Bexarotene and GM-CSF in Treating Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00425477
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 26
• Location: 1
• Arm: 1
• Actual Duration (Months): 119
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Bexarotene may help cancer or abnormal cells become more like normal cells, and to grow and spread more slowly. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving bexarotene together with GM-CSF may be an effective treatment for myelodysplastic syndrome (MDS) or acute myeloid leukemia.

PURPOSE: This phase II trial is studying how well giving bexarotene together with GM-CSF works in treating patients with MDS or acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases	Biological: sargramostim; Drug: bexarotene; Genetic: cytogenetic analysis; Genetic: fluorescence in situ hybridization; Other: flow cytometry; Other: laboratory biomarker analysis; Procedure: biopsy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Assess the clinical response in patients with myelodysplastic syndromes or acute myeloid leukemia treated with bexarotene and sargramostim (GM-CSF).

Secondary

• Determine the clinical activity of this regimen, in terms of transfusion requirements, in these patients.

• Determine the biological activity of this regimen, in terms of biological markers and cytogenetic abnormalities, in these patients.

• Assess the toxicity profile of this regimen in these patients.

OUTLINE: Patients receive oral bexarotene and sargramostim (GM-CSF) subcutaneously on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples are collected at baseline and after 1 or 2 courses of study therapy. Samples are examined by flow cytometry for laboratory studies, including biological markers, and by fluorescent in situ hybridization (FISH) for cytogenetic changes.

After completion of study treatment, patients are followed periodically for 6 months.

PROJECTED ACCRUAL: A total of 18 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Bexarotene + Sargromastastin as Agents of Differentiation in MDS and AML
• Actual Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Sep 30, 2016
• Actual Study Completion Date: Sep 30, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bexarotene + GM-CSF BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.	Biological: sargramostim; Drug: bexarotene; Genetic: cytogenetic analysis; Genetic: fluorescence in situ hybridization; Other: flow cytometry; Other: laboratory biomarker analysis; Procedure: biopsy

Outcome Measures

Primary Outcome Measures

1. Clinical Response (Complete and Partial) [assessed after 2 cycles, up to 2 years]

   Response to treatment was assessed after two cycles, according to International Working Group (IWG) criteria.

Secondary Outcome Measures

1. Clinical Activity as Measured by Change in Peripheral Blood Counts and Changes in Transfusion Requirements [Baseline and after two cycles]

   ANC count at baseline and after two cycles were measured and compared. Due to the limited number of clinical responders, the changes in transfusion requirements were not measured.

2. Biological Activity as Measured by in Vivo Induction of Terminal Differentiation of Myeloid Progenitors and in Vivo Changes in Detectable Chromosomal Abnormalities [Baseline and 6, 12, 24, and 36 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis (confirmed by bone marrow aspirate and/or biopsy) of 1 of the following:

• Myelodysplastic syndromes of 1 of the following cell types:

• Refractory anemia (RA) with ringed sideroblasts

• Refractory cytopenia with multilineage dysplasia (RCMD)

• RCMD and ringed sideroblasts

• RA with excess blasts-1

• RA with excess blasts-2

• Myelodysplastic syndromes, unclassified

• Chronic myelomonocytic leukemia

• Relapsed or refractory acute myeloid leukemia (AML), meeting 1 of the following criteria:

• Recurrent genetic abnormalities (11q23 [MLL] abnormalities)

• Multilineage dysplasia

• Therapy-related AML

• Not otherwise categorized, including any of the following:

• M0 minimally differentiated

• M1 without maturation

• M2 with maturation

• M4 myelomonocytic leukemia

• M5 monoblastic/monocytic leukemia

• M6 erythroid leukemia

• M7 megakaryoblastic leukemia

• Newly diagnosed untreated AML allowed provided patient does not qualify for or refused potentially curative intensive chemotherapeutic regimens

• No RA with 5q-syndrome

• No peripheral leukemia with blast count > 30,000/mm³ (uncontrolled with hydroxyurea)

• Relatively stable bone marrow function for > 7 days (i.e., no WBC doubling to > 10,000/mm^3)

• No acute promyelocytic leukemia

• No clinical symptoms of active CNS disease (if CNS disease is suspected, patient must have lumbar puncture with negative cytology)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Creatinine ≤ 2.0 mg/dL

• Bilirubin ≤ 1.6 mg/dL (unless secondary to hemolysis)

• AST and ALT ≤ 4 times upper limit of normal (unless disease related)

• Hemoglobin ≥ 8 g/dL (transfusions allowed)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception

