UARK 2008-01, Total Therapy 4 - A Phase III Trial for Low Risk Myeloma (TT4)

This study is currently recruiting participants.
Verified January 2014 by University of Arkansas
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
University of Arkansas
ClinicalTrials.gov Identifier:
NCT00734877
First received: August 12, 2008
Last updated: January 14, 2014
Last verified: January 2014
  Purpose

Toward improving the therapeutic index of standard TT3 (S-TT3), the investigators will employ a randomized Phase III trial design to determine whether S-TT3 treatment-related toxicities can be reduced by 50% in TT3-Lite (L-TT3).


Condition Intervention Phase
Multiple Myeloma
Drug: M-VTD-PACE
Drug: TT3-LITE Regimen (L-TT3)
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: UARK 2008-01, Total Therapy 4 - A Phase III Trial for Low Risk Myeloma: A Randomized Trial Comparing Standard Total Therapy 3 (S-TT3) With TT3-LITE (L-TT3)

Resource links provided by NLM:


Further study details as provided by University of Arkansas:

Primary Outcome Measures:
  • To determine whether anti-myeloma efficacy can be preserved or even enhanced in L-TT3 v S-TT3, due to anticipated enhanced treatment compliance and synergy between MEL and VTD. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To relate the anticipated improvement in the therapeutic index in L-TT3 to MEL pharmacokinetics using 50mg/m2/day for 4 successive days in L-TT3 (plus VTD) versus single short infusion of 200mg/m2 in S-TT3 [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 350
Study Start Date: July 2008
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: ARM A
The standard TT3 Regimen (S-TT3) will consist of 2 cycles of induction therapy with M-VTD-PACE and PBSC collection after the 1st cycle. MEL-based tandem transplant will be administered 6 weeks to 3 months apart, applying single dose MEL 200 mg/m2 with adjustments for age and renal function. Consolidation will consist of 2 cycles of dose-reduced VTD-PACE. Maintenance treatment will employ VRD for 3 years.
Drug: M-VTD-PACE
2 cycles of induction therapy with M-VTD-PACE and PBSC collection after the 1st cycle. MEL-based tandem transplant will be administered 6 weeks to 3 months apart, applying single dose MEL 200 mg/m2 with adjustments for age and renal function. Consolidation will consist of 2 cycles of dose-reduced VTD-PACE. Maintenance treatment will employ VRD for 3 years.
Other Names:
  • Melphalan
  • Velcade
  • Thalidomide
  • Dexamethasone
  • Cisplatin
  • Adriamycin
  • Cyclophosphamide
  • Etoposide
Experimental: ARM B
The TT3-LITE Regimen (L-TT3) will employ only 1 cycle of induction therapy with MVTD- PACE
Drug: TT3-LITE Regimen (L-TT3)
The TT3-LITE Regimen (L-TT3) will employ only 1 cycle of induction therapy with MVTD-PACE and, as in S-TT3, PBSC collection following recovery from this one and only induction treatment. MEL-based tandem transplant will be administered 6 weeks to 3 months apart, applying fractionated MEL200mg/m2 in 4 successive daily fractions of 50mg/m2 (MEL50 x 4) with addition of VTD with adjustments for age and renal function. Consolidation will consist of only 1 cycle of dose-reduced VTD-PACE. Maintenance treatment will employ VRD for 3 years.
Other Names:
  • Velcade (bortezomib)
  • Melphalan
  • Dexamethasone
  • Thalidomide
  • Cisplatin
  • Adriamycin
  • Cyclophosphamide
  • Etoposide

Detailed Description:

The major treatment-related toxicities in TT3 pertained to the high-dose melphalan 200mg/m2 (MEL200)-based tandem transplant approach, consisting of mucosal and other toxicities.

