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

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.

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).

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: zoledronic acid; Drug: vincristine; Drug: adriamycin; Drug: dexamethasone; Drug: thalidomide

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00921
    • San Juan VA Hospital
• United States
  • Florida
    • Clearwater, Florida, United States, 33756
      • Morton Plant Hospital
    • Lakeland, Florida, United States, 33805
      • Watson Clinic
    • Port Charlotte, Florida, United States, 33949
      • Fawcett Memorial Hospital
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Zoledronate; Zometa®; 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: Zoledronate; Zometa®; 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 Names: Thalomid™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	End of Cycle 4 - 4 Months per Participant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	4 Years, 7 Months
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).	4 Months
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.	Up to 10 Years

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Novartis
• Investigators: Principal Investigator: Melissa Alsina, MD, H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

Helpful Links

• Moffiitt Cancer Center Clinical Trials Website

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: September 15, 2005
• First Submitted That Met QC Criteria: September 15, 2005
• First Posted (Estimate): September 22, 2005

Study Record Updates

• Last Update Posted (Estimate): April 17, 2014
• Last Update Submitted That Met QC Criteria: April 1, 2014
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: hematologic malignancy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Multiple Myeloma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Antibiotics, Antineoplastic; Bone Density Conservation Agents; Dexamethasone; Thalidomide; Doxorubicin; Liposomal doxorubicin; Vincristine; Zoledronic Acid
• Other Study ID Numbers: MCC-13043; CZOL446E (Novartis)