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Phase III Randomized Trial of Thalidomide/Dexamethasone Versus Vincristine+Adriamycin+Dexamethasone (VAD)

Primary Purpose

Multiple Myeloma

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
zoledronic acid
dexamethasone
thalidomide
vincristine
adriamycin
Sponsored by
H. Lee Moffitt Cancer Center and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring hematologic malignancy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients must have newly diagnosed MM confirmed by the presence of bone marrow plasmacytosis with > 10 percent plasma cells, sheets of plasma cells, or biopsy-proven plasmacytoma. Patients must have Durie-Salmon Stage IIA-B or IIIA-B. Patients with non-secretory myeloma are eligible. (These patients will not be included in the analysis of response rates, but will be assessed for toxicity and survival). Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2, or 3 ≥ 18 years of age. Signed informed consent form Expected survival of greater than 8 weeks Capable of swallowing study medication tablets Capable of following directions regarding taking study medication, or has a daily care provider who will be responsible for administering study medication. Patients will be eligible for study even if they lack socioeconomic access to autologous transplantation. (These patients will be identified prior to randomization so as not to confound study results). All patients (in the event that they are randomized to the thalidomide/dexamethasone arm) must agree to take part in the "System for Education and Prescribing Safety" (S.T.E.P.S.)™. They must sign a separate informed consent for this program. Exclusion Criteria: Elevated direct bilirubin > 2 mg/dl Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN) Absolute neutrophil count (ANC) <1000/mL, unless felt to be secondary to myeloma Ongoing radiation therapy, or radiation therapy within 3 weeks prior to first treatment, unless the acute side effects associated with such therapy are resolved. Prior treatment for multiple myeloma Prior bisphosphonate use is allowed but they must be discontinued before starting treatment. Concurrent uncontrolled serious infection Patients with peripheral (sensory) neuropathy, grade 3 or higher Life-threatening illness (unrelated to tumor) History of any other ACTIVE and INVASIVE cancer other than the present condition (except non-melanoma skin cancer), unless in complete remission and off of all therapy for that disease for a minimum of 3 years. Women of childbearing potential (unless utilizing birth control) or who are pregnant or nursing will be excluded from this study. Patients with comorbid conditions that would contraindicate the use of vincristine, doxorubicin, dexamethasone, thalidomide, or zoledronate. Plasma Cell Leukemia

Sites / Locations

  • Morton Plant Hospital
  • Watson Clinic
  • Fawcett Memorial Hospital
  • H. Lee Moffitt Cancer Center & Research Institute
  • San Juan VA Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

VAD Treatment

Thalidomide and Dexamethasone Treatment

Arm Description

VAD (vincristine, adriamycin, dexamethasone). Vincristine and adriamycin was administered by continuous infusion via a venous catheter for 96 hours every 28 days. Each 28 days is considered one "cycle" of therapy. Patients were to receive 4 to 6 cycles of therapy. Dexamethasone was taken in pill form. During the first 2 cycles it was taken on days 1-4, 9-12, 17-20. For all other cycles dexamethasone was taken only on days 1-4. Patients were randomized to receive zoledronic acid IV on either Day 1 or 15 of each cycle.

Thalidomide was taken orally once every day in the evening for four to six months. The dexamethasone was taken in a pill form. During the first 2 cycles it was taken on days 1-4, 9-12, 17-20. For all other cycles dexamethasone was taken only on days 1-4.

Outcomes

Primary Outcome Measures

Response Rates of VAD vs. Thalidomide/Dexamethasone
Blade (15) criteria for remission in multiple myeloma was used to assess response. Complete Response (CR)includes: Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of 6 weeks by immunofixation studies. Partial Response (PR) includes: At least a 50% reduction in the level of serum monoclonal protein for at least two determinations 6 weeks apart. Minimal Response (MR)includes: At least a 25% to 49% reduction in the level of serum monoclonal protein for at least 2 determinations 2 weeks apart.

Secondary Outcome Measures

Number of Participants With Adverse Events, by Group
Number of participants with toxicities of Thalidomide/Dexamethasone vs. VAD as induction regimens in newly diagnosed multiple myeloma (MM).
Number of Participants With Progression Free Survival (PFS), by Treatment Arm
Number of participants with PFS for thalidomide/Dexamethasone vs. VAD with respect to progression free survival in newly diagnosed MM. Progressive Disease (PD): (for patients not in CR) Requires one or more of the following; > 25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation. > 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg and confirmed on a repeat investigation. >25% increase in plasma cells in a bone marrow aspirate, which also must be an absolute increase of at least 10%. Definite increase in the size of existing lytic lesions or plasmacytomas. Development of new bone lesions or plasmacytomas (except compression fractures). Development of hypercalcemia (corrected calcium > 11.5 mg/dL not attributable to other causes).
Overall Survival (OS), by Treatment Arm
Median OS for thalidomide/Dexamethasone participants vs. VAD participants. Months from On Study to Expired/Last Date Known Alive. Investigators had planned to accrue 176 participants to calculate median overall survival.

