17-N-Allylamino-17-Demethoxygeldanamycin in Treating Patients With Systemic Mastocytosis
17-N-Allylamino-17-Demethoxygeldanamycin in Treating Patients With Systemic Mastocytosis
RATIONALE: Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin
 (17-AAG), work in different ways to stop the growth of tumor cells, either by killing the
 cells or by stopping them from dividing.

 PURPOSE: This phase II trial is studying how well 17-AAG works in treating patients with
 systemic mastocytosis.
OBJECTIVES:

 Primary

 -  Determine the efficacy of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), in terms of
 decreases in the number of mast cells in the bone marrow and in serum tryptase levels,
 in patients with systemic mastocytosis.

 Secondary

 -  Determine the quality of life of patients treated with this drug.

 -  Determine hematological and non-hematological toxicity of this drug in these patients.

 OUTLINE: This is a multicenter study.

 Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days
 1, 4, 8, and 11. Treatment repeats every 21 days for at least 6 courses in the absence of
 disease progression or unacceptable toxicity. Patients achieving a complete response (CR)
 receive at least 2 additional courses beyond CR. Patients achieving a partial response
 receive at least 4 additional courses beyond their maximum response. Selected patients may
 receive additional courses of therapy beyond the protocol guidelines at the discretion of the
 principal investigator.

 Quality of life is assessed at baseline and before each treatment course.

 PROJECTED ACCRUAL: A total of 12-37 patients will be accrued for this study within
 approximately 10-18 months.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed systemic mastocytosis

 -  Objective evidence of disease, as defined by the following:

 -  Hemoglobin < 10 g/dL

 -  Recurrent mast cell mediator-release symptoms that impair the patient's
 quality of life

 -  Symptomatic hepatosplenomegaly

 -  Ascites

 -  Symptomatic bone disease

 -  Profound constitutional symptoms (e.g., fatigue, asthenia, flushing,
 hyperpyrexia, weight loss, myalgia, and arthralgia)

 -  Elevated serum tryptase level

 -  Mast cell leukemia allowed

 -  Mastocytosis associated with myeloproliferative disease (e.g., hypereosinophilic
 syndrome or chronic myelomonocytic leukemia) allowed

 -  Patients with eosinophilia (i.e., absolute eosinophil count ≥ 1,000/mm^3) must be
 evaluated for the presence or absence of FIP1L1-PDGFRA mutation; if the mutation is
 absent, the patient is eligible; if the mutation is present, the patient is eligible
 provided disease is refractory to imatinib mesylate

 -  Patients with indolent disease must have a serum tryptase level ≥ 50 ng/mL OR episodes
 of anaphylaxis that occur with a frequency of > 1 per month

 PATIENT CHARACTERISTICS:

 Age

 -  18 and over

 Performance status

 -  ECOG 0-2

 Life expectancy

 -  At least 3 months

 Hematopoietic

 -  See Disease Characteristics

 -  Platelet count ≥ 100,000/mm^3 (> 25,000/mm^3 for patients with organomegaly)

 -  Absolute granulocyte count ≥ 1,500/mm^3(> 750/mm^3 for patients with organomegaly)

 Hepatic

 -  AST and ALT ≤ 2 times upper limit of normal (ULN) (< 4 times ULN for patients with
 hepatomegaly)

 -  Bilirubin normal

 -  Alkaline phosphatase ≤ 3 times ULN

 Renal

 -  Creatinine ≤ 1.4 mg/dL OR

 -  Creatinine clearance ≥ 60 mL/min

 Cardiovascular

 -  No New York Heart Association class III-IV congestive heart failure

 -  No history of myocardial infarction within the past year

 -  No history of uncontrolled dysrhythmia

 -  No uncontrolled angina

 -  No ischemic heart disease within the past 12 months

 -  No congenital long QT syndrome

 -  No left bundle branch block

 -  No serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation
 ≥ 3 beats in a row)

 -  QTc interval < 450 msec for males or 470 msec for females

 -  LVEF > 40% by MUGA

 -  MUGA or echocardiogram normal

 -  No prior history of cardiac toxicity after receiving anthracyclines (e.g., doxorubicin
 hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or
 carmustine)

 -  No cardiac symptoms ≥ grade 2

 -  No other significant cardiac disease

 Pulmonary

 -  No symptomatic pulmonary disease requiring medication including any of the following:

 -  Dyspnea on or off exertion

 -  Paroxysmal nocturnal dyspnea

 -  Requirement for oxygen

 -  Significant pulmonary disease (e.g., chronic obstructive/restrictive pulmonary
 disease)

 -  No home oxygen meeting the Medicare requirement

 -  No compromised pulmonary status (i.e., DLCO ≤ 80%)

 -  No prior history of pulmonary toxicity after receiving anthracyclines (e.g.,
 doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride,
 bleomycin, or carmustine)

 -  No pulmonary symptoms ≥ grade 2

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for ≥ 6 months after
 completion of study treatment

 -  HIV negative

 -  No active uncontrolled infection

 -  No serious medical illness

 -  No other non-malignant systemic disease

 -  No history of serious allergic reaction to eggs

 -  No other malignancy within the past 2 years except dermatological cancer

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Not specified

 Chemotherapy

 -  At least 4 weeks since prior chemotherapy

 Endocrine therapy

 -  Steroids allowed provided tapering to the lowest level possible to treat
 thrombocytopenia, diarrhea, or malabsorption symptoms of systemic mastocytosis

 Radiotherapy

 -  At least 4 weeks since prior radiotherapy

 -  No prior radiation that included the heart in the field (e.g., mantle) or chest

 Surgery

 -  Not specified

 Other

 -  At least 4 weeks since prior tyrosine kinase inhibitors

 -  No concurrent complimentary or alternative medications* including, but not limited to,
 the following:

 -  Hypericum perforatum (St. John's wort)

 -  Milk thistle

 -  Kava kava

 -  Mistletoe extract

 -  No concurrent agents that cause QTc prolongation

 -  No concurrent antiarrhythmic therapy

 -  No other concurrent investigational therapy NOTE: *Unless approved by the investigator