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

This study has been terminated.
(Poor accrual, changes in management of newly diagnosed myeloma patients, new drugs/more effective regimens.)
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT00215943
First received: September 15, 2005
Last updated: April 1, 2014
Last verified: August 2013
  Purpose

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).


Condition Intervention Phase
Multiple Myeloma
Drug: zoledronic acid
Drug: dexamethasone
Drug: thalidomide
Drug: vincristine
Drug: adriamycin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Response Rates of VAD vs. Thalidomide/Dexamethasone [ Time Frame: End of Cycle 4 - 4 Months per Participant ] [ Designated as safety issue: No ]
    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 [ Time Frame: 4 Years, 7 Months ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 4 Months ] [ Designated as safety issue: No ]

    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 [ Time Frame: Up to 10 Years ] [ Designated as safety issue: No ]

    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.



Enrollment: 90
Study Start Date: June 2003
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: VAD Treatment
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.
Drug: zoledronic acid
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.
Other Names:
  • Zometa®
  • Zoledronate
Drug: vincristine
As outlined in VAD Treatment Arm
Other Names:
  • Oncovin
  • NSC-67574
Drug: adriamycin
As outlined in VAD Treatment arm
Other Names:
  • Doxorubicin
  • NSC-123127
Active Comparator: Thalidomide and Dexamethasone Treatment
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.
Drug: zoledronic acid
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.
Other Names:
  • Zometa®
  • Zoledronate
Drug: dexamethasone
As outlined in VAD Treatment arm and Thalidomide and Dexamethasone Treatment arm
Other Names:
  • Decadron
  • NSC-34521
Drug: thalidomide
As outlined in Thalidomide and Dexamethasone Treatment arm
Other Name: Thalomid™

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00215943

Locations
United States, Florida
Morton Plant Hospital
Clearwater, Florida, United States, 33756
Watson Clinic
Lakeland, Florida, United States, 33805
Fawcett Memorial Hospital
Port Charlotte, Florida, United States, 33949
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612
Puerto Rico
San Juan VA Hospital
San Juan, Puerto Rico, 00921
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Novartis
Investigators
Principal Investigator: Melissa Alsina, MD H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT00215943     History of Changes
Other Study ID Numbers: MCC-13043, CZOL446E
Study First Received: September 15, 2005
Results First Received: August 21, 2013
Last Updated: April 1, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
hematologic malignancy

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Liposomal doxorubicin
Doxorubicin
Thalidomide
Vincristine
BB 1101
Zoledronic acid
Diphosphonates
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on August 28, 2014