Low Dose Melphalan and Bortezomib for AML and High-Risk MDS

In patients who develop acute myelogenous leukemia (AML) or a high-risk myelodysplastic
syndrome (MDS), the current standard treatment involves multidrug induction chemotherapy
utilizing an anthracycline or anthraquinone with cytarabine. While chemotherapy has proven
effective at inducing remission in up to 90% of patients, elderly patients fair far worse. In
patients over the age of sixty, the disease is not only less responsive to therapy, but an
increased number of comorbid conditions makes induction therapy a more dangerous endeavor.
Because of this, many patients are not offered standard induction chemotherapy and there is a
dearth of viable alternatives for treatment of these otherwise fatal diseases.

Low dose melphalan has previously been shown to be an effective palliative treatment for
patients diagnosed with AML and high-risk MDS. It was found to have an overall response rate
of 40% in AML patients (30% complete remission and 10% partial remission) and a 57% overall
response in high-risk MDS patients (33% complete remission, 5% partial remission, and 19%
minor responses). This therapy, while not curative, is one of the few options for patients
unable to tolerate more intensive treatment regimens, but desiring a potentially effective
palliative regimen.

Bortezomib (VELCADE®) is an intravenously administered reversible, selective inhibitor of the
26S proteosome. Although all of the mechanisms by which this novel drug acts as an
antineoplastic agent are not fully understood, in vivo and in vitro studies indicate they
ultimately result in the inhibition of the gene expression necessary for cell growth and
survival pathways, apoptotic pathways, and cellular adhesion, migration, and angiogenesis
mechanisms.

Preclinical and clinical evaluation of the combination of melphalan and bortezomib has
demonstrated impressive synergy in refractory multiple myeloma cell lines and patients with
myeloma. This study aims to determine if these findings hold true in AML and MDS patients.

Inclusion Criteria:

- Pathologic diagnosis of AML or high-risk MDS Patients with chronic myelomonocytic
leukemia or a refractory cytopenia with multilineage dysplasia are eligible if that
have one of the following criteria:

- >4 units of red blood cells transfused during the previous 3 months

- platelet count <50,000/uL

- absolute neutrophil count <1000/uL and a recent infection requiring antibiotics

- Patients may either be considered to be poor candidates for standard induction
chemotherapy based on reasonable medical evidence or have declined such therapy, but
still desire palliative treatment beyond that of best supportive care

- Primary refractory disease or have disease that has relapsed after prior cytoxic
therapy

- Karnofsky performance status of >50%

- Patients may receive prior growth factor therapy

- Patients who received prior therapies (ex. melphalan, 5-azacitidine, low-dose
cytarabine) to control their MDS or AML prior to registration (Stratum 2), but are
clearly nonresponders are eligible for enrollment if expected toxicity of the prior
therapy has resolved

- Voluntary written informed consent

- If female, the subject is either post-menopausal or surgically sterilized or willing
to use an acceptable method of birth control (ie, a hormonal contraceptive,
intra-uterine device, diaphragm with spermicide, condom with spermicide, or
abstinence) for the duration of the study

- If male, the subject agrees to use an acceptable method for contraception for the
duration of the study

- Patients that have been previously treated will be eligible for study if:

1. the previous therapy was ineffective and

2. all expected toxicity of the previous treatment has resolved

3. In general the following guidelines regarding the elapsed time from previous
treatment to eligibility should be followed

1. High intensity cytotoxic treatment (7&3 induction, High Dose Ara-C): 4 weeks

2. Hematopoeitic growth factors: no delay required

3. Low intensity treatment (such as oral melphalan or hydrea, low dose
cytarabine or 5-azacitidine) No delay required if expected toxicity has
resolved and regimen ineffective

Exclusion Criteria:

- AML FAB M3

- No concomitant malignancy other than a curatively treated carcinoma in situ of cervix
or basal or squamous cell carcinoma of the skin

- Active, uncontrolled infections

- Chronic liver disease not due to AML, or bilirubin >2.0mg/dL

- End stage kidney disease on dialysis

- Active CNS disease. A lumbar puncture prior to treatment is not required and should
not be performed in the absence of significant CNS symptoms or signs

- Patient has sensory peripheral neuropathy > grade 2 or painful peripheral neuropathy >
grade 1 (see appendix A for NCI sensory neuropathy toxicity criteria) within 14 days
before enrollment

- Hypersensitivity to bortezomib, boron or mannitol

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum B-human chorionic gonadotropin
(B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
required for post-menopausal or surgically sterilized women

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study