Full Information

First Posted
September 15, 2005
Last Updated
April 1, 2014
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT00215943
Brief Title
Phase III Randomized Trial of Thalidomide/Dexamethasone Versus Vincristine+Adriamycin+Dexamethasone (VAD)
Official Title
Phase III Randomized Trial of Thalidomide/Dexamethasone vs VAD as Induction Chemotherapy for Newly Diagnosed Myeloma Patients and Evaluation of the Effects of Zoledronate on Chemotherapy Induced Apoptosis and Antigen Presentation.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2013
Overall Recruitment Status
Terminated
Why Stopped
Poor accrual, changes in management of newly diagnosed myeloma patients, new drugs/more effective regimens.
Study Start Date
June 2003 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Novartis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Investigators planned to accrue 176 participants, to compare the response rate, overall response rate and survival of patients with multiple myeloma (MM) when randomized to two regimens (thalidomide+Dexamethasone versus Vincristine+Adriamycin+Dexamethasone). Investigators also planned to test if treatment with zoledronate immediately prior to chemotherapy results in an enhanced response to treatment (i.e. increase in complete response rates).
Detailed Description
Patients Randomized to receive VAD (vincristine, adriamycin, dexamethasone): All patients received four cycles of VAD repeated every 4 weeks. Chemotherapy was administered by continuous IV Infusion for 96 hours: vincristine at a dose of 0.4 mg/day and doxorubicin at a dose of 9 mg/m^2/day. Patients were administered dexamethasone 40 mg by mouth (PO) on days 1 to 4, 9 to 12, and 17 to 20 of the initial two cycles. Dexamethasone was given only on days 1-4 of all subsequent cycles. Patients were randomized to receive zoledronic acid IV on either Day 1 or 15 of each cycle. This schedule continued monthly as long as the patient remained on study. The dose was calculated based on the patients' monthly creatinine clearance. Upon initiation of Zometa therapy, the following guidelines were applied: For patients with creatinine clearance >60 mL/min, the recommended dose remained at 4mg. For patients with reduced creatinine clearance, dosing was calculated to achieve the same area under curve (AUC) as in patients with creatinine clearance of 75 mL/min. Creatinine clearance was calculated using the Cockcroft-Gault formula.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
hematologic malignancy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Actual)

