Arsenic Trioxide With or Without Tretinoin in Treating Patients With Hematologic Cancer That Has Not Responded to Previous Therapy

Sponsor

Washington University School of Medicine (Other)

Overall Status

Terminated

CT.gov ID

NCT00006220

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arms

32.1

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Tretinoin may help hematologic cancer cells develop into normal white blood cells.

PURPOSE: Phase I/II trial to study the effectiveness of arsenic trioxide with or without tretinoin in treating patients who have hematologic cancer that has not responded to previous therapy.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes	Drug: arsenic trioxide Drug: tretinoin	Phase 1/Phase 2

Detailed Description

This is a dose escalation and efficacy study of arsenic trioxide. In the efficacy study, patients are stratified according to diagnosis (acute myelogenous leukemia vs acute lymphocytic leukemia vs myelodysplastic syndrome vs multiple myeloma vs non-Hodgkin's lymphoma and Hodgkin's disease). Phase I: Patients receive arsenic trioxide IV over 2 hours daily for 28 days. Treatment repeats every 42-59 days in the absence of disease progression or unacceptable toxicity. Patients who achieve complete remission (CR) or partial remission (PR) receive up to 4 courses. Patients who fail to achieve CR or PR or who experience disease progression may receive arsenic trioxide and tretinoin daily for 28 days every 42-59 days for up to 7 courses. Patients who fail to achieve CR or PR or experience disease progression with arsenic trioxide and tretinoin are removed from study. Cohorts of 3-6 patients receive escalating doses of arsenic trioxide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicities. Phase II: Patients receive the MTD of arsenic trioxide as in phase I for up to 7 courses. Patients who fail to achieve CR or PR after 3 courses or experience disease progression are either taken off study or treated with arsenic trioxide and tretinoin as in phase I. Patients are followed monthly for 6 months, and then every 3 months for 18 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Primary Purpose:

Treatment

Official Title:

Arsenic Trioxide Alone or With ATRA (Vesanoid) for Resistant Hematologic Malignancy

Study Start Date :

Jun 1, 1999

Actual Primary Completion Date :

Nov 1, 2000

Actual Study Completion Date :

Feb 1, 2002

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Starting dose of arsenic trioxide of 0.15 mg/kg/day	Drug: arsenic trioxide
Experimental: Phase II MTD of arsenic trioxide	Drug: arsenic trioxide
Experimental: Treatment Failure Arsenic trioxide and tretinoin	Drug: arsenic trioxide Drug: tretinoin

Arm

Intervention/Treatment

Experimental: Phase I

Starting dose of arsenic trioxide of 0.15 mg/kg/day

Drug: arsenic trioxide

Experimental: Phase II

MTD of arsenic trioxide

Drug: arsenic trioxide

Experimental: Treatment Failure

Arsenic trioxide and tretinoin

Drug: arsenic trioxide

Drug: tretinoin

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) [28 days]
Likelihood of complete (CR) or partial (PR) response following therapy [6 months]

Secondary Outcome Measures

Explore the pharmacokinetics of arsenic trioxide alone and in combination with ATRA []
Evaluate acute and chronic toxicities of arsenic trioxide alone and in combination with ATRA. []
Determine the effects of arsenic trioxide alone and combined with ATRA on bcl-2, pml, and class I antigen expression and on apoptosis. Determine the effects of arsenic trioxide on T and B cell number and function []
Only when patients are circulating tumor cells.

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS: Patients with any of the following diagnoses: Acute lymphocytic leukemia OR acute myeloid leukemia Failed to achieve complete remission (CR) with induction chemotherapy OR Relapsed within one year of initial CR OR Relapsed after autologous or allogeneic transplant OR Any subsequent relapse OR Refractory following relapse CR2 or more (phase I only) Blastic phase chronic myelogenous leukemia Prior therapy allowed Myelodysplastic syndrome, including the following: Refractory anemia with excess blasts (RAEB) OR RAEB in transformation (high intermediate or high risk only) Relapsed after transplant CR2 or more (phase I only) Non-Hodgkin's lymphoma OR Hodgkin's disease Newly diagnosed or in first relapse and failed to achieve CR or partial remission after induction or salvage chemotherapy OR Second or later relapse OR Relapsed after transplant No disease that can be encompassed in a standard radiation port No asymptomatic, minimally symptomatic, or low grade lymphoma Multiple myeloma Symptomatic, progressive, or recurrent disease after treatment with alkylating agents, high dose corticosteroids, or anthracyclines OR Relapsed following transplant Not eligible for autologous or allogeneic transplant 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.

PATIENT CHARACTERISTICS: Age: 15 and over Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 500/mm3* Platelet count at least 50,000/mm3* *Unless caused by marrow infiltration by tumor No congenital bleeding disorder Hepatic: Bilirubin less than 2 times upper limit of normal (ULN) SGOT less than 3 times ULN Renal: Creatinine clearance greater than 25 mL/min Cardiovascular: No myocardial infarction, stroke, or unstable angina within the past 12 months No uncompensated congestive heart failure Left ventricular ejection fraction at least 40% Other: No active infection HIV negative HTLV I/II negative Not pregnant Fertile patients must use effective contraception during and for 2 years following study

PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics Chemotherapy: See Disease Characteristics Prior hydroxyurea allowed Endocrine therapy: See Disease Characteristics Radiotherapy: See Disease Characteristics Surgery: Not specified Other: At least 3 weeks since prior antileukemic therapy (except leukapheresis)