Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information

Alternate Title

Tretinoin Plus Phenylbutyrate in Treating Patients With Acute Promyelocytic Leukemia, Neuroblastoma, Non-small Cell Lung Cancer, or Prostate Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed Not specified NCI MSKCC-98081 NCI-T98-0043, T98-0043

Objectives

I.  Evaluate the safety of phenylbutyrate when used in combination with 
tretinoin in patients with acute promyelocytic leukemia, neuroblastoma, 
non-small cell lung cancer, or prostate cancer.

II.  Evaluate the in vivo activity of phenylbutyrate as an inhibitor of 
histone deacetylase.

III.  Evaluate potential pharmacokinetic interactions between these two agents.

IV.  Evaluate potential antitumor effects of this drug combination in this 
patient population.

Entry Criteria

Disease Characteristics:

Diagnosis of acute promyelocytic leukemia (APL) confirmed by morphology and
cytogenetics or RT-PCR testing
OR
Diagnosis of one of the following diseases:
 Neuroblastoma
 Non-small cell lung cancer
 Prostate cancer

APL patients must have received prior treatment that has included both
chemotherapy with an anthracycline antibiotic and tretinoin

Patients with other diseases must have failed conventional therapy (if
appropriate), and there must be no other curative therapy available

APL patients must have documented resistance to tretinoin (RA) therapy, which
must have included at least 7 days of therapy with RA in the week immediately
preceding entry into this study at a dose of at least 45 mg/m2/day

Prior/Concurrent Therapy:

Biologic therapy:
 See Disease Characteristics

Chemotherapy:
 See Disease Characteristics
 At least 3 weeks since prior cytotoxic chemotherapy

Endocrine therapy:
 See Disease Characteristics

Radiotherapy:
 See Disease Characteristics
 At least 3 weeks since prior radiotherapy

Surgery:
 See Disease Characteristics

Patient Characteristics:

Age:
 Not specified

Performance status:
 Not specified   

Life expectancy:
 Not specified

Hematopoietic:
 WBC at least 2,500/mm3 (except for non-APL and neuroblastoma patients) 
 Platelet count at least 75,000/mm3 (except for non-APL and neuroblastoma
  patients) 

Hepatic:
 Bilirubin no greater than 2.5 mg/dL

Renal:
 Creatinine no greater than 2.5 mg/dL

Other:
 Not pregnant or nursing
 Negative pregnancy test
 Fertile patients must use effective contraception during and for at least 4
  weeks after study

Expected Enrollment

A total of 15 patients will be accrued for this study.

Outline

Patients are stratified according to whether they have acute promyelocytic 
leukemia (APL) or another disease.

All patients receive tretinoin (RA) as a single agent orally twice a day for 
at least 7 days, then in combination with phenylbutyrate (PB) for 25 days.  
APL patients must demonstrate clinical resistance to RA therapy before 
starting PB.  PB IV is administered over 1-2 hours daily, shortly after each 
RA dose, beginning on day 8 and continuing for 25 days.  For APL patients 
only, if there is evidence of a positive biological response by day 25 of PB 
therapy, treatment during the first course may be extended to a cumulative 
maximum of 35 days of PB therapy.  The first course of treatment is followed 
by 3 weeks of rest.

Treatment continues for a maximum of 6 courses for APL patients who have 
achieved and maintained at least a partial remission, and for other patients 
who are stable or responding.  In all subsequent courses, both drugs will be 
given concurrently for 25 days.  After the second course of therapy, the rest 
period may range from 4-6 weeks.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

Raymond Warrell, MD, Protocol chair(Contact information may not be current)		Ph: 212-639-8168; 800-525-2225