UARK 2006-15: A Study of Tandem Transplants With or Without Bortezomib and Thalidomide

Study Overview
=================
Brief Summary
-----------------
Add three drugs, bortezomib, thalidomide, and dexamethasone (VTD) to the high dose chemotherapy regimen immediately before transplant (DPACE/Melphalan) to try to improve myeloma response and acquire longer survival for participants.

Official Title
-----------------
UARK 2006-15: A Phase III Randomized Study of Tandem Transplants With or Without Bortezomib (Velcade) and Thalidomide (Thalomid) to Evaluate Its Effect on Response Rate and Durability of Response in Multiple Myeloma Patients

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Interim/Maintenance Dexamethasone
* Drug: Induction/Consolidation Dexamethasone
* Drug: Induction/Consolidation Cisplatin
* Drug: Induction/Consolidation Adriamycin
* Drug: InductionConsolidation Cyclophosphamide
* Drug: Induction/Consolidation Etoposide
* Drug: Induction Pegfilgrastim
* Drug: Transplant 1 Dexamethasone
* Drug: Transplant 1 Cisplatin
* Drug: Transplant 1 Adriamycin
* Drug: Transplant 1 Cyclophosphamide
* Drug: Transplant 1 Etoposide
* Drug: Transplant 1 Melphalan
* Drug: Transplant 1 and 2 Pegfilgrastim
* Procedure: Autologous Peripheral Blood Stem Cell Transplant (ASCT)
* Drug: Transplant 2 Carmustine
* Drug: Transplant 2 Etoposide
* Drug: Transplant 2 Cytarabine
* Drug: Transplant 2 Melphalan
* Drug: Transplant 2 Dexamethasone
* Drug: Transplant 1 and 2 Bortezomib
* Drug: Transplant 1 and 2 Thalidomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with symptomatic multiple myeloma, sensitive or refractory to at least one prior line of chemotherapy. Karnofsky performance score > 60%, unless due to MM. Patients must be <75 years of age at the time of registration. Patient must not have had a prior auto- or allotransplant. Patient must have signed an IRB-approved informed consent and understand the investigational nature of the study. Negative serology for HIV. Baseline biopsies and laboratory studies are to be completed within 35 days of registration, within 60 days for scans and radiological studies; patients must not have a history of severe chronic obstructive or chronic restrictive pulmonary disease. Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. Patients unable to complete pulmonary function tests because of myeloma-related chest pain, must have a high resolution CT scan of the chest and must also have acceptable arterial blood gases defined as P02 greater than 70. Patients with recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias are ineligible. Ejection fraction by ECHO or MUGA must be > 40% and must be performed within 60 days prior to registration, unless the patient has received chemotherapy within that period of time (dexamethasone and thalidomide excluded), in which case the LVEF must be repeated. No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease free for at least three years. Prior malignancy is acceptable provided there has been no evidence of disease within the three-year interval or if the malignancy is considered much less life threatening than the myeloma. Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Women/men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Patients must be able to receive full doses of D PACE, in the opinion of the treating investigator, with the exception that patients with creatinine clearance 30-50 ml/min will receive only 50% of the cisplatin dose. Exclusion Criteria: Fever or active infection requiring intravenous antibiotic, defined as fever or antibiotics within 72 hours from baseline. Severe renal dysfunction, defined as a creatinine > 3mg/dl or a creatinine clearance of < 30ml/min. Significant neurotoxicity, defined as grade > 3 neurotoxicity per NCI Common Toxicity Criteria (See Appendix). Platelet count < 100,000/mm^3, or ANC < 1,000/μl POEMS Syndrome. Clinically significant hepatic dysfunction as noted by direct bilirubin or AST >3 times the upper normal limit or clinically significant concurrent hepatitis. New York Hospital Association (NYHA) Class III or Class IV heart failure. Myocardial infarction within the last 6 months. Patients with a history of treatment for clinically significant ventricular cardiac arrhythmias. Poorly-controlled hypertension, diabetes mellitus, or other serious medical illness or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol. Prior adriamycin exposure >450 mg/m^2 Prior exposure to thalidomide which resulted in severe toxicity requiring drug discontinuation.