Study of Vorinostat Plus Melphalan and Prednisone (Zmp) in Advanced, Refractory Multiple Myeloma Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether the association of ZMP is safe and provides benefits in patients with relapsed/refractory MM.

Official Title
-----------------
A Phase I/II, Multi-Center, Open Label Study of Vorinostat Plus Melphalan and Prednisone (ZMP) in Advanced, Refractory Multiple Myeloma Patients

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Vorinostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements. Patient has given voluntary written informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. Female patient is either post-menopausal for 24 consecutive months or surgically sterilized or agree to continuous abstinence from heterosexual sexual contact or willing to use effective contraception for 4 weeks prior to beginning study drug therapy, during study drug therapy (including dose interruption) and for 4 weeks after discontinuation of therapy; female patients not pregnant or nursing; female with a negative pregnancy test. Male patient agrees to use an acceptable method for contraception during study drug therapy (including dose interruption) and for 4 weeks after discontinuation of Vorinostat therapy. Patient was previously diagnosed with symptomatic MM based on standard criteria, and has measurable disease. Patient is relapsed or refractory after a minimum of 3 weeks from prior therapies (patients must have recovered from toxicities related to prior therapies). Patient has a Karnofsky performance status ≥ 60%. Patient has a life-expectancy > 3 months. Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness or social situation that would prevent the subject from signing the informed consent form or limit the compliance with study medications and requirements. Pregnant or beast feeding females. Use of any other concomitant standard/experimental anti-myeloma drug or therapy. Known positive for HIV or active infectious hepatitis, type B or C. Known congenital long QT syndrome. Ongoing therapy with anti-arrhythmic drugs or other medicinal products which led to QT prolongation and cumulative high dose of anthracycline. Any clinically significant illness that would, in the investigator's opinion, increase the patient's risk for toxicity. Patients has not plasmacell leukaemia defined as the presence of more than 20% plasma cells in the peripheral blood and an absolute plasma cell count of at least 2000/uL. Patients has not a currently active malignancy, except non melanoma skin cancer and carcinoma in situ of the cervix. Patients should not be considered to have a currently active second malignancy if they have completed therapy for a prior malignancy and are disease free from prior malignancies for >5 years and are considered by their physicians to be at less then 30% risk of relapse History of allergic reactions related to study drugs. Prior exposure to HDACi. Patients exposed to valproic acid could be eligible with a wash out period of at least 30 days. Patients scheduled to undergo autologous or allogenic bone marrow transplant within 4 week of the initiation of Vorinostat administration.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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: ZMP<br>Combination with Vorinostat, Melphalan and Prednisone | Drug: Vorinostat<br>* Patients will start induction treatment with a standard dose of MP and escalating doses of Vorinostat: Melphalan 0.18 mg/Kg for 4 days; Prednisone 1.5 mg/Kg for 4 days. Each cycle will be repeated every 28 days for a total of 6 courses In the first part of the study, the standard oral MP will be combined with escalating doses of Vorinostat. Level -1 Vorinostat = 100 mg daily on days 1-21 Melphalan = 0.18 mg/kg on days 1 - 4 Prednisone = 1.5 mg/kg on days 1 - 4 Level 0 Vorinostat = 200 mg daily on days 1-21 Melphalan = 0.18 mg/kg on days 1 - 4 Prednisone = 1.5 mg/kg on days 1 - 4 Level +1 Vorinostat = 300 mg daily on days 1-21 Melphalan = 0.18 mg/kg on days 1 - 4 Prednisone = 1.5 mg/kg on days 1 - 4 Level +2 Vorinostat = 400 mg daily on days 1-21 Melphalan = 0.18 mg/kg on days 1 - 4 Prednisone = 1.5 mg/kg on days 1 - 4<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The dose limiting toxicity (DLT)of Vorinostat with MP |  | one year | 
| The maximum tolerated dose (MTD) of Vorinostat in association with MP |  | 1 year | 
| A significant number of PR or higher (>40%) following the proposed ZMP therapy |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression Free Survival |  | 5 Years | 
| Duration of Overall Survival |  | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Refractory or relapsed patients, dose-finding, Vorinostat