	27
Cardiac disorders
Atrial fibrillation	1/12 (8.3%)	3
Sinus bradycardia	1/12 (8.3%)	2
Ear and labyrinth disorders
Hearing loss	1/12 (8.3%)	1
Eye disorders
Eye disorder	1/12 (8.3%)	1
Photophobia	1/12 (8.3%)	1
Gastrointestinal disorders
Abdominal pain	3/12 (25%)	4
Constipation	3/12 (25%)	3
Diarrhea	1/12 (8.3%)	1
Dyspepsia	2/12 (16.7%)	2
Flatulence	1/12 (8.3%)	1
Nausea	8/12 (66.7%)	15
Oral hemorrhage	1/12 (8.3%)	1
Rectal hemorrhage	1/12 (8.3%)	1
Vomiting	2/12 (16.7%)	3
General disorders
Chills	2/12 (16.7%)	2
Disease progression	1/12 (8.3%)	1
Edema limbs	3/12 (25%)	9
Facial pain	1/12 (8.3%)	1
Fatigue	6/12 (50%)	15
Fever	3/12 (25%)	6
Flu-like symptoms	2/12 (16.7%)	4
Infections and infestations
Sinusitis	1/12 (8.3%)	1
Injury, poisoning and procedural complications
Bruising	1/12 (8.3%)	2
Investigations
Alanine aminotransferase increased	5/12 (41.7%)	13
Alkaline phosphatase increased	3/12 (25%)	14
Aspartate aminotransferase increased	4/12 (33.3%)	14
Creatinine increased	4/12 (33.3%)	9
Hyperbilirubinemia	2/12 (16.7%)	9
INR increased	1/12 (8.3%)	1
Leukopenia	2/12 (16.7%)	6
Lymphopenia	4/12 (33.3%)	9
Neutrophil count decreased	6/12 (50%)	22
Platelet count decreased	7/12 (58.3%)	23
Weight loss	1/12 (8.3%)	1
Metabolism and nutrition disorders
Anorexia	5/12 (41.7%)	6
Blood bicarbonate decreased	1/12 (8.3%)	1
Dehydration	2/12 (16.7%)	3
Hypercalcemia	1/12 (8.3%)	1
Hyperglycemia	8/12 (66.7%)	19
Hyperkalemia	2/12 (16.7%)	2
Hypermagnesemia	3/12 (25%)	5
Hypernatremia	1/12 (8.3%)	1
Hyperuricemia	1/12 (8.3%)	2
Hypoalbuminemia	6/12 (50%)	21
Hypocalcemia	6/12 (50%)	14
Hypoglycemia	3/12 (25%)	3
Hypokalemia	5/12 (41.7%)	7
Hyponatremia	5/12 (41.7%)	14
Hypophosphatemia	2/12 (16.7%)	3
Musculoskeletal and connective tissue disorders
Back pain	2/12 (16.7%)	4
Bone pain	1/12 (8.3%)	1
Chest wall pain	2/12 (16.7%)	4
Joint pain	1/12 (8.3%)	1
Muscle weakness	2/12 (16.7%)	2
Pain in extremity	1/12 (8.3%)	1
Nervous system disorders
Dizziness	3/12 (25%)	3
Headache	5/12 (41.7%)	5
Mental status changes	1/12 (8.3%)	1
Taste alteration	1/12 (8.3%)	1
Psychiatric disorders
Confusion	2/12 (16.7%)	2
Depression	1/12 (8.3%)	3
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)	2
Dyspnea	3/12 (25%)	3
Hemorrhage nasal	2/12 (16.7%)	2
Pleural effusion	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Skin hyperpigmentation	1/12 (8.3%)	4
Vascular disorders
Hematoma	1/12 (8.3%)	1
Hemorrhage	1/12 (8.3%)	1
Hypotension	4/12 (33.3%)	7

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.