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
Overview
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 58
- Locations
- 1
- Primary Endpoint
- Phase I - Maximum Planned Dose (MPD) Level
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
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.
Arms & Interventions
A. Phase I - Dose Escalation
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
Intervention: Cyclophosphamide (Drug)
A. Phase I - Dose Escalation
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
Intervention: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD) (Drug)
B. Phase II - Maximum Planned Dose (MPD)
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.
Intervention: Cyclophosphamide (Drug)
B. Phase II - Maximum Planned Dose (MPD)
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.
Intervention: Bortezomib; Pegylated Liposomal Doxorubicin; Dexamethasone (VDD) (Drug)
Outcomes
Primary Outcomes
Phase I - Maximum Planned Dose (MPD) Level
Time Frame: 9 months
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.
Phase II: Overall Response Rate (ORR)
Time Frame: Up to 6 months
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.
Secondary Outcomes
- Phase II: Two Year Overall Survival (OS)(2 years)
- Phase II: Progression-Free Survival (PFS)(Up to 50.9 months)