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Phase I Study of Suberoylanilide Hydroxamic Acid in Patients With Advanced Solid Tumors or Hematologic Malignancies

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

Alternate Title

Suberoylanilide Hydroxamic Acid in Treating Patients With Advanced Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs
Phase I Treatment Completed 18 and over NCI, Pharmaceutical / Industry MSKCC-01021
ATON-0101, NCI-G02-2099, NCT00045006

Objectives

Determine the maximum tolerated dose of suberoylanilide hydroxamic acid in patients with advanced solid tumors or hematologic malignancies.
Evaluate the pharmacokinetic profile of this drug in these patients.
Determine the effects of this drug on absorption in the fasting and non-fasting states in these patients.
Determine any anti-tumor effects of this drug in these patients.
Correlate clinical outcomes with histone acetylation in circulating mononuclear cells and tumor biopsy samples in patients treated with this drug.

Entry Criteria

Disease Characteristics:

One of the following diagnoses:
- Histologically confirmed advanced primary or metastatic solid tumor, including, but not limited to, the following:
  - Androgen-independent prostate cancer
  - Breast cancer
  - Ovarian cancer
  - Head and neck cancer
  - Non-small cell lung cancer
  - Bladder cancer
  - Kidney cancer
- Diagnosis of lymphoma, multiple myeloma, leukemia, or myelodysplastic syndromes (MDS), including, but not limited to, the following:
  - Intermediate-grade or follicular non-Hodgkin's lymphoma
  - Hodgkin's lymphoma

Patients with lymphoma or multiple myeloma must be ineligible for peripheral blood stem cell transplantation

For patients with solid tumors (except prostate cancer):
- Disease progression based on development of new lesions or an increase in pre-existing lesions
- Biochemical marker increase must not be sole criterion for disease progression

For prostate cancer patients only:
- Disease progression based on rising prostate-specific antigen (PSA) values, transaxial imaging, or radionuclide scans
- Increase in disease-related symptoms must not be sole manifestation of progression
- Patients receiving an antiandrogen as part of first-line hormonal therapy must show disease progression off of the antiandrogen prior to study
- Biochemical progression (at least 25% increase over range of values) defined as 1 of the following:
  - Rising PSA documented by at least 3 consecutive measurements obtained at least 1 week apart
  - Rising PSA documented by at least 2 consecutive measurements obtained more than 1 month apart
- PSA at least 4 ng/mL
  - Testosterone no greater than 50 ng/mL
  - If no prior orchiectomy, must maintain castrate levels of testosterone

Disease must be refractory to standard therapy or for which no curative therapy exists

No active CNS or epidural tumors

Hormone receptor status:
- Not specified

[Note: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.]

Prior/Concurrent Therapy:

Biologic therapy

See Disease Characteristics

Chemotherapy

At least 4 weeks since prior chemotherapy

Endocrine therapy

See Disease Characteristics
At least 4 weeks since prior ketoconazole
At least 2 weeks since prior steroids for patients with lymphoma
Concurrent gonadotropin-releasing hormone analogs or diethylstilbestrol to maintain castrate levels of testosterone allowed for prostate cancer patients
No concurrent ketoconazole

Radiotherapy

At least 4 weeks since prior radiotherapy
No concurrent radiotherapy to sole measurable lesion

Surgery

See Disease Characteristics
No concurrent surgery

Other

Recovered from all prior therapy
At least 4 weeks since prior palliative therapy for solid tumor patients with progressive metastatic disease (if present)
At least 4 weeks since prior investigational anticancer therapeutic drugs
At least 2 weeks since prior conventional cytotoxic therapy for patients with leukemia or MDS
At least 4 weeks since prior investigational therapy for patients with leukemia or MDS
No other concurrent investigational drugs
No other concurrent anticancer agents

Patient Characteristics:

Age

18 and over

Sex

Male or female

Menopausal status

Not specified

Performance status

Karnofsky 70-100%

Life expectancy

Not specified

Hematopoietic

WBC at least 3,500/mm³
Platelet count at least 100,000/mm³ (patients with solid tumors)
Platelet count greater than 25,000/mm³ (patients with hematologic malignancy)
Absolute neutrophil count at least 500/mm³ (patients with hematologic malignancy)

Hepatic

Bilirubin no greater than 1.5 times upper limit of normal (ULN)
AST and ALT no greater than 3 times ULN
PT no greater than 15 seconds

Renal

Creatinine no greater than 2.0 mg/dL

Cardiovascular

No New York Heart Association class III or IV heart disease

Pulmonary

No severe debilitating pulmonary disease

Other

No infection requiring IV antibiotics
No other severe medical problems that would preclude study participation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception

Expected Enrollment

A maximum of 114 patients (42 with solid tumors, 36 with lymphoma or multiple myeloma, and 36 with leukemia or myelodysplastic syndromes) will be accrued for this study within 1 year.

Outline

This is a dose-escalation study. Patients are stratified according to disease (solid tumor vs multiple myeloma or lymphoma vs leukemia or myelodysplastic syndromes).

The initial 15-20 patients (in the solid tumor or multiple myeloma or lymphoma stratum) receive suberoylanilide hydroxamic acid (SAHA) IV over 2 hours on day 1 of week 0 and then orally once or twice daily beginning on day 1 of week 1. All remaining patients receive oral SAHA once or twice daily beginning on day 1 of week 1. Courses repeat every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

In each stratum, cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed monthly for resolution of adverse events.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

William Kelly, DO, Protocol chair(Contact information may not be current)
Ph: 203-737-2572; 800-525-2225

Registry Information

Official Title		Phase I Clinical Trial of Oral Suberoylanilide Hydroxamic Acid - SAHA (MSK390) in Patients with Advanced Solid Tumors and Hematologic Malignancies

Trial Start Date		2001-07-30

Trial Completion Date		2005-12-13

Registered in ClinicalTrials.gov		NCT00045006

Date Submitted to PDQ		2002-06-26

Information Last Verified		2003-10-09

NCI Grant/Contract Number		CA08748

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.