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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the response rate of the combination of bortezomib and melphalan in patients with Acute Myelogenous Leukemia (AML) or high-risk Myelodysplastic Syndromes (MDS).

Detailed Description
-----------------
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.

Official Title
-----------------
A Pilot Study of Low Dose Melphalan and Bortezomib for Treatment of Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndromes

Conditions
-----------------
Acute Myelogenous Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: Melphalan
* Drug: Bortezomib
* Drug: Melphalan and bortezomib


Participation Criteria
=================
Eligibility Criteria
-----------------
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: the previous therapy was ineffective and all expected toxicity of the previous treatment has resolved In general the following guidelines regarding the elapsed time from previous treatment to eligibility should be followed High intensity cytotoxic treatment (7&3 induction, High Dose Ara-C): 4 weeks Hematopoeitic growth factors: no delay required 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
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment<br>All patients will receive the following regimen: 1) Melphalan 2 mg orally, once daily. 2) Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11. | Drug: Melphalan<br>* Melphalan: 2mg orally, once daily<br>* Other names: Velcade;Drug: Bortezomib<br>* Bortezomib: 1.0mg/M2 IV on days 1, 4, 8, 11<br>Drug: Melphalan and bortezomib<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate of the Combination of Bortezomib and Melphalan in Patients With AML and High-risk MDS. | Determine disease response to treatment using Cheson 2000 report of an international working group to standardize response criteria for myelodysplastic syndromes. | Post Cycle 1 through 28 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Safety Profile of the Combination of Bortezomib and Melphalan. | The safety profile is based on the number of adverse events experienced by participants as reported in the Adverse Events results section for this protocol. | Start of treatment through 28 days post-treatment | 
| Number of Participants With Correlation Between in Vitro and in Vivo Activity of the Combination of Bortezomib and Melphalan. | Leukemic cells will be collected to test the presence of the study drugs using a cell viability assay in vitro and in vivo. | Pre-treatment and at complete response | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MDS, Acute Myelogenous Leukemia, AML, Myelodysplastic Syndromes, Melphalan, Bortezomib, Velcade