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A Phase I, Dose-Finding Trial of Sodium Phenylbutrate (NSC 657802) in Combination With All Trans-retinoic Acid (ATRA, NSC 122758) in Patients With Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)


Phase 1
18 Years
N/A
Not Enrolling
Both
Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

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Trial Information

A Phase I, Dose-Finding Trial of Sodium Phenylbutrate (NSC 657802) in Combination With All Trans-retinoic Acid (ATRA, NSC 122758) in Patients With Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)


OBJECTIVES:

- Determine the safety and toxicity of phenylbutyrate and tretinoin in patients with
myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

- Determine the pharmacokinetic interaction of this regimen in these patients.

- Determine any potential therapeutic activity of this regimen in these patients.

OUTLINE: This is a dose escalation study of tretinoin.

Patients receive phenylbutyrate IV continuously on days 1-7 of weeks 1, 5, 7, 9, 11, 13, 15,
17, and 19. Patients also receive oral tretinoin three times daily on days 1-7 of weeks 3,
5, 7, 9, 11, 13, 15, 17, and 19. Treatment continues in the absence of disease progression
or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tretinoin until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6
patients experience dose limiting toxicities.

An additional cohort of 6 patients is accrued at the MTD. These patients receive
phenylbutyrate IV continuously on days 1-3 of weeks 1 and 3-18. These patients also receive
oral tretinoin three times daily on days 1-3 of weeks 2-18. Treatment continues in the
absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 3-24 patients will be accrued for this study within 18 months.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed myelodysplastic syndrome (MDS)

- Refractory anemia

- Primary refractory leukopenia or thrombocytopenia with morphologic features of
MDS

- Refractory anemia with excess blasts (RAEB)

- Refractory anemia with ringed sideroblasts

- RAEB in transformation

- Must have excess blasts or be hematopoietically compromised, defined as one of
the following:

- RBC transfusion dependent

- Granulocyte count less than 1,000/mm^3

- Platelet count less than 50,000/mm^3 OR

- Diagnosis of chronic myelomonocytic leukemia

- Hematopoietically compromised (as defined above) OR

- Excess blasts OR

- Evaluable disease related symptomatology (organomegaly or leukemia cutis) OR

- Diagnosis of acute myeloid leukemia

- WBC less than 20,000/mm^3 and stable for at least 2 weeks

- Unlikely to require cytotoxic therapy during study

- No CNS or pulmonary leukostasis or CNS leukemia

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Performance status:

- Zubrod 0-2

Life expectancy:

- Not specified

Hematopoietic:

- See Disease Characteristics

- Hemoglobin at least 8 g/dL (transfusion allowed)

- No disseminated intravascular coagulation

Hepatic:

- Bilirubin less than 2.0 mg/dL (unless due to hemolysis or Gilbert's syndrome)

Renal:

- Creatinine less than 2.0 mg/dL

Other:

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception for 2 weeks prior, during, and for
3 months after study

- No active infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- See Disease Characteristics

- At least 3 weeks since prior biologic therapy, including hematopoietic growth
factors, and recovered

Chemotherapy:

- See Disease Characteristics

- At least 3 weeks (1 month for MDS patients) since prior chemotherapy and recovered

Endocrine therapy:

- Not specified

Radiotherapy:

- At least 3 weeks since prior radiotherapy and recovered

Surgery:

- Not specified

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Steven D. Gore, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CDR0000068164, J9879

NCT ID:

NCT00006239

Start Date:

December 2000

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Diseases
  • recurrent adult acute myeloid leukemia
  • untreated adult acute myeloid leukemia
  • refractory anemia
  • refractory anemia with ringed sideroblasts
  • refractory anemia with excess blasts
  • refractory anemia with excess blasts in transformation
  • chronic myelomonocytic leukemia
  • previously treated myelodysplastic syndromes
  • atypical chronic myeloid leukemia
  • myelodysplastic/myeloproliferative disease, unclassifiable
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410