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

NCT00750815 | Completed Phase 1 Results DMC

• 4 other identifiers: MCC-15399106692Millennium X05248DOXILMMY2008
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Myeloma

Keywords

B Cell; hematologic malignancy; plasma; bone marrow

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Phase II: Progression-Free Survival (PFS)

  Up to 50.9 months

• Phase II: Two Year Overall Survival (OS)

  2 years

Study Arms (2)

A. Phase I - Dose Escalation

EXPERIMENTAL

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; Drug: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD)

B. Phase II - Maximum Planned Dose (MPD)

EXPERIMENTAL

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; Drug: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD)

Interventions

Cyclophosphamide DRUG

Enroll patients into 4 different dose levels. The dose of Cyclophosphamide they receive will depend on how many patients have been treated.

Also known as: Cytoxan

A. Phase I - Dose Escalation; B. Phase II - Maximum Planned Dose (MPD)

Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD) DRUG

Patients will receive Bortezomib, Pegylated Liposomal Doxorubicin and Dexamethasone at standard doses.

Also known as: VELCADE, DOXIL®, PLD, CVDD, VDD

A. Phase I - Dose Escalation; B. Phase II - Maximum Planned Dose (MPD)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Ongoing severe infection requiring intravenous antibiotic treatment
• Life expectancy \< 3 months
• 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

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• Ortho Biotech, Inc.: collaborator

Study Sites (1)

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

MeSH Terms

Conditions

Multiple Myeloma; Hematologic Neoplasms

Interventions

Cyclophosphamide; Bortezomib; liposomal doxorubicin; Dexamethasone; 1-dodecylpyridoxal

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

Trial closed early after 58 patients were enrolled due to slow accrual and shortage of pegylated liposomal doxorubicin. Only 54 participants had cytogenetics and fluorescence in situ hybridisation (FISH) results available for risk stratification.

Results Point of Contact

• Title: Melissa Alsina, M.D.
• Organization: H. Lee Moffitt Cancer Center and Research Institute

melissa.alsina@moffitt.org

813-745-6886

Study Officials

• Melissa Alsina, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2008
• First Posted: September 11, 2008
• Study Start: September 1, 2008
• Primary Completion: December 1, 2012
• Study Completion: May 1, 2013
• Last Updated: January 20, 2014
• Results First Posted: January 20, 2014

Record last verified: 2013-09

Locations

US (1)