For the TT4 trial, we are proposing to compare standard TT3 (S-TT3) to TT3-Lite (L-TT3). L-TT3 will employ various strategies aimed at improving the therapeutic Index of S-TT3 by reducing toxicities while maintaining the superior results reported for S-TT3 in terms of frequency and duration of CR, EFS, and. The following strategies will be utilized in L-TT3:

  • Applying only 1 instead of 2 cycles of induction and consolidation therapy prior to and after tandem transplant. This is supported by the well known association between prior exposure to mucotoxic therapies4, 5 and worse post-transplant mucositis, particularly when etoposide is used in the mobilizing regimen6 such as in VDTPACE.
  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
  • Patients must be either untreated or have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation.
  • Participants must have low-risk disease, as defined by any of the following:

    • GEP risk score of < 0.66
    • lack of GEP-defined TP53 deletion (Affymetrix signal <727)
    • No metaphase based abnormalities of 1q or 1p
    • LDH <360 U/L Rule out hemolysis, infection, and contact PI for Clarification
  • Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease.
  • Patients must be at least 18 years of age and not older than 75 years of age at the time of registration.
  • Participants must have preserved renal function as defined by a serum creatinine level of < 3 mg/dL.
  • Participants must have an ejection fraction by ECHO or MUGA ≥ 40%
  • Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principal investigator documents that the patient is a candidate for high dose therapy.
  • Patients must have signed an IRB-approved informed consent indicating their understanding of the proposed treatment and understanding that the protocol has been approved by the IRB.

Exclusion Criteria:

  • High risk disease defined by high-risk gene array features as determined by any of the following:

    • GEP risk score of ≥ 0.66 or
    • Presence of GEP-defined TP53 deletion, or
    • Presence of abnormalities of chromosome 1 (amp1q, del 1p).
  • 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.
  • Platelet count < 30 x 109/L, unless myeloma-related.
  • Grade > 2 peripheral neuropathy.
  • Hypersensitivity to bortezomib, boron, or mannitol.
  • Recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias.
  • Evidence of chronic obstructive or chronic restrictive pulmonary disease.
  • Patients must not have light chain deposition disease or creatinine > 3 mg/dl
  • 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00734877

Contacts
Contact: Nathan Petty 501-526-6990 ext 2435 pettynathanm@uams.edu

Locations
United States, Arkansas
University of Arkansas for Medical Sciences, Myeloma Institute for Research and Therapy Recruiting
Little Rock, Arkansas, United States, 72205
Contact: Nathan Petty    501-526-6990 ext 2435    pettynathanm@uams.edu   
Sub-Investigator: Bart Barlogie, MD, PhD         
Sub-Investigator: Frits van Rhee, MD, PhD         
Sub-Investigator: Monica Grazziutti, MD         
Sub-Investigator: Michele Fox, MD         
Sub-Investigator: Jameel Muzaffar, MD         
Sub-Investigator: Saad Usmani, MD         
Sub-Investigator: Senu Apewokin, MD         
Sub-Investigator: Shebli Atrash, MD         
Sub-Investigator: Aziz Bakhous, MD         
Sub-Investigator: Maurizio Zangari, MD         
Sub-Investigator: Yogesh Jethava, MD         
Sub-Investigator: Rashid Khan, MD         
Sub-Investigator: Vyjayanthi Ganga, MD         
Sponsors and Collaborators
University of Arkansas
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Bart Barlogie, MD, PhD UAMS
Study Director: Bart Barlogie, MD, PhD UAMS
  More Information

Additional Information:
No publications provided by University of Arkansas

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Arkansas
ClinicalTrials.gov Identifier: NCT00734877     History of Changes
Other Study ID Numbers: UARK 2008-01
Study First Received: August 12, 2008
Last Updated: January 14, 2014
Health Authority: United States: Institutional Review Board

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
Cisplatin
Cyclophosphamide
Dexamethasone
Doxorubicin
Etoposide
Melphalan
Thalidomide
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Immunosuppressive Agents

ClinicalTrials.gov processed this record on April 15, 2014