8. Arms, Groups, and Interventions

Arm Title
VAD Treatment
Arm Type
Active Comparator
Arm Description
VAD (vincristine, adriamycin, dexamethasone). Vincristine and adriamycin was administered by continuous infusion via a venous catheter for 96 hours every 28 days. Each 28 days is considered one "cycle" of therapy. Patients were to receive 4 to 6 cycles of therapy. Dexamethasone was taken in pill form. During the first 2 cycles it was taken on days 1-4, 9-12, 17-20. For all other cycles dexamethasone was taken only on days 1-4. Patients were randomized to receive zoledronic acid IV on either Day 1 or 15 of each cycle.
Arm Title
Thalidomide and Dexamethasone Treatment
Arm Type
Active Comparator
Arm Description
Thalidomide was taken orally once every day in the evening for four to six months. The dexamethasone was taken in a pill form. During the first 2 cycles it was taken on days 1-4, 9-12, 17-20. For all other cycles dexamethasone was taken only on days 1-4.
Intervention Type
Drug
Intervention Name(s)
zoledronic acid
Other Intervention Name(s)
Zometa®, Zoledronate
Intervention Description
Patients were randomized to receive zoledronic acid I.V. on either Day 1 or 15 of each cycle. This schedule continued monthly as long as the patient remained on study. The dose was calculated based on the patients' monthly creatinine clearance.
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Other Intervention Name(s)
Decadron, NSC-34521
Intervention Description
As outlined in VAD Treatment arm and Thalidomide and Dexamethasone Treatment arm
Intervention Type
Drug
Intervention Name(s)
thalidomide
Other Intervention Name(s)
Thalomid™
Intervention Description
As outlined in Thalidomide and Dexamethasone Treatment arm
Intervention Type
Drug
Intervention Name(s)
vincristine
Other Intervention Name(s)
Oncovin, NSC-67574
Intervention Description
As outlined in VAD Treatment Arm
Intervention Type
Drug
Intervention Name(s)
adriamycin
Other Intervention Name(s)
Doxorubicin, NSC-123127
Intervention Description
As outlined in VAD Treatment arm
Primary Outcome Measure Information:
Title
Response Rates of VAD vs. Thalidomide/Dexamethasone
Description
Blade (15) criteria for remission in multiple myeloma was used to assess response. Complete Response (CR)includes: Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of 6 weeks by immunofixation studies. Partial Response (PR) includes: At least a 50% reduction in the level of serum monoclonal protein for at least two determinations 6 weeks apart. Minimal Response (MR)includes: At least a 25% to 49% reduction in the level of serum monoclonal protein for at least 2 determinations 2 weeks apart.
Time Frame
End of Cycle 4 - 4 Months per Participant
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events, by Group
Description
Number of participants with toxicities of Thalidomide/Dexamethasone vs. VAD as induction regimens in newly diagnosed multiple myeloma (MM).
Time Frame
4 Years, 7 Months
Title
Number of Participants With Progression Free Survival (PFS), by Treatment Arm
Description
Number of participants with PFS for thalidomide/Dexamethasone vs. VAD with respect to progression free survival in newly diagnosed MM. Progressive Disease (PD): (for patients not in CR) Requires one or more of the following; > 25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation. > 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg and confirmed on a repeat investigation. >25% increase in plasma cells in a bone marrow aspirate, which also must be an absolute increase of at least 10%. Definite increase in the size of existing lytic lesions or plasmacytomas. Development of new bone lesions or plasmacytomas (except compression fractures). Development of hypercalcemia (corrected calcium > 11.5 mg/dL not attributable to other causes).
Time Frame
4 Months
Title
Overall Survival (OS), by Treatment Arm
Description
Median OS for thalidomide/Dexamethasone participants vs. VAD participants. Months from On Study to Expired/Last Date Known Alive. Investigators had planned to accrue 176 participants to calculate median overall survival.
Time Frame
Up to 10 Years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have newly diagnosed MM confirmed by the presence of bone marrow plasmacytosis with > 10 percent plasma cells, sheets of plasma cells, or biopsy-proven plasmacytoma. Patients must have Durie-Salmon Stage IIA-B or IIIA-B. Patients with non-secretory myeloma are eligible. (These patients will not be included in the analysis of response rates, but will be assessed for toxicity and survival). Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2, or 3 ≥ 18 years of age. Signed informed consent form Expected survival of greater than 8 weeks Capable of swallowing study medication tablets Capable of following directions regarding taking study medication, or has a daily care provider who will be responsible for administering study medication. Patients will be eligible for study even if they lack socioeconomic access to autologous transplantation. (These patients will be identified prior to randomization so as not to confound study results). All patients (in the event that they are randomized to the thalidomide/dexamethasone arm) must agree to take part in the "System for Education and Prescribing Safety" (S.T.E.P.S.)™. They must sign a separate informed consent for this program. Exclusion Criteria: Elevated direct bilirubin > 2 mg/dl Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN) Absolute neutrophil count (ANC) <1000/mL, unless felt to be secondary to myeloma Ongoing radiation therapy, or radiation therapy within 3 weeks prior to first treatment, unless the acute side effects associated with such therapy are resolved. Prior treatment for multiple myeloma Prior bisphosphonate use is allowed but they must be discontinued before starting treatment. Concurrent uncontrolled serious infection Patients with peripheral (sensory) neuropathy, grade 3 or higher Life-threatening illness (unrelated to tumor) History of any other ACTIVE and INVASIVE cancer other than the present condition (except non-melanoma skin cancer), unless in complete remission and off of all therapy for that disease for a minimum of 3 years. Women of childbearing potential (unless utilizing birth control) or who are pregnant or nursing will be excluded from this study. Patients with comorbid conditions that would contraindicate the use of vincristine, doxorubicin, dexamethasone, thalidomide, or zoledronate. Plasma Cell Leukemia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Melissa Alsina, MD
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Morton Plant Hospital
City
Clearwater
State/Province
Florida
ZIP/Postal Code
33756
Country
United States
Facility Name
Watson Clinic
City
Lakeland
State/Province
Florida
ZIP/Postal Code
33805
Country
United States
Facility Name
Fawcett Memorial Hospital
City
Port Charlotte
State/Province
Florida
ZIP/Postal Code
33949
Country
United States
Facility Name
H. Lee Moffitt Cancer Center & Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
San Juan VA Hospital
City
San Juan
ZIP/Postal Code
00921
Country
Puerto Rico

12. IPD Sharing Statement

Learn more about this trial

Phase III Randomized Trial of Thalidomide/Dexamethasone Versus Vincristine+Adriamycin+Dexamethasone (VAD)

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