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Phase I, Dose De-Escalation to Minimal Effective Pharmacologic Dose Trial of Sodium Phenylbutyrate (PB, NSC 657802) in Combination With 5-Azacytidine (5-AZA, NSC 102816) 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

Phase I, Dose De-Escalation to Minimal Effective Pharmacologic Dose Trial of Sodium Phenylbutyrate (PB, NSC 657802) in Combination With 5-Azacytidine (5-AZA, NSC 102816) in Patients With Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)


OBJECTIVES:

- Determine the safety and toxicity of azacitidine in combination with phenylbutyrate in
patients with recurrent, refractory, or untreated acute myeloid leukemia or
myelodysplastic syndrome.

- Determine the minimal effective pharmacologic dose of azacitidine required to
consistently inhibit DNA methyltransferase in this patient population.

- Obtain preliminary clinical and/or laboratory data suggesting potential therapeutic
activity of this combination regimen in these patients.

OUTLINE: This is a dose deescalation study of azacitidine.

Patients receive azacitidine subcutaneously daily on days 1-5 and 29-33 followed by
phenylbutyrate IV continuously on days 5-12 and 33-40. Treatment continues for at least 2
courses in the absence of disease progression. Patients with responsive disease may receive
an additional 2 months of therapy.

Cohorts of 3-6 patients receive deescalating doses of azacitidine until the minimal
effective pharmacologic dose (MEPD) is determined. The MEPD is defined as the dose above the
dose at which more than 1 of 6 patients do not meet the target enzyme inhibition of greater
than 90%.

Once the MEPD and toxicity have been established for a 5 day schedule, daily dose schedule
of azacitidine is increased to 10, 14, and 21 days, followed by phenylbutyrate for 7 days.
Courses are repeated every 28 days.

PROJECTED ACCRUAL: Approximately 32 patients will be accrued for this study within 2 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed myelodysplastic syndrome (MDS) indicating
one of the following:

- Refractory anemia (RA)

- Primary refractory leukopenia or thrombocytopenia with MDS morphology

- RA with excess blasts (RAEB)

- RA with ringed sideroblasts (RARS)

- Chronic myelomonocytic leukemia

- RAEB in transformation

- RA or RARS must have at least one of the following:

- Absolute neutrophil count less than 1,000/mm^3

- Untransfused hemoglobin less than 8 g/dL

- Platelet count less than 20,000/mm^3

- Anemia

- Thrombocytopenia requiring transfusion

- High risk chromosomal abnormalities

- Any stage of MDS allowed including:

- Previously untreated MDS

- Refractory MDS allowed if failure to achieve remission following prior intensive
chemotherapy of at least 1 month ago

- Relapsed, refractory, or untreated acute myeloid leukemia (AML) with the following:

- WBC less than 30,000/mm^3

- Stable for at least 2 weeks

- Unlikely to require cytotoxic therapy during study

- Untreated AML with poor risk factors for response to standard therapy including:

- Greater than 60 years old

- AML occurs in setting of antecedent hematologic disorder

- High risk chromosomes (e.g., abnormalities of chromosome 5 or 7 or complex
cytogenetic abnormalities)

- Medical conditions that preclude cytotoxic chemotherapy as primary therapy

- Refusal of cytotoxic chemotherapy allowed

- No clinical evidence of CNS 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)

Hepatic:

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

Renal:

- Creatinine less than 2.0 mg/dL

Cardiovascular:

- No disseminated intravascular coagulation

Pulmonary:

- No pulmonary leukostasis

Other:

- No active infection

- Not pregnant or nursing

- Negative pregnancy test

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

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- At least 3 weeks since prior biologic therapy including colony stimulating factors
and recovered

Chemotherapy:

- See Disease Characteristics

- At least 3 weeks since prior chemotherapy and recovered

Endocrine therapy:

- At least 3 weeks since prior hormonal therapy and recovered

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:

CDR0000067531, J9950

NCT ID:

NCT00004871

Start Date:

May 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
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • atypical chronic myeloid leukemia
  • myelodysplastic/myeloproliferative disease, unclassifiable
  • 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