Cyclophosphamide, VELCADE, DOXIL, and Dexamethasone, (CVDD) in Newly Diagnosed Patients With Multiple Myeloma (MM)

Study Overview
=================
Brief Summary
-----------------
Cyclophosphamide is a chemotherapy agent with known activity in myeloma. The new regimen that we will test in this study is called CVDD and contains Cyclophosphamide with Bortezomib (VELCADE), Pegylated Liposomal Doxorubicin (DOXIL®, PLD), and Dexamethasone (VDD). The purpose of this study is to determine if the addition of another type of chemotherapy agent, Cyclophosphamide, to the regimen VDD (CVDD) is well tolerated and improves response rates in myeloma. We will also find the highest safe dose of the study drugs taken together that a patient can tolerate, and how long it takes for multiple myeloma patients to respond after they have taken the study drugs and how long the response lasts.

Detailed Description
-----------------
The first cohort of 3 participants enrolled into Phase I of the study will receive dose level 1. A full safety evaluation will be conducted when these participants have completed one cycle (21 days) of combination therapy. Further patient accrual will be suspended while the safety data is evaluated at each dose level. Dose escalation for subsequent patients will proceed through dose levels 2, 3 and 4 as follows: If no dose limiting toxicity (DLT) is reported in the first 3 participants at a dose level, that dose level will be considered safe and 3 participants will be enrolled at the next dose level. If 1/3 participants in a cohort at a dose level has a DLT, the dose level will be expanded to obtain 6 evaluable participants. If > 1 of 3 participants in a cohort experience DLT, that dose level will not be considered safe. No further dose escalation will take place, and the immediate lower dose level will be considered the maximum planned dose (MPD) if 6 patients had been enrolled at that dose level. Otherwise, expand the immediate lower dose level to 6 evaluable patients*. If there are < 2 participants with a DLT among the expanded cohort of 6 evaluable participants, a cohort of 3 participants will be enrolled in the next higher dose level. If there are 2 or more participants with a DLT among the expanded cohort of 6 evaluable participants, that dose level will not be considered safe. No further dose escalation will take place, and the immediate lower dose level will be considered the MPD if 6 patients had been enrolled at that dose level. Otherwise, expand the immediate lower dose level to 6 evaluable patients*. * If DLT occurs in no more than 1 patient in the expanded dose cohort, then that dose level will be considered MPD. Otherwise, the dose will be further de-escalated in a similar fashion until the MPD is reached.

Official Title
-----------------
An Open Label Phase I/II Study of the Safety and Efficacy of Cyclophosphamide, Bortezomib (VELCADE), Pegylated Liposomal Doxorubicin (DOXIL), and Dexamethasone, (CVDD) in Newly Diagnosed Patients With Multiple Myeloma

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

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Understand and voluntarily sign informed consent form; equal to or greater than 18 years of age at time of consent Able to adhere to the study visit schedule and other protocol requirements Diagnosed active multiple myeloma Measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g excreted in a 24-hour urine collection sample), or serum involved free light chains ( >10mg/dl) provided that the k/l ratio is abnormal Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Performance status of 3 allowed if related to bony disease. Bilirubin ≤ 1.5x upper limits of normal (ULN) Liver enzymes: alanine transaminase (ALT)or aspartic transaminase (AST) ≤ 2.5 x ULN. In the presence of liver metastases, AST / ALT, alkaline phosphatase and total bilirubin must not exceed 3x upper limit of normal (i.e.: must be ≤ 3x ULN). Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ (1.0 x 10^9/L). Patients with bone marrow >50% plasma cells are permitted to have a neutrophil count of < 1,000 cells/mm³. Platelets ≥ 100,000 cells/mm³. Patients with bone marrow >50% plasma cells are permitted to have a Platelet count ≤ 100, 000 cells/mm³ Hemoglobin > 8 g/dL (transfusion allowed to increase the Hgb) Adequate renal function: Creatinine ≤ 2.5 mg/dL Must have 2-d echocardiogram or multigated acquisition (MUGA) scan indicating left ventricular ejection fraction (LVEF) ≥ 50% within 42 days prior to first dose of study drug. A MUGA scan or 2- d Echocardiogram may be used, but the same test must be used throughout study) to evaluate LVEF. Women of childbearing potential(WCBP)† must have negative serum or urine pregnancy test 10 to 14 days prior to starting therapy. Patients with reproductive potential must use an adequate contraceptive method during treatment and for 3 months after completing treatment. In addition, sexually active WCBP must agree to use adequate contraceptive methods per the requirements outlined in protocol document. Patients treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, are eligible. 4 weeks must have lapsed since last date of radiotherapy. Patients who require concurrent radiotherapy should have entry to the protocol deferred until radiotherapy is completed and 4 weeks have passed since last date of therapy. Exclusion Criteria: Ongoing severe infection requiring intravenous antibiotic treatment Life expectancy < 3 months Prior malignancy, except; adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the participant has been disease-free for at least 5 years. Concurrent prostate cancer for which patient is receiving therapy will not be considered an exclusion if prostatic specific antigen (PSA) has been stable for 3 years. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia Patients receiving therapeutic dosages of steroids for multiple myeloma Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities Uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary, hepatic and renal diseases unless renal insufficiency is felt to be secondary to multiple myeloma Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form Pregnant or breast-feeding females. Lactating females must agree not to breast-feed. Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Prior chemotherapy for multiple myeloma, except for radiation to symptomatic bony disease, plasmapheresis for hyperviscosity, kyphoplasty and/or vertebroplasty History of hypersensitivity reactions attributed to a conventional formulation of doxorubicin hydrochloride (HC1) or the components of DOXIL® Prior anthracycline dose exceeding 360 mg/m² for doxorubicin (including DOXIL) or 720 mg/m² for epirubicin Grade 2 or higher peripheral neuropathy on clinical examination within 14 days before enrollment Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome or plasma cell leukemia Hypersensitivity to bortezomib, boron or mannitol Has received other investigational drugs within 14 days before enrollment

