RATIONALE: Some cancers become resistant to chemotherapy drugs. Combining cyclosporine with chemotherapy may prevent resistance to the drugs and allow the cancer cells to be killed.

PURPOSE: Randomized phase II trial to study the effectiveness of adding cyclosporine to combination chemotherapy in treating patients with relapsed or refractory acute myeloid leukemia.

Condition	Treatment or Intervention	Phase
Leukemia, Myeloid	Drug: cyclosporine  Drug: etoposide  Drug: mitoxantrone	Phase II

Further Study Details: 

OBJECTIVES: I. Evaluate whether the addition of cyclosporine (CYSP) to mitoxantrone (DHAD) and etoposide (VP-16) increases the response rate and duration of response in adults with refractory or relapsed acute myelogenous leukemia (AML).

II. Correlate response to this treatment with the presence of P-glycoprotein (P-gp) multidrug resistance (MDR) and the degree of in vitro modulation of leukemic blasts, including CD34+ blasts.

III. Correlate response with the presence of other resistance mechanisms, such as atypical MDR and non-P-gp phenotype.

IV. Evaluate the toxicity of this treatment in AML patients.

V. Study the effect of CYSP on DHAD and VP-16 pharmacokinetics and metabolism and, potentially, on intracellular drug accumulation.

PROTOCOL OUTLINE: Randomized study. The following acronyms are used: CYSP Cyclosporine, NSC-290193 DHAD Mitoxantrone, NSC-301739 VP-16 Etoposide, NSC-141540

Arm I: 2-Drug Combination Chemotherapy. DHAD; VP-16.

Arm II: 2-Drug Combination Chemotherapy with Drug Resistance Inhibition. DHAD; VP-16; with CYSP.

PROJECTED ACCRUAL: At least 25 patients/arm will be entered over approximately 3 years.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Acute myelogenous leukemia (AML) in the following categories: Refractory to initial standard therapy consisting of idarubicin/cytarabine and amsacrin/cytarabine (on protocol HOVON 29); First or subsequent relapse following complete response to standard chemotherapy (on protocols HOVON 4/4A or 11 or any other protocol); At least 6 months between mitoxantrone/etoposide and relapse
• No myelodysplasia

--Prior/Concurrent Therapy--

• See Disease Characteristics

--Patient Characteristics--

• Age: 18 and over
• Performance status: Not specified
• Hematopoietic: Not applicable
• Hepatic: Bilirubin no greater than 2 x normal; Alkaline phosphatase no greater than 2 x normal
• Renal: Creatinine no greater than 1.7 mg/dl (150 micromoles/liter) OR Creatinine clearance at least 60 ml/min
• Cardiovascular: No uncontrolled hypertension; No other severe cardiac disease
• Pulmonary: No severe pulmonary disease
• Other: No known intolerance to any study drug; No uncontrolled severe infection; Not HIV seropositive; No severe neurologic or metabolic disease; No concomitant malignancy except: Nonmelanomatous skin cancer; In situ cervical carcinoma; No pregnant women

Belgium
      Cliniques Universitaires Saint-Luc, Brussels (Bruxelles),  1200,  Belgium
      U.Z. Gasthuisberg, Leuven,  B-3000,  Belgium
Netherlands
      Academisch Medisch Centrum, Amsterdam,  1105 AZ,  Netherlands
      Academisch Ziekenhuis der Vrije Universiteit, Amsterdam,  1007 MB,  Netherlands
      Academisch Ziekenhuis Groningen, Groningen,  9713 EZ,  Netherlands
      Academisch Ziekenhuis Maastricht, Maastricht,  6202 AZ,  Netherlands
      Academisch Ziekenhuis Utrecht, Utrecht,  3508 GA,  Netherlands
      Leyenburg Ziekenhuis, 's-Gravenhage (Den Haag, The Hague),  2545 CH,  Netherlands
      University Hospital - Rotterdam Dijkzigt, Rotterdam,  3000 CA,  Netherlands
Switzerland
      Inselspital, Bern, Bern,  CH-3010,  Switzerland
      Universitaetsspital, Zurich,  CH-8091,  Switzerland
      University Hospital, Basel,  CH-4031,  Switzerland

Study chairs or principal investigators

Simon Daenen,  Study Chair,  Academisch Ziekenhuis Groningen   

Study ID Numbers:  CDR0000064413; DUT-KWF-CKVO-9412; EU-95003
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002688
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08