• No untreated positive blood cultures or progressive infection as assessed by radiographic studies

• No history of intolerance to sargramostim (GM-CSF)

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy

• At least 2 weeks since prior treatment for myeloid disorder, including any of the following:

• Chemotherapy

• Hematopoietic growth factors

• Biologic therapy (e.g., monoclonal antibodies)

• Hydroxyurea for patients with WBC > 10,000/mm^3 allowed

• No concurrent vitamin A supplementation

• No concurrent gemfibrozil

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Study Chair: B. Douglas Smith, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00425477
• Other Study ID Numbers: J0675 CDR0000525989; P30CA006973; JHOC-J0675; JHOC-NA_00003076
• First Posted: Jan 23, 2007
• Last Update Posted: Oct 5, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: refractory anemia with excess blasts; recurrent adult acute myeloid leukemia; untreated adult acute myeloid leukemia; secondary acute myeloid leukemia; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; myelodysplastic/myeloproliferative disease, unclassifiable; refractory anemia with ringed sideroblasts; refractory cytopenia with multilineage dysplasia; chronic myelomonocytic leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute minimally differentiated myeloid leukemia (M0); adult acute myeloblastic leukemia without maturation (M1); adult acute myeloblastic leukemia with maturation (M2); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult pure erythroid leukemia (M6b); adult erythroleukemia (M6a); adult acute megakaryoblastic leukemia (M7); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); adult acute myeloid leukemia with inv(16)(p13;q22)
• Additional relevant MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Bexarotene; Sargramostim

Study Results

Participant Flow

Arm/Group Title	Bexarotene + GM-CSF
Arm/Group Description	BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.
Period Title: Overall Study
STARTED	26
COMPLETED	13
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Bexarotene + GM-CSF
Arm/Group Description	BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.
Overall Participants	26
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72
Sex: Female, Male (Count of Participants)
Female	7 26.9%
Male	19 73.1%
Region of Enrollment (participants) [Number]
United States	26 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Response (Complete and Partial)
Description	Response to treatment was assessed after two cycles, according to International Working Group (IWG) criteria.
Time Frame	assessed after 2 cycles, up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene + GM-CSF
Arm/Group Description	BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.
Measure Participants	13
PR (partial remission)	0 0%
HI (hematologic improvement)	4 15.4%
SD (stable disease)	4 15.4%
PD (progressive disease)	5 19.2%

2. Secondary Outcome

Title	Clinical Activity as Measured by Change in Peripheral Blood Counts and Changes in Transfusion Requirements
Description	ANC count at baseline and after two cycles were measured and compared. Due to the limited number of clinical responders, the changes in transfusion requirements were not measured.
Time Frame	Baseline and after two cycles

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene + GM-CSF
Arm/Group Description	BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.
Measure Participants	13
ANC at baseline	524 (95)
ANC after 2 cycles	931 (244)

3. Secondary Outcome

Title	Biological Activity as Measured by in Vivo Induction of Terminal Differentiation of Myeloid Progenitors and in Vivo Changes in Detectable Chromosomal Abnormalities
Time Frame	Baseline and 6, 12, 24, and 36 weeks

Outcome Measure Data

Analysis Population Description

Due to the limited number of clinical responders, this research assay was not done.

Arm/Group Title	Bexarotene + GM-CSF
Arm/Group Description	BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.
Measure Participants	0

Adverse Events

Arm/Group Title	Bexarotene + GM-CSF
Arm/Group Description	BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.
All Cause Mortality
	Bexarotene + GM-CSF
	Affected / at Risk (%)	# Events
Total	3/26 (11.5%)
Serious Adverse Events
	Bexarotene + GM-CSF
	Affected / at Risk (%)	# Events
Total	7/26 (26.9%)
Blood and lymphatic system disorders
sepsis	2/26 (7.7%)
Cardiac disorders
Atrial flutter	1/26 (3.8%)
Infections and infestations
Neutropenic infection	2/26 (7.7%)
Nervous system disorders
acute subdural hemmorrhage	1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/26 (15.4%)
Other (Not Including Serious) Adverse Events
	Bexarotene + GM-CSF
	Affected / at Risk (%)	# Events
Total	7/26 (26.9%)
Hepatobiliary disorders
Elevated ALT	3/26 (11.5%)
Metabolism and nutrition disorders
Hypertriglyceridemia	2/26 (7.7%)
Musculoskeletal and connective tissue disorders
Muscle weakness	2/26 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.