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A. Phase I - Dose Escalation<br>Dose of Cyclophosphamide to depend on how many patients we treated: Dose Level 1: Cyclophosphamide 250 mg /m^2 IV Day 1; VELCADE, 1.0 mg/m^2 IV days 1,4,8, and 11; DOXIL 30 mg/m^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Dose Level 2: Cyclophosphamide 500 mg /m^2 IV Day 1; VELCADE, 1.0 mg/m^2 IV days 1,4,8, and 11; DOXIL 30 mg/m^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Dose Level 3: Cyclophosphamide 750 mg /m^2 IV Day 1; VELCADE, 1.0 mg/m^2 IV days 1,4,8, and 11; DOXIL 30 mg/m^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Dose Level 4: Cyclophosphamide 750 mg /m^2 IV Day 1; VELCADE, 1.3 mg/m^2 IV days 1,4,8, and 11; DOXIL 30 mg/m^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 | Drug: Cyclophosphamide<br>* Enroll patients into 4 different dose levels. The dose of Cyclophosphamide they receive will depend on how many patients have been treated.<br>* Other names: Cytoxan;Drug: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD)<br>* Patients will receive Bortezomib, Pegylated Liposomal Doxorubicin and Dexamethasone at standard doses.<br>* Other names: VDD;|
| Experimental: B. Phase II - Maximum Planned Dose (MPD)<br>Participants received Cyclophosphamide and VELCADE at Level 4 (the MPD) at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule as the Phase I part of study. | Drug: Cyclophosphamide<br>* Enroll patients into 4 different dose levels. The dose of Cyclophosphamide they receive will depend on how many patients have been treated.<br>* Other names: Cytoxan;Drug: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD)<br>* Patients will receive Bortezomib, Pegylated Liposomal Doxorubicin and Dexamethasone at standard doses.<br>* Other names: VDD;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Maximum Planned Dose (MPD) Level | Maximum Phase II planned dose of cyclophosphamide when given in combination with bortezomib, pegylated liposomal doxorubicin and Dexamethasone (CVDD) in participants with newly diagnosed active multiple myeloma. Dose levels 1, 2, 3, 4 as outlined in Treatment Arm A. If no dose limiting toxicity (DLT) was reported in the first 3 participants at a dose level, that dose level was to be considered safe and 3 participants would be enrolled at the next dose level. If 1/3 participants in a cohort at a dose level had dose limiting toxicity (DLT), the dose level would be expanded to obtain 6 evaluable participants. MPD reflects the highest dose of drug that did not cause a DLT in 33% of participants. | 9 months | 
| Phase II: Overall Response Rate (ORR) | Best response to CVDD chemotherapy. Overall Response: Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR). PR: ≥ 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein with urine M-protein level < 100 mg per 24 hours; CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and ≤ 5% plasma cells in bone marrow. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Progression-Free Survival (PFS) | Progression-free survival after CVDD in participants with newly diagnosed active multiple myeloma. PFS: time from the initiation of therapy to progression, relapse or death from any causes. Progressive Disease (PD): Progressive Disease requires any one or more of the following: Increase of ≥ 25% from baseline in: serum M-component and /or (the absolute increase must be ≥ 0.5 g/dL) urine M-component and/or (the absolute increase must be ≥ 200 mg/24 h) | Up to 50.9 months | 
| Phase II: Two Year Overall Survival (OS) | Overall survival by disease risk stratification after CVDD. OS: time from initiation of therapy until death from any cause. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
B Cell, hematologic malignancy, plasma, bone marrow