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>DPACE Induction, Melphalan/DPACE Transplant 1, BEAM Transplant 2, DPACE Consolidation, Dexamethasone Maintenance with Interim dexamethasone between treatment phases | Drug: Interim/Maintenance Dexamethasone<br>* 20 mg Days 1-4 every 3 weeks in the interim between treatment phases and during maintenance<br>* Other names: Dexamethasone acetate;Drug: Induction/Consolidation Dexamethasone<br>* 40 mg Days 1-4<br>* Other names: Dexamethasone acetate;Drug: Induction/Consolidation Cisplatin<br>* 10 mg/m2 by continuous infusion Days 1-4<br>Drug: Induction/Consolidation Adriamycin<br>* 10 mg/m2 by continuous infusion Days 1-4<br>Drug: InductionConsolidation Cyclophosphamide<br>* 400 mg/m2 by continuous infusion Days 1-4<br>Drug: Induction/Consolidation Etoposide<br>* 40 mg/m2 by continuous infusion Days 1-4<br>Drug: Induction Pegfilgrastim<br>* 6 mg Days 6 and 13<br>Drug: Transplant 1 Dexamethasone<br>* 20 mg Days -4, -3, -2, -1 and +4, +5, +6, and +7<br>Drug: Transplant 1 Cisplatin<br>* 20 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Adriamycin<br>* 20 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Cyclophosphamide<br>* 800 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Etoposide<br>* 80 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Melphalan<br>* 50 mg/m2 Days -2 and -1<br>Drug: Transplant 1 and 2 Pegfilgrastim<br>* 6 mg Day +6<br>Procedure: Autologous Peripheral Blood Stem Cell Transplant (ASCT)<br>* Day 0<br>Drug: Transplant 2 Carmustine<br>* 300 mg/m2 Day -5<br>Drug: Transplant 2 Etoposide<br>* 200 mg/m2 Days -5, -4, -3, -2<br>Drug: Transplant 2 Cytarabine<br>* 400 mg/m2 Days -5, -4, -3, -2<br>* Other names: Ara-C;Drug: Transplant 2 Melphalan<br>* 140 mg/m2 Day -1<br>Drug: Transplant 2 Dexamethasone<br>* 20 mg Days -5, -4, -3, -2, +4, +5, +6, +7<br>|
| Experimental: Arm B<br>DPACE Induction, Melphalan/DPACE + VTD Transplant 1, BEAM + VTD Transplant 2, DPACE Consolidation, Dexamethasone Maintenance with Interim dexamethasone between treatment phases | Drug: Interim/Maintenance Dexamethasone<br>* 20 mg Days 1-4 every 3 weeks in the interim between treatment phases and during maintenance<br>* Other names: Dexamethasone acetate;Drug: Induction/Consolidation Dexamethasone<br>* 40 mg Days 1-4<br>* Other names: Dexamethasone acetate;Drug: Induction/Consolidation Cisplatin<br>* 10 mg/m2 by continuous infusion Days 1-4<br>Drug: Induction/Consolidation Adriamycin<br>* 10 mg/m2 by continuous infusion Days 1-4<br>Drug: InductionConsolidation Cyclophosphamide<br>* 400 mg/m2 by continuous infusion Days 1-4<br>Drug: Induction/Consolidation Etoposide<br>* 40 mg/m2 by continuous infusion Days 1-4<br>Drug: Induction Pegfilgrastim<br>* 6 mg Days 6 and 13<br>Drug: Transplant 1 Dexamethasone<br>* 20 mg Days -4, -3, -2, -1 and +4, +5, +6, and +7<br>Drug: Transplant 1 Cisplatin<br>* 20 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Adriamycin<br>* 20 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Cyclophosphamide<br>* 800 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Etoposide<br>* 80 mg/m2 by continuous infusion Days -3 and -2<br>Drug: Transplant 1 Melphalan<br>* 50 mg/m2 Days -2 and -1<br>Drug: Transplant 1 and 2 Pegfilgrastim<br>* 6 mg Day +6<br>Procedure: Autologous Peripheral Blood Stem Cell Transplant (ASCT)<br>* Day 0<br>Drug: Transplant 2 Carmustine<br>* 300 mg/m2 Day -5<br>Drug: Transplant 2 Etoposide<br>* 200 mg/m2 Days -5, -4, -3, -2<br>Drug: Transplant 2 Cytarabine<br>* 400 mg/m2 Days -5, -4, -3, -2<br>* Other names: Ara-C;Drug: Transplant 2 Melphalan<br>* 140 mg/m2 Day -1<br>Drug: Transplant 2 Dexamethasone<br>* 20 mg Days -5, -4, -3, -2, +4, +5, +6, +7<br>Drug: Transplant 1 and 2 Bortezomib<br>* 1 mg/m2 Days -4, -1, +3, +7<br>* Other names: Velcade;Drug: Transplant 1 and 2 Thalidomide<br>* 200 mg Days -4 to +5<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Time from study registration until disease progression or death. | Up to 3 years 8 months |